Study in Circulation Research: Journal of the American Heart Association Could Adult Stem Cells
( CD34+ stem cells ) Help Repair Hearts

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HOUSTON, TX - An injection of stem cells into the heart could offer hope to many of the 950,000 Americans whose chest pain doesn’t subside even with medicine, angioplasty or surgery, according to a study in Circulation Research: Journal of the American Heart Association.

Heart disease patients who received the new treatment reported half as many chest pain episodes and improved exercise capability compared to those who received a placebo.

The study was the first randomized, controlled trial of stem-cell therapy to show significant improvements in both chest pain and exercise tolerance – the two debilitating features of “refractory” angina, or chest pain that persists in spite of medication, surgery or angioplasty.

Other heart disease studies have been negative and some have shown improvements in either chest pain or exercise time, but no previous study has shown improvements in both chest pain and exercise time, said Douglas W. Losordo, M.D., lead researcher and professor of medicine and director of the Feinberg Cardiovascular Research Institute at Northwestern University in Chicago.

“One exciting potential of this procedure is that it will offer these folks an opportunity to get part of their lives back,” said Losordo, who is also director of the Program in Cardiovascular Regenerative Medicine at Northwestern Memorial Hospital.

Researchers used the patients’ CD34+ stem cells, which circulate through the blood and are important in forming new blood vessels. The stem cell injection is meant to create new vessels in the diseased heart muscle, improving blood flow to the area and reducing episodes of chest pain.

In the study, 167 heart disease patients at 26 U.S. medical centers were randomized to one of three injection groups: low dose (100,000 CD34+ cells/kg body weight); high dose (500,000 CD34+ cells/kg body weight); or a placebo.

Normally, there are too few CD34+ cells to provide enough for therapy. So, researchers used a drug to increase the number of the cells in the body before collecting them. Using a catheter threaded into the heart, the researchers injected CD34+ cells into muscle identified as receiving insufficient blood.

Among the study’s findings:

• At six months, low-dose patients had 6.8 angina attacks per week – significantly fewer than 10.9 per week for those receiving placebo. High-dose patients had fewer episodes than the placebo group, but the difference was not statistically significant, so the results could be due to chance.

• At 12 months, the low-dose group had 6.3 episodes per week and the placebo patients had 11 episodes per week; high-dose patients had fewer angina episodes than the control group, but the difference remained insignificant. “It is not rare in clinical trials for high doses to be less effective than low doses,” Losordo said.

• The improvement in exercise tolerance at six months in low-dose patients was 139 seconds, which was significantly greater compared to the 69-second tolerance of the placebo patients. The high-dose group had a greater, but not significant, improvement than the placebo patients.

• At six and 12 months, both heart disease treated groups were using less nitroglycerine to treat angina than control patients, but the differences were not significant.

“The net difference in exercise tolerance is highly clinically significant, particularly in a patient population that is severely limited by symptoms,” Losordo said.

“It translates as going from being able to watch television to being able to walk at a normal pace or going from being able to walk slowly to being able to ride a bike.”

About a third of the heart disease participants had minor elevations of troponin, an enzyme that signals a heart attack when accompanied by changes in an electrocardiogram (EKG), researchers said. However, patients felt no chest pain and experienced no EKG changes.

“Most troponin changes were inconsequential,” Losordo said. “Nevertheless, we will continue to watch troponin levels, especially in phase III, where we will closely monitor cardiac enzymes.”

Later this year, the researchers will begin a phase III trial of the therapy, the level usually required before the Food and Drug Administration considers approving a drug.

Co-authors are: Timothy D. Henry, M.D.; Charles Davidson, M.D.; Joon Sup Lee, M.D.; Marco A. Costa, M.D.; Theodore Bass, M.D.; Farrell Mendelsohn, M.D.; F. David Fotuin, M.D.; Carl J. Pepine, M.D.; Jay H. Traverse, M.D.; David Amrani, Ph.D.; Bruce M. Ewenstein, M.D., Ph.D.; Norbert Riedel, Ph.D.; Kenneth Story; Kerry Barker, Ph.D.; Thomas J. Povsic, M.D., Ph.D.; Robert A. Harrington, M.D.; and Richard A. Schatz, M.D.

Adult Stem Cells Injected in Heart Boost Blood Flow

Heart disease patients with clogged arteries and severe chest pain who were injected with stem cells from their own bone marrow had a small improvement in blood flow and the pumping ability of their hearts, along with an easing of pain, researchers found.

Doctors in the Netherlands drew bone marrow from the hips of heart disease patients in the study. After isolating the stem cells, they injected them back into the patients’ hearts and monitored their progress. The results were published in the Journal of the American Medical Association.(JAMA)

FACT : To treat a range of conditions, and several thousand heart disease patients have been treated with adult stem cells, those found in mature organs. While some cardiologists originally hoped bone marrow cells might generate new heart muscle to replace damaged tissue, that hasn’t been found to occur, said Warren Sherman, a cardiologist at Columbia University in New York.

“The focus has shifted,” said Sherman, in a telephone interview today. “Cardiologists are now hoping that bone marrow stem cells can promote the growth of new blood vessels and improve the quality of life and level of chest pain patients have.” The new study, in 50 heart disease patients, showed that adult stem cells can improve blood flow and ease chest pain, Sherman said. In the study, half of the heart disease patients got their own stem cells and the others got a simulated treatment. The cardiologists used a catheter, a thin wire threaded through their arteries that also carried a small camera to guide the injections. 

Less Discomfort

The key finding in Sherman’s view was that the treated patients reported greater easing of their chest pain at three months and six months after the procedure than did the placebo patients. On a scale of 0 to 100, the patients who got their own stem cells improved from 56 to 69 after six months, while the placebo patients went from 57 to 64. “Most patients with heart disease are looking for relief of chest pain more than improvement in ventricular function,” or pumping action, Sherman said. He said to truly demonstrate effectiveness of bone marrow cells, larger studies will need to be completed.

Louisville Clinical Trial Will Use Cardiac Stem Cells To Re-grow Muscle After Attack

The University of Louisville and Jewish Hospital & St. Mary's HealthCare will conduct a clinical trial using adult cardiac stem cells to try to regrow dead heart muscle after heart attacks -- research that's especially relevant in a state where heart disease kills at one of the highest rates in the nation.

Dr. Piero Anversa, a physician at Brigham and Women's Hospital in Boston who is collaborating with Louisville doctors, said it would be the only trial in the world to use cardiac stem cells. "This would be, unequivocally, the first one," he said. U of L and Jewish Hospital officials would not comment yesterday, saying they wanted to hold off until a news conference scheduled for this morning.

According to a description of the trial filed with the U.S. National Institutes of Health, the research will test whether cardiac stem cells -- from adult subjects, not embryos -- will regenerate dead heart muscle by turning into heart muscle cells and other cell types. The therapy involves injecting a patient's own stem cells into the heart as a treatment for coronary artery disease and congestive heart failure.

"Currently," the NIH document says, "there is no effective intervention to regenerate (regrow) dead heart muscle after a heart attack." John Daniel of Pleasure Ridge Park, a 56-year-old who suffered a heart attack in 1998 that he said almost killed him, was glad to hear about the research.

"If it works and helps people, that would be good," he said. "A lot of people have heart attacks." According to the American Heart Association, coronary heart disease causes one of every five deaths in the United States, and an estimated 785,000 Americans will suffer their first coronary attack this year.

Heart disease is a particular problem in Kentucky, which has the nation's highest adult smoking rate and high rates of obesity and diabetes -- all risk factors. The state's death rate from coronary heart disease is higher than the national average, while Indiana's is just below that average.

In the new clinical trial, Anversa said Louisville doctors, including Dr. Roberto Bolli, Jewish Hospital Heart and Lung Institute distinguished chair in cardiology, would take a piece of heart tissue from a subject and send it to Brigham and Women's. There, he said, the stem cells would be isolated, expanded and prepared before being sent back to Louisville to be injected into the patient.

As a Phase I clinical trial, Anversa said, the major objective is to determine the safety of the procedure. "That's the first thing we want to do -- do no harm," said Anversa, who described himself as a longtime friend and colleague of Bolli.

Anversa and his team have been working on the project for two decades -- and were responsible for identifying cardiac stem cells that could generate the growth of heart muscle cells as well as coronary arteries. Anversa said he is hopeful about this type of cell because "it's a cell which sits in the heart; it is destined to make heart."

Clinical trials elsewhere have used different types of stem cells to try to treat heart problems. For example, the University of California, San Diego Medical Center is researching the use of stem cells taken from the bone marrow of an adult donor to treat congestive heart failure.

In the medical journal Circulation Research, U of L's Bolli co-authored an article describing "an explosion of basic and clinical studies that support the notion that the diseased heart can be repaired by administration of stem cells." That article said the issue of which stem cells will work best remains unresolved.

"Although most of the clinical studies reported to date have used bone marrow- or skeletal muscle-derived cells, a host of other cells are being investigated in the experimental laboratory," the article said. "Among these, resident cardiac stem cells … discovered by Anversa's group in 2003, hold great promise."

Anversa said the new clinical trial should provide some answers -- and could potentially have wide implications. "If this works," he said, "the thought is that it could also work in many other types of conditions that affect the heart."

Can Stem Cells help Heart Disease and Repair a Damaged Heart? Heart attacks and congestive heart failure remain among the Nation's most prominent health challenges despite many breakthroughs in cardiovascular medicine. In fact, despite successful approaches to prevent or limit heart disease, the restoration of function to the damaged heart remains a formidable challenge.

Recent research is providing early evidence that adult and embryonic stem cells may be able to replace damaged heart muscle cells and establish new blood vessels to supply them and reducing heart disease.Discussed here are some of the recent discoveries that feature stem cell replacement and muscle regeneration strategies for repairing the damaged heart and healing the heart disease.

Heart Disease - What You should Know

How might stem cells play a part in heart disease? To answer this question, researchers are building their knowledge base about how stem cells are directed to become specialized cells. One important type of cell that can be developed is the cardiomyocyte, the heart muscle cell that contracts to eject the blood out of the heart's main pumping chamber (the ventricle).

Two other cell types are important to a properly functioning heart are the vascular endothelial cell, which forms the inner lining of new blood vessels, and the smooth muscle cell, which forms the wall of blood vessels. The heart has a large demand for blood flow, and these specialized cells are important for developing a new network of arteries to bring nutrients and oxygen to the cardiomyocytes after a heart has been damaged.

The potential capability of both embryonic and adult stem cells to develop into these cells types in the damaged heart is now being explored as part of a strategy to restore heart function to people who have had heart attacks, congestive heart failure or heart disease. It is important that work with stem cells is not confused with recent reports that human cardiac myocytes may undergo cell division after myocardial infarction [1]. This work suggests that injured heart cells can shift from a quiescent state into active cell division. This is not different from the ability of a host of other cells in the body that begin to divide after injury. There is still no evidence that there are true stem cells in the heart which can proliferate and differentiate.

Heart disease Researchers now know that under highly specific growth conditions in laboratory culture dishes, stem cells can be coaxed into developing as new cardiomyocytes and vascular endothelial cells. Scientists are interested in exploiting this ability to provide replacement tissue for the damaged heart. This approach has immense advantages over heart transplant, particularly in light of the paucity of donor hearts available to meet current transplantation needs.

What is the evidence that such an approach to restoring cardiac function might work? In a heart disease research laboratory, investigators often use a mouse or rat model of a heart attack to study new therapies (see Figure 9.1. Rodent Model of Myocardial Infarction). To create a heart attack in a mouse or rat, a ligature is placed around a major blood vessel serving the heart muscle, thereby depriving the cardiomyocytes of their oxygen and nutrient supplies.

During the past year, researchers using such models have made several key discoveries that kindled interest in the application of adult stem cells to heart muscle repair in animal models of heart disease.

Rodent Model of Myocardial Infarction.

(© 2001 Terese Winslow, Lydia Kibiuk)

Recently, Orlic and colleagues [9] reported on an experimental application of hematopoietic stem cells for the regeneration of the tissues in the heart. In this study,heart disease was induced in mice by tying off a major blood vessel, the left main coronary artery. Through the identification of unique cellular surface markers, the investigators then isolated a select group of adult primitive bone marrow cells with a high capacity to develop into cells of multiple types. When injected into the damaged wall of the ventricle, these cells led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells, thus generating de novo myocardium, including coronary arteries, arterioles, and capillaries.

The newly formed myocardium occupied 68 percent of the damaged portion of the ventricle nine days after the bone marrow cells were transplanted, in effect replacing the dead myocardium with living, functioning tissue. The researchers found that mice that received the transplanted cells survived in greater numbers than mice with heart attacks that did not receive the mouse stem cells. Follow-up heart disease experiments are now being conducted to extend the posttransplantation analysis time to determine the longer-range effects of such therapy [8]. The partial repair of the damaged heart muscle suggests that the transplanted mouse hematopoietic stem cells responded to signals in the environment near the injured myocardium. The cells migrated to the damaged region of the ventricle, where they multiplied and became "specialized" cells that appeared to be cardiomyocytes.

A second study concerning heart disease by Jackson et al. [3], demonstrated that cardiac tissue can be regenerated in the mouse heart attack model through the introduction of adult stem cells from mouse bone marrow. In this model, investigators purified a "side population" of hematopoietic stem cells from a genetically altered mouse strain.

These cells were then transplanted into the marrow of lethally irradiated mice approximately 10 weeks before the recipient mice were subjected to heart attack via the tying off of a different major heart blood vessel, the left anterior descending (LAD) coronary artery. At two to four weeks after the induced cardiac injury, the survival rate was 26 percent. As with the study by Orlic et al., analysis of the region surrounding the damaged tissue in surviving mice showed the presence of donor-derived cardiomyocytes and endothelial cells.

Thus, the mouse hematopoietic stem cells transplanted into the bone marrow had responded to signals in the injured heart, migrated to the border region of the damaged area, and differentiated into several types of tissue needed for cardiac repair. This study suggests that mouse hematopoietic stem cells may be delivered to the heart through bone marrow transplantation as well as through direct injection into the cardiac tissue, thus providing another possible therapeutic strategy for regenerating injured cardiac tissue and reducing heart disease.

More evidence for potential stem cell-based therapies for heart disease is provided by a study that showed that human adult stem cells taken from the bone marrow are capable of giving rise to vascular endothelial cells when transplanted into rats [6]. As in the Jackson study, these researchers induced a heart attack by tying off the LAD coronary artery. They took great care to identify a population of human hematopoietic stem cells that give rise to new blood vessels.

These stem cells demonstrate plasticity meaning that they become cell types that they would not normally be. The cells were used to form new blood vessels in the damaged area of the rats' hearts and to encourage proliferation of preexisting vasculature following the experimental heart attack.

Like the mouse stem cells, these human hematopoietic stem cells can be induced under the appropriate culture conditions to differentiate into numerous tissue types, including cardiac muscle [10] Heart Muscle Repair with Adult Stem Cells). When injected into the bloodstream leading to the damaged rat heart, these cells prevented the death of hypertrophied or thickened but otherwise viable myocardial cells and reduced progressive formation of collagen fibers and scars.

Control rats that underwent surgery with an intact LAD coronary artery, as well as LAD-ligated rats injected with saline or control cells, did not demonstrate an increase in the number of blood vessels. Furthermore, the hematopoietic cells could be identified on the basis of highly specific cell markers that differentiate them from cardiomyocyte precursor cells, enabling the cells to be used alone or in conjunction with myocyte-regeneration strategies or pharmacological therapies. (For more about stem cell markers and heart disease, see Appendix E.i. How Do Researchers Use Markers to Identify Stem Cells?)

Heart Muscle Repair with Adult Stem Cells

(© 2001 Terese Winslow, Lydia Kibiuk)

Exciting new advances in cardiomyocyte regeneration are being made in human embryonic stem cell research. Because of their ability to differentiate into any cell type in the adult body, embryonic stem cells are another possible source population for cardiac-repair cells.

The first step in this application was taken by Itskovitz-Eldor et al. [2] who demonstrated that human embryonic stem cells can reproducibly differentiate in culture into embryoid bodies made up of cell types from the body's three embryonic germ layers. Among the various cell types noted were cells that had the physical appearance of cardiomyocytes, showed cellular markers consistent with heart cells, and demonstrated contractile activity similar to cardiomyocytes when observed under the microscope.

In a continuation of this early work, Kehat et al. [4] displayed structural and functional properties of early stage cardiomyocytes in the cells that develop from the embryoid bodies. The cells that have spontaneously contracting activity are positively identified by using markers with antibodies to myosin heavy chain, alpha-actinin, desmin, antinaturietic protein, and cardiac troponin—all proteins found in heart tissue.

These investigators have done genetic analysis of these cells and found that the transcription-factor genes expressed are consistent with early stage cardiomyocytes. Electrical recordings from these cells, changes in calcium-ion movement within the cells, and contractile responsiveness to catecholamine hormone stimulation by the cells were similar to the recordings, changes, and responsiveness seen in early cardiomyocytes observed during mammalian development.

A next step in this research is to see whether the experimental evidence of improvement in outcome from heart attack in rodents can be reproduced using embryonic stem cells.

These breakthrough discoveries in rodent models present new opportunities for using stem cells to repair damaged heart muscle. The results of the studies discussed above are growing evidence that adult stem cells may develop into more cell types than first thought. In those studies, hematopoietic stem cells appear to be able to develop not only into blood, but also into cardiac muscle and endothelial tissue.

This capacity of adult stem cells, increasingly referred to as "plasticity," may make such adult stem cells a viable candidate for heart repair. But this evidence is not complete; the mouse hematopoietic stem cell populations that give rise to these replacement cells are not homogenous. Rather, they are enriched for the cells of interest through specific and selective stimulating factors that promote cell growth. Thus, the originating cell population for these injected cells has not been identified, and the possibility exists for inclusion of other cell populations that could cause the recipient to reject the transplanted cells.

This is a major issue to contend with in clinical applications, but it is not as relevant in the experimental models described here because the rodents have been bred to be genetically similar.

What are the implications for extending the research on differentiated growth of replacement tissues for damaged hearts? There are some practical aspects of producing a sufficient number of cells for clinical application.

The repair of one damaged human heart would likely require millions of cells. The unique capacity for embryonic stem cells to replicate in culture may give them an advantage over adult stem cells by providing large numbers of replacement cells in tissue culture for transplantation purposes.

Given the current state of the science, it is unclear how adult stem cells could be used to generate sufficient heart muscle outside the body to meet patients' demand [7].

Although there is much excitement because researchers now know that adult and embryonic stem cells can repair damaged heart tissue, many questions remain to be answered before clinical applications can be made.

For example, how long will the replacement cells continue to function? Do the rodent research models accurately reflect human heart conditions and transplantation responses? Do these new replacement cardiomyocytes derived from stem cells have the electrical-signal-conducting capabilities of native cardiac muscle cells?

Stem cells may well serve as the foundation upon which a future form of "cellular therapy" is constructed. In the current animal models, the time between the injury to the heart and the application of stem cells affects the degree to which regeneration takes place, and this has real implications for the patient who is rushed unprepared to the emergency room in the wake of a heart attack.

In the future, could the patient's cells be harvested and expanded for use in an efficient manner? Alternatively, can at-risk patients donate their cells in advance, thus minimizing the preparation necessary for the cells' administration?

Moreover, can these stem cells be genetically "programmed" to migrate directly to the site of injury and to synthesize immediately the heart proteins necessary for the regeneration process? Investigators are currently using stem cells from all sources to address these questions, thus providing a promising future for therapies for repairing or replacing the damaged heart and addressing the Nation's leading causes of death.

References Beltrami, A.P., Urbanek, K., Kajstura, J., Yan, S.M., Finato, N., Bussani, R., Nadal-Ginard, B., Silvestri, F., Leri, A., Beltrami, C.A., and Anversa, P. (2001). Evidence that human cardiac myocytes divide after myocardial infarction. N. Engl. J. Med. 344, 1750–1757. Itskovitz-Eldor, J., Schuldiner, M., Karsenti, D., Eden, A., Yanuka, O., Amit, M., Soreq, H., and Benvenisty, N. (2000). Differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers. Mol. Med. 6, 88–95. Jackson, K.A., Majka, S.M., Wang, H., Pocius, J., Hartley, C.J., Majesky, M.W., Entman, M.L., Michael, L.H., Hirschi, K.K., and Goodell, M.A. (2001). Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1–8. Kehat, I., Kenyagin-Karsenti, D., Druckmann, M., Segev, H., Amit, M., Gepstein, A., Livne, E., Binah, O., Itskovitz-Eldor, J., and Gepstein, L. (2001). Human embryonic stem cells can differentiate into myocytes portraying cardiomyocytic structural and functional properties. J. Clin. Invest. (in press) Kessler, P.D. and Byrne, B.J. (1999). Myoblast cell grafting into heart muscle: cellular biology and potential applications. Annu. Rev. Physiol. 61, 219–242. Kocher, A.A., Schuster, M.D., Szabolcs, M.J., Takuma, S., Burkhoff, D., Wang, J., Homma, S., Edwards, N.M., and Itescu, S. (2001). Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat. Med. 7, 430–436. Lanza, R., personal communication. Orlic, D., personal communication. Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S.M., Li, B., Pickel, J., McKay, R., Nadal-Ginard, B., Bodine, D.M., Leri, A., and Anversa, P. (2001). Bone marrow cells regenerate infarcted myocardium. Nature. 410, 701–705. Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Moorman, M.A., Simonetti, D.W., Craig, S., and Marshak, D.R. (1999). Multilineage potential of adult human mesenchymal stem cells. Science. 284, 143–147.

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