First Randomized Trial Of Adult Stem Cell Injections In Heart Failure Patients Shows Benefit

Amit Patel, M.D., from the Division of Cardiac Surgery at the University of Pittsburgh School of Medicine and a faculty member of the university's McGowan Institute for Regenerative Medicine, and colleagues from the University of Pittsburgh, Baylor University Medical Center in Dallas and the Department of Cardiovascular Surgery at 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 (New York Heart Association heart failure classification III and IV) 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 (CD34+ and CD45- cells) 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.

To evaluate cellular changes, the researchers examined tissue samples obtained before and after surgery to look for the presence of a protein marker of gap junctions, which are important for communication between cells. The marker, Connexin 43, is typically reduced in patients with heart failure. Six months after surgery, there was a notable increase in the marker in the patients who received stem cells compared to the patients who did not receive the cell transplant.

"We don't know if this increase was due to the growth of new heart muscle cells resulting from the stem cell injections or whether the stem cells coaxed existing cells to come out of hibernation," explained Dr. Patel.

"What we do know is that stem cell transplantation led to significant improvement in cardiac function in these patients undergoing off-pump bypass surgery. But, further investigation is needed to replicate these results, quantify the optimal timing of injection and to look at the cellular effects of the therapy," he added.

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 the University of Pittsburgh, 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, M.D., professor of surgery at the University of Pittsburgh School of Medicine and medical director of the University of Pittsburgh's McGowan Institute for Regenerative Medicine.

In addition to Drs. Patel and Kormos, other researchers involved in the study were senior author Federico Benetti, M.D., Luis Geffner, M.D., Roberto F. Vina, M.D., and Jorge Saslavsky, M.D., of the Benetti Foundation in Rosario, Argentina; and Harold C. Urschel, Jr., M.D., of Baylor University Medical Center in Dallas.