Nov. 18, 2002 CHICAGO, Nov. 17 – Researchers safely transplanted 16 patients' skeletal muscle cells into their own severely damaged hearts in the first human testing in the United States, according to a study reported today at the American Heart Association's Scientific Sessions 2002.
"We have been able to regenerate dead heart muscle, or scar tissue, in the area of heart attack without increasing risk of death," says lead author Nabil Dib, M.D., director of cardiovascular research at the Arizona Heart Institute in Phoenix. "Our findings will allow us to move forward with testing if the procedure can improve the contractility of the heart."
The interim results indicate the procedure is safe and feasible, he says.
When patients suffer a heart attack, scar tissue develops, resulting in a decrease in heart contractility – its ability to compress and force blood through its chambers. Since heart cells can't repair themselves, this damage is irreversible and eventually results in heart failure.
Researchers conducted the multi-center trial, overseen by the U.S. Food and Drug Administration, in patients who had suffered heart attacks or heart failure and whose hearts had reduced pumping ability evidenced by left-ventricular ejection fraction (EF) less than 30 percent. EF measures the quantity of blood pumped from the heart with each beat. A healthy heart pumps out a little more than half the heart's volume of blood with each beat for an EF of 55 percent or higher.
Eleven patients were undergoing coronary artery bypass surgery (CABG) and five were having a left ventricular assist device (LVAD) implanted. An LVAD helps a failing heart until a donor heart becomes available for transplant.
The patients' myoblasts cells (immature cells that become muscle cells) were extracted from thigh muscle. Large quantities of the cells were grown in the laboratory for three to four weeks using a controlled cell expansion manufacturing process. During the surgery, one to 30 direct injections – containing 10 million cells each – were made into the damaged area of the hearts. The dosages ranged from 10 million to 300 million cells.
"We found that the transplanted myoblasts survived and thrived in patients. Areas damaged by heart attack and cardiovascular disease showed evidence of repair and viability," Dib says.
No significant adverse reactions were found related to the cell transplant procedure in either group of patients in follow-up testing nine months later.
There was one death due to infection of the device in the LVAD group three months after cell transplantation, and one patient in the CABG group had non-sustained ventricular tachycardia – a fast heart rate that starts in the lower chambers (ventricles).
While the trial was not designed to evaluate the effect of cell transplant on cardiac function, Dib calls the results extremely encouraging. Examining the heart by echocardiogram, magnetic resonance imaging (MRI), and positron emission tomography (PET scan) showed evidence of scar tissue regeneration in the area of the graft, which indicates repair.
EF rates improved, on average, from 22.7 percent to 35.8 percent – a 58 percent increase – after 12 weeks.
"The important finding in the LVAD clinical study, is that we were able to directly examine and observe histological changes in the heart muscle of patients after they received a new heart and their old one was removed," Dib says.
The results were also compared against a group of historical controls from a Yale University study, published in the Journal of the American College of Cardiology (93:22:1411-7) of 83 patients with EF less than 30 percent before bypass surgery. In the Yale group, there was a 13 percent overall death rate and an 11 percent heart death rate at one year.
After bypass, the Yale group's EF improved from 24.6 percent to 33.2 percent – a 36 percent increase.
At Scientific Sessions 2000, French researchers described the first human experience with autologous skeletal myoblast transplantation. The transplant improved EF in a 72-year-old man undergoing a bypass procedure. Subsequent procedures in other patients have been reported at other meetings. Those studies showed similar improvement in viability of dead or damaged heart tissue, but several adverse reactions, such as life-threatening arrhythmias also were reported.
No such complications were found in this study, Dib notes.
Other promising cellular and molecular procedures are being explored as ways to repair and strengthen the damaged heart by replacing dysfunctional or dead heart cells with cells from other sites and those grown in laboratories, Dib says. These include embryonic and adult cardiomyocytes, embryonic stem cells, genetically altered fibroblasts, smooth muscle cells, bone marrow-derived cells, and adult skeletal myoblasts.
Co-authors are Patrick McCarthy, M.D.; Ann Campbell, R.N.; Johnathan Dinsmore, Ph.D.; Michael Yeager, R.N.; Francis D. Pagani, M.D.; Susan Wright, R.N.; W. Robb MacLellan, M.D.; Gregg Fonarow, M.D.; Howard J. Eisen, M.D.; Satoshi Furukawa, M.D.; Robert E. Michler, M.D.; Diane Buchele, R.N.; Marwan Ghazoul, M.D.; and Edward B. Diethrich, M.D. The study was funded by Diacrin, Inc.
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