Aug. 29, 2000 DALLAS, Aug. 29 -- Scientists significantly increased blood flow to the hearts of seriously ill patients by injecting the gene for vascular endothelial growth factor (VEGF) into areas of dead or unresponsive heart muscle, according to a report in today's Circulation: Journal of the American Heart Association. The VEGF gene stimulates new blood vessel growth (or angiogenesis) in the heart.
"To my knowledge, this is the first study using objective findings that has demonstrated improvement in blood flow to the heart using gene therapy," says the study's senior author Jeffrey M. Isner, M.D., professor of medicine and pathology at Tufts University School of Medicine in Boston. "There has been great concern about whether gene therapy works. This is very solid evidence that it does."
Isner and his colleagues reported on 13 individuals treated in a gene therapy trial. All eight men and five women in the study had experienced severe angina (or chest pain), had at least one heart attack, and had undergone by-pass surgery. Twelve of the patients had undergone one or more balloon angioplasties to open narrowed arteries.
In some patients, Isner's team found that the gene therapy revived areas of the heart that appeared to be dead, but which were only "hibernating."
"This is a potentially important finding that was quite unexpected," he says. "We saw large areas where there was no blood flow to the heart when the patient was at rest, but many of those resting defects were gone after gene transfer." None of the participants in the study had suffered a heart attack, death or other serious complication at a six-month follow-up after their procedure. An editorial accompanying the report warns that gene therapy remains a highly experimental procedure for treating heart disease. Nonetheless, "The progress of the major groups in this field is extraordinary," write cardiologists Cam Patterson, M.D., and Marschall S. Runge, M.D., Ph.D., of the University of Texas Medical Branch, Galveston.
The participants were evaluated with two tests before and after receiving gene therapy: NOGA left ventricular electromechanical mapping (EMM) and single-photon emission CT-sestamibi (SPECT) imaging.
SPECT imaging, a technique used for almost two decades, involves injecting a tiny amount of a radioactive substance, stressing the patient's heart with exercise or a drug, then scanning the heart to see where the substance goes. A second scan is done 24 to 48 hours later without physical stress. The results indicate which parts of the heart are not receiving enough blood when it is at rest, as well as when it is working harder during physical stress.
EMM involves threading a device into the left ventricle, the heart's main pumping chamber. The device measures the heart's electrical activity at about 100 different sites. A computer produces two three-dimensional maps -- one shows areas of live heart muscle, the second differentiates areas that are or are not working properly. By combining the two maps, researchers can distinguish normal muscle, dead muscle, and areas receiving insufficient blood supply.
After participants had their initial EMM and SPECT tests, they received gene therapy through a small incision a little more than 1 inch in diameter in the chest. Through this "keyhole" incision, a surgeon injected doses of the VEGF gene into four places in the heart.
Patients were tested again with SPECT imaging and EMM 60 days after treatment. Isner says both tests showed objective evidence of improved blood flow to the heart.
The average number of angina attacks among participants dropped from 48 per week before gene therapy to 2 per week six months afterward. Average weekly use of nitroglycerin tablets to fight chest pain fell from 55 to 2 in the same period. Most importantly, areas of heart muscle that were assumed to be dead scar tissue caused by a heart attack had restored function in nine patients, partially or completely, within 60 days after gene therapy. Four patients had partial and five patients had complete restoration of blood flow to "hibernating" areas.
"What we have shown is that VEGF gene transfer is sufficiently potent to provide enough blood supply to rescue an area of hibernating heart muscle," Isner says. "This study provides objective evidence that both gene therapy and a strategy of therapeutic angiogenesis do achieve meaningful biological results."
Co-authors of the study are Peter R. Vale, M.D.; Douglas W. Losordo, M.D.; Charles E. Milliken, M.A.; Michael Maysky, M.D.; Darryl D. Esakof, M.D.; and James F. Symes, M.D.
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