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  By Sherry Baker  

Carroll Payne feels better than he has in years. That wasn't the case last July, when he suffered a major heart attack after working in his yard in the hot Georgia sun. Today, the 53-year-old Payne is back on the job as a fire battalion chief in suburban Gwinnett County. He resumed his life and livelihood of 33 years after being treated for myocardial infarction (MI) at Emory Crawford Long Hospital. Payne's life is different now. He has a stent in his coronary artery and takes medication to prevent his blood from clotting. He no longer eats red meat or fried foods. He exercises regularly. And he is involved in a groundbreaking clinical trial to determine whether the adult stem cells in his body—the cells that renew themselves to become specific types of cells—can be manipulated to heal his damaged heart.

  The physicians leading the study are hopeful that the stem cells harvested from the bone marrow in Payne's hip will promote formation of new blood vessels to improve heart circulation and enhance function.
     While many patients recover at least partially from heart attacks, approximately 70% suffer permanent damage because the artery blockage causing the attack keeps oxygen from reaching parts of the heart muscle. Currently, no treatment is available to restore function in damaged heart muscle, including those patients on the brink of heart failure.
     Emory cardiologist Arshed Quyyumi and hematologist Edmund Waller believe that may change, based on previous studies in Europe showing that infusing stem cells into the heart after heart attack improved heart function. They are directing the Emory arm of a multi-center Phase I/II clinical study in which stem cells harvested from bone marrow are reinfused into patients through cardiac catheterization. The Texas Heart Center, Vanderbilt, and Atlanta's Piedmont Hospital are partnering with Emory as well.
The idea that a damaged heart can be renewed is the result of an extraordinary paradigm shift that occurred in medicine over the past decade. Its repercussions may forever change the concept of how the human body can be healed.
  A ‘renewed' way of thinking
The idea that the damaged heart can be "renewed" is the result of an extraordinary paradigm shift that occurred in medicine over the past decade. It didn't garner loud headlines like heart pacemaker recalls or unexpectedly serious drug side effects. Nor did it spur TV news and radio debates like the Terri Schiavo case or the political controversy over embryonic stem cell research.
     In fact, it has been overlooked by a lot of people, including many in the medical community. But its repercussions may forever change the concept of how the human body can be healed.
     "In the past, cardiology focused on finding out where injuries were and using surgery to repair them when possible, as well as identifying risk factors," says Quyyumi. "But we now realize that hearts and blood vessels can be regenerated.
     "We now know that the endothelium is continually dying and being replaced, and we also understand how this turnover occurs—from progenitor cells, or adult stem cells, most of which come from bone marrow."
     How well an individual's body is able to turn over cells and adequately repair blood vessels may well depend on possible factors for cardiovascular disease, such as high cholesterol, high blood pressure, smoking, and diabetes. "These are paramount in terms of what causes atherosclerosis and, ultimately, heart attacks," says Quyyumi. "Now we believe the bone marrow's ability to replenish the endothelium and stop atherosclerosis from occurring probably is affected by the same risk factors that can damage blood vessels."
  How many stem cells does it take?
The process of manipulating the body's own progenitor cells to spark or speed up repair of blood vessels and heart muscle has worked in animal models, Quyyumi points out. In a handful of human trials, some but not all of the studies showed positive benefits.
     "All have shown that it is a safe thing to do—there were no obvious dangers or downsides. But the benefit, how much recovery and function is occurring, has varied among trials," he says. "We suspect the variation has a lot to do with timing and dosing. This is part of a series of studies designed to refine the technology and define what will work."
To that end, researchers are investigating the infusion of progenitor cells into the coronary arteries of recent MI survivors in ways never studied before. For example, in previous studies, researchers have used all of the bone marrow cells or a fraction of smaller, mononuclear cells without knowing specifically what type was being given to MI survivors.
     In the Emory study, researchers are isolating a specific population of cells from bone marrow for infusion into heart muscle. "These are CD34-positive cells—mononuclear white blood cells that are enriched with a population of stem cells," says Waller, who directs the Bone Marrow and Stem Cell Transplant Center. "These cells can restore normal bone marrow function when we transplant them into patients with leukemia. We think the same cells may be therapeutic in repairing blood vessels and damage to the heart."
     This trial, unlike previous ones, is a dose-response study. Each group of 10 patients (40 in all) receives a randomized titrated dosage of 5, 10, 20, or 30 million CD34-positive cells.
     "A lot of earlier studies used very small bone marrow aspirates and relatively small doses of cells," says Quyyumi. "We are giving larger numbers to discover if there is a threshold beyond which there may be a benefit not seen in previous studies."
  Arshed Quyyumi uses cardiac catheterization to place a patient's stem cells into the coronary artery. Researchers hope these stem cells will attach to the endothelium and generate new blood vessels to improve circulation in the heart  
  Timing may be everything
As Waller notes, cancer specialists are well aware that stem cells found in the bone marrow can be induced to enter the blood circulation through drug therapy. So why not use the same drugs to help move stem cells to help heart attack patients, instead of physically removing the cells via aspiration and reinfusing them?
     "These drugs cause the white blood count to go up considerably and that can help cancer patients, but their use for heart attack patients has been associated with adverse events related to reocclusion of coronary vessels," Waller says. "It might be dangerous to mobilize the blood cells so soon after heart attack."
     In fact, timing may be crucial to successfully using stem cells to help repair hearts. For the Emory study, initial testing and aspiration and reinfusion of cells are done within the first nine days after a heart attack.
     "There might be a narrow window of opportunity when we think these cells must be injected for them to be effective," Quyyumi explains. "We don't know yet how long that time period is or whether it can be extended. But we do know we can't do this effectively a day or so right after the MI. It appears not to be efficacious, probably because of the extensive inflammatory reaction that occurs after the MI, which makes the environment uninviting for stem cells to grow. However, five or six days afterward seems to be the optimal time we are aiming for. At this time, previous researchers have also observed benefits."
     Recent MI patients are still being recruited for the study. Thus far, the first cohort of patients has been treated with 5 million CD34-positive cells. During the 90-minute bone marrow harvest procedure, the longest part of the study process for patients, Waller collects a number of small aspirations of the bone marrow. The goal is to achieve a product that is mainly bone marrow cells with little blood.
     The cells are shipped immediately to Amorcyte, the biotech company that is funding the clinical trial, in New Jersey. Amorcyte separates the CD34-positive cells and ships them back to Emory within 24 to 36 hours. During cardiac catheterization, the stem cells are placed in the coronary artery where a blockage caused the patient's heart attack.
     "A portion of the stem cells is infused, and then a balloon is inflated around the catheter, sealing off the artery from any other blood flow," Quyyumi explains. "After a minute, normal blood flow is allowed to resume, and the process is repeated until the entire dose of cells is injected into the affected artery. The hope is that the stem cells will ‘home' or attach to the endothelium.
     "There may be many factors that explain the potential benefits of this technique. We believe the cells initiate angiogenesis, which improves heart function by getting more oxygen to the heart. There is also evidence that they may prevent further dilation of the heart and prevent development of congestive heart failure."
     Follow-up with patients is important to learn whether the stem cell transfer is as beneficial as expected. At three months and again at six months, patients undergo an MRI, nuclear scan, and echocardiogram to measure heart function and perfusion to document how well blood is reaching the damaged area of the heart. Patients will return for additional follow-up of these markers and an exercise test at one year. Long-term follow-up is slated for five years.
What matters most in that stem cell research has the potential to revolutionize treatment for heart attack patients. If theres any possibility to improve the damage to my heart, it's well worth it says Carroll Payne
  Pushing the envelope
Quyyumi believes that CD34-positive cells are much more likely than nonspecific bone marrow cells to become endothelial cells that improve circulation and function of the heart. But he has his eye on what may become the ultimate goal for this type of research—the creation of new heart muscle cells using a stem-cell type that replenishes the cardiac cells that died as a result of a heart attack.
     In a previous study, Quyyumi and Waller successfully mobilized cells from the blood marrow to improve circulation in patients with peripheral vascular disease. Eventually, adult stem cells may prove helpful in treating other cardiovascular problems, including heart failure caused by cardiomyopathy and angina in patients beyond treatment with angioplasty and/or bypass surgery. Notes Waller, "The bone marrow is a rich source of adult stem cells that appear to be able to help repair a number of different tissues."
     "Stroke is another area where this kind of technology, once it is refined, has great promise," Quyyumi adds. "This is just the beginning, and much basic science research still needs to be done, but a lot of clinical translation is now occurring. The NIH has been a driving force in terms of funding this research in the United States and has created a funding mechanism to develop stem cell therapy centers. That's an important impetus to show it is time for this to be in the clinical arena."
     Sonia Skarlatos, acting director of the National Heart, Lung and Blood Institute's Division of Cardio-vascular Diseases, is excited by the potential for stem cell–based therapies in cardiology. Some European studies have shown that infusion of stem cells from bone marrow has improved left ventricular ejection fraction, indicating improved pumping ability in damaged hearts.
     "It's minimal—just 3% to 4%—but significant and gives us reason to think this line of research is a positive development in cardiology," she says. "Many questions still need to be answered, but there are certain good signs to be encouraged."
    What matters most is that stem cell research has the potential to revolutionize treatment for heart attack patients like Carroll Payne. At first, Payne was reluctant to enroll in the Emory clinical trial because it meant more time in the hospital. His wife, who happens to be a nurse, quickly convinced him otherwise.
    "If there's any possibility to improve the damage to my heart," says Payne, "it's well worth it."
  Getting to the core of stem cell research  

While Arshed Quyyumi and Edmund Waller are using adult stem cells to treat heart attack patients, their work will be informed by the research of anesthesiologist Marie Csete, who directs the core facility for human embryonic stem cell research in the School of Medicine.
     Csete is working to answer some still-unknown and critical basic science questions about stem cells. For instance, how do they age? How does oxygen mediate the development of embryonic stem cells? How can they be used to understand drug toxicity in the developing fetus?
     Emory's core facility does not derive stem cells but maintains stem cell lines approved for use in federally supported research. The cells are stored and cultivated in mini-incubators where they are exposed to low physiologic levels of oxygen of about 3%. This protocol is based on Csete's prior findings that stem cells exposed to oxygen levels close to those inside the human body, instead of the oxygen levels found in a lab's ambient air, are better protected from chromosomal damage.


     The core facility provides embryonic stem cells to researchers at Emory and those with the joint Georgia Tech/Emory Center for the Engineering of Living Tissues. It also serves as a resource center, providing technical assistance and education for investigators conducting various stem cell research projects.
     Csete collaborates regularly with researchers outside of Emory, including the University of Georgia. With UGA, Csete focuses on creating the ideal gaseous environment to reduce oxidative stress and lower rates of cell mutation. She also collaborates with the University of Michigan's Electrical Engineering and Computer Science Department on a study to develop oxygen gradients on which stem cells can be grown. The patterning of stem cells into functional organs takes place along these gradients.
     If adult stem cells hold promise for repairing damaged hearts, why not derive all stem cells from adults—and avoid the controversy surrounding the use of embryonic stem cells? According to the NIH, human embryonic stem cells appear to have significantly greater developmental potential than adult stem cells. Simply put, embryonic stem cells may be pluripotent—able to give rise to cells found in all tissues of the embryo except for germ cells—as opposed to multipotent adult stem cells that appear to be restricted to specific subpopulations of cell types. However, pluripotency comes at a price: Human embryonic cells are more difficult to control than adult cells because they have many more options.
     Yet, while adult stem cells are difficult to grow in the lab, embryonic stem cells can reproduce indefinitely. Because the number of adult stem cells and their ability to reproduce diminish with age, obtaining clinically significant numbers of cells can be difficult.
     The issue is not adult versus embryonic stem cells, however. "Both are important parts of the big picture," says Waller. "The embryonic stem cell research that Dr. Csete is conducting will advance our understanding of how cells work, grow, and differentiate in ways that ultimately will benefit patients."
     To learn more about Csete's work, visit Momentum magazine's In the Air and On Point.

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