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April 29, 2004

Research Notes

Adult Stem Cell Injections Benefit Heart Failure Patients

Injections of adult stem cells into damaged heart tissue significantly improved heart function in patients with severe congestive heart failure, according to results of the first prospective randomized trial of the experimental therapy presented April 25 at the American Association for Thoracic Surgery.
Amit Patel, of the Pitt medical school’s Division of Cardiac Surgery and a faculty member of the University’s McGowan Institute for Regenerative Medicine, along with colleagues from Pitt, Baylor University Medical Center in Dallas and the Benetti Foundation in Rosario, Argentina, say their findings provide the first convincing evidence that transplantation of adult stem cells that promote growth of blood vessels and heart muscle can be a viable treatment for congestive heart failure. While some previous studies have suggested benefit, results of these studies have been questioned due to the small number of patients studied and lack of comparison data from patients not receiving the therapy.
The idea behind the current multi-center trial and others is that stem cells introduced into a heart damaged from heart attack or chronic illness could feasibly differentiate into heart muscle cells and cells that promote new vessel growth, thereby improving the heart’s ability to contract more effectively and restoring blood supply to the heart itself.
The study involved 20 patients with severe heart failure who had ejection fractions less than 35 percent. Ejection fraction is a standard measure of heart function and is determined by the total amount of blood that the left ventricle pumps out per heart beat.
A patient with good heart function has an ejection fraction of at least 55 percent. Each patient was scheduled for off-pump (beating heart) cardiac bypass surgery; 10 were randomized to also receive stem cells during surgery. The other 10 patients underwent the bypass operation alone. Each group consisted of eight men and two women.
After undergoing anesthesia, those selected to receive stem cells had bone marrow removed from their hipbones. While bypass surgery was taking place, the particular stem cells that influence blood vessel and heart muscle growth were isolated from other cells in the bone marrow. After the bypass was complete, in a process taking about 10 minutes, the surgeons then injected the cell preparation into 25 to 30 sites where muscle damage was apparent. Prior imaging studies guided the team to the specific injection sites and helped them avoid injecting vessels or inserting the needle too far into the walls of the heart’s chambers.
Before surgery, the average ejection fraction in the patients randomized to bypass surgery alone was 30.7 percent with a range of 26 to 34 percent. The patients randomized to receive stem cells in addition to bypass surgery had an average ejection fraction of 29.4 percent before treatment, with a range of 23 to 34 percent.
At one-, three- and six-month follow-up, the ejection fraction rates for the stem cell patients were significantly improved compared to the other patients. At one month, the stem cell patients improved to an average ejection fraction of 42.1 percent (37 to 48 percent range); the patients who did not receive stem cells saw an improvement to 36.4 percent on average (33 to 40 percent range). Three months after surgery, the stem cell patients continued to improve with an average ejection fraction of 45.5 percent (42 to 50 percent range) compared to a rate of 36.5 percent in the other patients (33 to 43 percent range). At six months, the average ejection fraction rates were 46.1 and 37.2 percent, respectively, with ranges of 44 to 50 percent in the stem cell patients and 33 to 44 percent in the bypass alone group.
None of the patients experienced serious side effects or complications and there were no abnormal heart rhythms associated with the stem cell injections.
The 20 patients in the study underwent treatment at centers in South America. The researchers obtained the necessary institutional and government health agency approval to conduct the study and all patients provided informed consent. More than 40 patients have been enrolled in the multi-center trial.
A separate study is underway for patients with inoperable congestive heart failure whereby stem cells are injected into the heart using a minimally invasive surgical technique. Two patients have undergone the procedure in Uruguay. The team also expects to perform the procedure soon in Palermo, Italy, at the Mediterranean Institute for Transplantation and Advanced Specialized Therapies, a program that is managed by the University of Pittsburgh Medical Center in partnership with the Sicilian government and the local health care community. In another study being planned to take place at Pitt, researchers will give stem cells to patients who are being implanted with heart assist devices. When a donor heart becomes available for transplantation, the native heart will be removed, allowing the rare opportunity to look at the heart in its entirety and to more closely examine the effects of the stem cells.
“These results encourage us to aggressively pursue cellular therapies as an option for congestive heart failure. It will revolutionize our approach, which is largely palliative, to one that is truly regenerative,” said co-author Robert L. Kormos, a Pitt professor of surgery and medical director of the McGowan Institute.
$1.5 million awarded for study of pancreatic cancer prevention agent

A newly funded study at the University of Pittsburgh Cancer Institute (UPCI) is seeking to determine whether cruciferous vegetables, such as broccoli and cabbage, reduce the risk of pancreatic cancer. Pancreatic cancer, the fourth-leading cause of cancer-related deaths in the United States, is one of the most aggressive and deadliest cancers.
UPCI researcher Sanjay K. Srivastava, assistant professor of pharmacology at Pitt’s School of Medicine, has received $1.5 million from the National Cancer Institute to study phytochemicals found in vegetables called isothiocyanates. Srivastava’s study will focus on a special type of isothiocyanate called benzyl isothiocyanate, or BITC, and its affect on the onset and progression of pancreatic cancer.
“Epidemiological studies have suggested that increased consumption of cruciferous vegetables reduces the risk of pancreatic cancer,” said Srivastava. “Despite these findings, we know little about the mechanisms and cellular pathways by which certain dietary agents in vegetables, such as benzyl isothiocyanate, protect against pancreatic cancer.”
According to Srivastava, studies have established that the cancer preventive effects of cruciferous vegetables are attributable to isothiocyanates, or ITCs, which are generated when vegetables are cut or chewed. ITCs are known to offer significant protection against chemically-induced cancer in animal models, and epidemiological research has shown that increased consumption of vegetables that contain ITCs significantly reduces the risk for cancer. BITC is a very promising ITC because it impacts the ability of pancreatic cancer cells to survive and proliferate by down-regulating a transcription factor, NF-kB, that is over-expressed in pancreatic cancer. A transcription factor is a protein involved in the expression of a gene.
Through the grant, Srivastava seeks to further define the mechanisms by which BITC induces apoptosis, or cancer cell death, to provide insights into the key structural relationships between BITC and various cell processes.
“Our goal is to start with a preclinical model and lay the foundation for future clinical studies directed at developing much needed strategies to prevent and control pancreatic cancer,” Srivastava said.
Grant awarded for Alzheimer’s research
Pravat K. Mandal, assistant professor in the Pitt medical school’s Department of Psychiatry, has been awarded a two-year, $100,000 grant from the American Health Assistance Foundation for research aimed at identifying “good” and “bad” gangliosides in the human brain, using NMR spectroscopy.
Understandings gained from the research should help in making early diagnoses of Alzheimer’s through use of magnetic resonance spectroscopy. Mandal will conduct his research in the psychiatry department’s Neurophysics Laboratory.
Preeclampsia risk rises with increased pre-pregnancy body mass index
A Magee-Womens Research Institute study of 1,179 pregnant women found the risk of preeclampsia, a leading cause of premature delivery and maternal and fetal death, rose sharply with even relatively small increases in pre-pregnancy body fat. Most surprising, say the Pitt-affiliated researchers, was the fact that the risk was elevated even among women who would not normally be classified as overweight when compared to women with less body fat.
This is one of the first studies to compare the development of preeclampsia to body mass index (BMI, a widely used method of calculating percentage of body fat) as a continuum rather than simply by conventional classification units. It also is the first study to try to determine the mechanisms by which body fat increases preeclampsia risk.
Preeclampsia affects about 7 percent of first pregnancies nationwide, and is characterized by high blood pressure and protein in the urine. The condition has negative – sometimes lethal – consequences for the mother and fetus by causing reduced blood flow to organs. Having had preeclampsia also increases maternal risk of cardiovascular disease in later life.
The study was presented by Lisa Bodnar, a postdoctoral fellow in the lab of James M. Roberts, director of the Magee-Womens Research Institute, at Experimental Biology 2004, the annual meeting of the American Society for Nutritional Sciences.
The Pittsburgh research team enrolled women at or before the 16th week of their first pregnancy. Preeclampsia usually begins to appear by the 20th week of pregnancy. By the time all women in the study had delivered, 6 percent of the group had developed preeclampsia. After the researchers adjusted their analysis to take into account differences in age, smoking, race, marital status and education, one factor stood out clearly: the higher a woman’s body mass index, the more likely she was to develop preeclampsia.
While weight loss prior to becoming pregnant may hold the most promise in lowering the risk of preeclampsia, weight loss during pregnancy is discouraged, say the researchers. The dramatic increase in obesity among Americans is well documented and the epidemic’s health consequences on non-pregnant individuals have been widely recognized. Less is known about its impact on reproductive outcomes. The researchers say these results suggest that as obesity continues to rise, so will the rates of preeclampsia.
Pitt researchers include Bodnar and Roberts, both in the medical school’s Department of Obstetrics, Gynecology and Reproductive Sciences, and Nina Markovic and Gail Harger, both in the epidemiology department at Pitt’s Graduate School of Public Health.

UPMC surgeons implant heart assist device as part of U.S. trial

Surgeons from the University of Pittsburgh Medical Center (UPMC) have implanted the HeartMate II, a new left ventricular assist system (LVAS), in a 22-year-old woman. The implant is the third in the United States as part of a pilot trial sponsored by Thoratec Corporation to test the safety and potential effectiveness of the HeartMate II.
The device is a miniature rotary pump with axial flow bearings and is intended for patients with end-stage heart failure. A key feature of the design is a sophisticated control system developed by researchers at Pitt’s McGowan Institute for Regenerative Medicine that senses when to increase or decrease the rate of blood flow. Other approved and experimental devices require manual adjustments.
The operation took place on April 7 and was performed by a team led by Robert L. Kormos, professor of surgery at Pitt’s School of Medicine, director of UPMC’s Artificial Heart Program and medical director of the McGowan Institute.
UPMC is one of four centers that will test the device in seven patients who are candidates for heart transplantation. The device will be evaluated initially for use as a bridge to heart transplantation, but its developers see its eventual use for long-term support.
The control system developed by Pitt researchers involves a patented algorithm that permits the LVAS to respond to the needs of the patient based on the level of activity, generating up to 10 liters of blood flow per minute, a rate that would be required to climb stairs, for example. The controller was the brainchild of James Antaki, a member of the McGowan Institute who is associate professor of bioengineering and surgery at Pitt and also an associate professor at Carnegie Mellon University.
“This algorithm is essentially the intelligence of the system,” said Kormos, principal investigator of the Pittsburgh site of the HeartMate II trial. “Engineers don’t need to stand at the patient’s side in order to adjust the device to one of a few fixed settings, which is the case with other devices, even newer ones in trials. We are especially proud of this contribution to the design of HeartMate II.”
Pitt became involved in development of the device about eight years ago when it and Nimbus Inc. entered into a five-year contract with the National Institutes of Health to conduct studies of what was then called the Nimbus pump. The pump was among the first axial flow devices; instead of mimicking the heart’s pumping mechanism, the Nimbus pump was designed as a much smaller rotary device that results in continuous flow of blood.
As an axial flow device, HeartMate II produces no pulsatile action; patients being supported by the device have only minimal pulse. Weighing 12 ounces and approximately 1.5 inches in diameter and 2.5 inches long – about the size of a D-cell battery – it is significantly smaller than currently approved devices which weigh closer to 3 pounds. As such, it may be suitable for a wider range of patients, including small adults and children. The design also makes the device quieter and simpler to use.
It is implanted just below the diaphragm and attached between the apex of the left ventricle and the aorta, the main artery that feeds blood to the entire body. A system driver regulates pump speed. When implanted, HeartMate II takes over most of the function of the left ventricle, the heart’s main pumping chamber, and helps generate the force necessary to propel oxygen-rich blood throughout the body. Without such circulatory support, patients are unable to produce blood flow adequate to meet their body’s metabolic needs.
Heart failure accounts for more than 250,000 deaths in the United States each year. Currently, about 3,500 patients are on the national heart transplant waiting list. According to the United Network for Organ Sharing, 506 patients died waiting for a heart transplant in 2003.
UPMC’s Artificial Heart Program has supported more than 275 patients on assist devices for a period of time that equates to more than 60 years. The program often serves as both a proving ground for manufacturers and a training center for surgeons from around the world. Devices that UPMC has used over the years include the Jarvik/Cardiowest Total Artificial Heart, Novacor Left Ventricular Assist Device (LVAD), Thoratec VAD and HeartMate I, making it one of the most experienced and active programs in the United States.
UPMC was the first center to discharge a patient still on a device to await a human donor outside the hospital. Based on UPMC’s experience, the U.S. Food and Drug Administration later allowed patients implanted with the Novacor to be discharged to home to await heart transplant.

Bradford staff wins award for research

Glenn R. Melvin, director of alumni relations and annual giving at Pitt’s Bradford campus, received a second place award for his research project, “Illusions – Seeing Beyond the Obvious,” which he presented April 3 at the 2004 Penn State-Behrend Xi Undergraduate Research and Creative Accomplishment Conference in Erie.
Melvin’s presentation, the result of work that he did as an undergraduate student at Pitt-Bradford in fall 2003, was one of seven presentations in the humanities category. Melvin focused on the question, “Do we see the obvious, what is in front of us or can we see what is beyond?”
He created impression-like art using a digital camera and a computer, taking more than 700 images. Using a PowerPoint slide show, he blended images of the West Branch of the Tunungwant Creek with sounds of the stream along with the song, “Exile,” by Enya. “I experimented with various types of movement to get the final art images I was after,” Melvin said. “The song gives emotion to the work.” He included the different sights and sounds to show observers what they would see if they were to take the time to admire this piece of nature. He used all original images.
Melvin, a December 2003 graduate of Pitt-Bradford, is an award-winning photographer who operated his own studio in Bradford. For the past 15 years, he has been the campus’s chief photographer. He recently was named the university’s director of alumni relations and annual giving.


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