McGowan Institute?
January 2005 | VOL. 1 | www.McGowan.pitt.edu
First Heart Failure Patients Ever to Receive Stem Cells in Minimally Invasive Procedure Have Improved Heart Function
Patients with severe congestive heart failure who had exhausted all other treatment options showed markedly improved heart function following a procedure in which their own stem cells were deployed directly into the heart by way of four tiny incisions in the chest, according to results of a trial presented on January 25, 2005 at the 41st Annual Meeting of the Society for Thoracic Surgery.
The study, led by Amit N. Patel, M.D., M.S., of the University of Pittsburgh McGowan Institute for Regenerative Medicine, is the first to use a minimally invasive surgical technique.
While preliminary, the results of the prospective randomized trial indicate that a minimally invasive approach to cell therapy is feasible for the estimated 40 percent of heart failure patients whose disease is unrelated to coronary blockages and who therefore cannot benefit from bypass procedures. Moreover, the experience so far suggests the novel stem-cell approach may be a viable treatment for these and other heart failure patients, reported Dr. Patel, director of clinical cardiac cell therapies at the McGowan Institute.
All 15 of the patients who received stem cell injections had some degree of improvement, some with dramatic results, while the conditions essentially remained unchanged in the 15 randomized to receive injections of their own blood serum.
“It is remarkable the level of improvement we’ve seen in these patients, who came to us with no other medical or surgical options available to them. However, we don’t yet fully understand how these cells work, whether they differentiate to become heart muscle cells or cells that promote vessel growth, or whether they serve as homing signals to other cells and substances that help with repair,” explained Dr. Patel.
The study took place at centers in South America. The research team obtained the necessary institutional and government health agency approval and each patient provided informed consent.
All 30 patients enrolled had severe heart failure (New York Heart Association heart failure classifications III and IV) with ejection fraction rates of 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.
Patients were scheduled to undergo the minimally invasive procedure but were unaware whether they would receive their own bone marrow stem cells or their own serum. Regardless, while under general anesthesia, each patient had bone marrow harvested from their hipbones. The cells believed to have the greatest therapeutic benefit, CD34+ cells, were isolated from the bone marrow and either injected into the hearts of patients randomized for therapy or placed in frozen storage if the patients were randomized to the control group. These patients received the same number of injections into the heart – about 25 to 30 – as the patients in the treatment group but instead of containing their stem cells, the injections were loaded with their serum. Neither group experienced any significant side effects or complications, including abnormal heart rhythms, which had been associated with other stem cell trials.
Prior to the study, the two groups had comparable ejection fraction rates. The treatment study group had an average rate of 26 percent, with the range between 21 and 34 percent, and the control group averaged 27 percent, with the range being 22 to 34 percent. Yet six months later, those receiving stem cells improved to an average rate of 46 percent, the lowest rate of improvement going up to 38 and the highest climbing to 52 percent. By comparison, the control patients average went up one percentage point, to 27, with a range between 22 and 31, indicating that some had worsening heart function.
With a six-month follow-up period now complete, the patients who had been randomized to receive the placebo treatment are now eligible to receive their own bone-marrow stem cells that had been kept frozen.
Last April, Dr. Patel reported the results of a trial looking at stem cell therapy given in conjunction with beating-heart bypass surgery for patients whose hearts were damaged by heart attack or chronic coronary disease. That study involving 20 patients also demonstrated the potential benefits of using a patient’s own bone marrow-derived stem cells to treat their ischemic heart disease.
Dr. Patel and his colleagues are in discussions with the U.S. Food and Drug Administration and hope to receive the agency’s approval to conduct a trial at the University of Pittsburgh that would involve giving stem cells to patients who are being implanted with heart assist devices. When a donor heart becomes available for transplantation, the native heart would be removed, allowing researchers the rare opportunity to look at the heart in its entirety and to more closely examine the effects of the stem cells.
If approved, the protocol will be performed under the umbrella of the newly established Center for Cardiovascular Cellular Therapy, a collaboration that includes the McGowan Institute, the University of Pittsburgh School of Medicine’s department of surgery, the University of Pittsburgh Schools of the Health Sciences and the University of Pittsburgh Medical Center. The center will encompass clinical and research programs focused on the use of stem cells as an adjuvant treatment for a wide array of heart failure patients and for those with peripheral vascular disease.
In addition to Dr. Patel, co-authors of the current research include Federico Benetti, M.D., and Luis Geffner, M.D., of the Benetti Foundation in Rosario, Argentina; Roberto Paganini, M.D. and Daniel Brusich, M.D., of Asociacion Espanola Primera de Socorros Mutos in Montevideo, Uruguay; Robert L. Kormos of the University of Pittsburgh’s McGowan Institute; and Harold C. Urschel, Jr., M.D., of Baylor University Medical Center in Dallas.
The McGowan Institute Scientific Retreat will be held on March 7-8, 2005 at the Nemacolin Woodlands Hotel. The meeting will provide unique opportunities for networking and collaboration amongst colleagues and new scientists, engineers and clinicians. Under the leadership of Timothy Billiar, M.D. the retreat program has been finalized and includes many distinguished speakers including:
- Elliot Chaikof, MD, PhD: Emory School of Medicine
- Toshiharu Shinoka, MD: Tokyo Women's Medical University
- U.S. Army Combat Casualty Care Unit
- FDA Specilaists
The Pittsburgh Tissue Engineering Initiative is a cosponsor of the retreat and many of their constituents will be participating in the retreat, bringing new perspectives to the technical and scientific issues to be addressed during this two-day meeting.
On-line registration, room reservation instructions and program information are available at www.mirm.pitt.edu/events/retreat2005.htm.
Remember – Register NOW for March 7-8, 2005. The deadline for room reservations in February 2nd!
In a review paper entitled "Molecular Aspects of Vascular Tissue Engineering" that was published in Frontiers in Bioscience (10, 768-789, January 1, 2005) by Dr. David Vorp and his colleagues Timothy Maul and Alejandro Nieponice, M.D. the authors assess the current state-of-art in vascular grafts and vascular tissue engineering. The authors note that cardiovascular disease remains the number one cause of death in the United States and most current surgical procedures to alleviate this disease rely on the availability of suitable small diameter vascular grafts, which are constrained by several limitations.
Tissue engineering brings new hope to this field, but still faces many challenges. The review focuses on the molecular aspects of the different components of vascular tissue engineering. The paper concludes that it is necessary to control all aspects of a TEVG - including its cellular, physical, and biochemical environments - in order to produce a viable, functional vascular tissue-engineered construct.
A viable TEVG needs to be functional, both mechanically and biologically, in order to be clinically efficacious. To date, there exist limitations in each of the components of vascular tissue engineering that the authors outline in the paper. They note that while great progress has been made in the past 5 years, manipulating the overlapping molecular pathways that govern the components of a functional TEVG remains challenging. A new vascular graft is largely needed and future progress in tissue engineering will likely provide a solution once all the key factors discussed in this review become at least partially controlled.
Marie C. DeFrances, M.D., Ph.D., Assistant Professor of Pathology, has received an RO1 entitled "A Novel Regulator of PI-3-Kinase in Human Liver Cancer". This award is based on the discovery by the DeFrances lab of a novel kringle containing transmembrane protein that they have named Phosphatidylinositol-3-Kinase Regulator (PIKR) based on its ability to associate with and modulate the activity of the p110 subunit of PI3K. To test the hypothesis that this novel protein is involved in liver growth and neoplasia, the lab plans to determine the molecular mechanism(s) through which this protein exerts its effect on liver cell growth regulation. The lab will also determine the expression and association patterns of PIKR and p110 as well as the mutational profiles of its gene in normal, diseased and malignant human liver tissues. Lastly, the study will examine the in vivo function of the PIKR protein in liver growth, regeneration and tumorigenesis through gain-of-function and loss-of-function animal models.
McGowan Institute researchers have developed a way that could prolong the effectiveness of antioxidants that are commonly used in products to protect against the harmful effects caused by sun and air exposure. Reporting in the January 10, 2005 print issue of Biomacromolecules, a journal of the American Chemical Society, they describe a chemically formulated co-polymer that in laboratory studies was able to withstand significantly longer periods of intense ultraviolet light than other formulations.
Antioxidants are added to many types of products, from sunscreens and cosmetics to exterior paints and industrial and consumer plastics, in order to stave off oxidation – a process whereby UV radiation or oxygen in air or water produces a chemical reaction to the surface of an object. Oxidation causes skin to burn or wrinkle, iron to rust and plastics to turn yellow or crack. Yet even the addition of antioxidants cannot provide complete protection. Eventually, the antioxidants themselves become vulnerable to oxidation caused by UV light, hence the need to reapply sunscreen, repaint homes and replace sun-damaged materials.
The scientists conducting the study are Bhalchandra S. Lele, Ph.D. (left in photo), research associate and Alan J. Russell, Ph.D. (right in photo), professor of surgery and director of McGowan Institute. They have developed a co-polymer that acts as a super sunscreen of sorts, whereby one chemical sacrificially takes the hit of UV rays to allow its partner, the antioxidant, to work longer. Specifically, the co-polymer consists of benzotriazole, a chemical that absorbs UV light, and an antioxidant called Trolox, a water-soluble derivative of vitamin E that has been shown to protect against the harmful effects of UV radiation.
The University of Pittsburgh has applied for a U.S. patent for the process involved in using a UV-absorber to stabilize an antioxidant.
The Pittsburgh Post Gazette (December 28, 2004) recognized Dr. Alan Russell as one of the “Dozen Making a Difference” in the region. His recent scientific accomplishments include developing a material that might be used to build an artificial retina, finding a way to preserve follicles in a test tube so women might have babies after cancer treatment and being selected for one of the Army's top 10 inventions. As director of the McGowan Institute the Post Gazette notes that Dr. Russell was equally busy, recruiting six new faculty, folding in a biotech company donated by industrial giant Rohm & Haas; and addressing how to maintain a technological edge as California embarks on its new $3 billion stem cell initiative.