The so-called Phase I study is designed to test the safety of injecting adult stem cells at varying doses in patients who have recently suffered a heart attack.
An estimated 7 million Americans alive today have suffered at least one heart attack and so are at greater risk for chronic heart failure, sudden cardiac death or another, potentially fatal, heart attack.
"This is an important milestone on the journey to better cardiovascular care and to realization of the promise of adult stem cell research," says lead study investigator and cardiologist Joshua Hare, M.D., professor of medicine at The Johns Hopkins University School of Medicine and its Heart Institute.
"Current approaches to cardiovascular disease can prevent heart attack or alleviate its after-effects, but they have not included repair of damage that leaves sizably dead portions of heart tissue as dangerous scars in the heart," says study co-investigator and cardiologist Steven Schulman, M.D., a professor at Hopkins and director of the coronary care unit at The Johns Hopkins Hospital.
Previous research in animals showed that when adult stem cells were injected directly into the heart muscle, heart function was restored to its original condition within two months. Last November, at the American Heart Association Scientific Sessions 2004, the Hopkins team showed, again in animal studies, that more than 75 percent of dead scar tissue disappeared after therapy, which produced mostly healthy, normal-looking heart tissue and left only a small trace of the heart attack.
The Phase I study is being conducted at Hopkins, with support from Baltimore-based Osiris Therapeutics, which developed the stem cell product. The study will involve 48 adults who have had their first heart attack within 10 days of enrollment in the trial. All patients will have been stabilized before acceptance to the trial, and have undergone cardiac catheterization and ultrasound echocardiography to check that their main coronary vessels are clear of blockages that may precipitate another heart attack.
Eligible candidates must be able to safely travel to Hopkins Hospital in Baltimore, Md., be referred by a physician, be between 21 and 85 years old, and have no pre-existing heart condition that has been treated or requires treatment during the study period. Physicians interested in referring patients should call tel. 410-955-1160 for further information.
Upon acceptance in the study, patients will be randomly assigned to one of four groups, each made up of 12 patients who will receive a preset dose of stem cell therapy or placebo. The study is double blinded, with neither researchers nor patients aware of who received stem cells until the Phase I study ends, six months after the last patient has enrolled.
After injecting stem cells taken from the bone marrow of an adult, human donor, into subjects' bloodstream, the researchers will monitor the patient's progress for two years to ensure that patients safely tolerated the infusion, determine any side effects and assess any differences in the three doses under study, each involving millions of adult stem cells. Initially, study participants will spend four days in the hospital, immediately after the procedure. The patients will then return for preset checkups, monthly for the first three months, and again after six months, 18 months and 24 months.
Magnetic resonance imaging (MRI) studies, to show the size of the area of heart muscle scarred by the infarct and gauge the organ's ability to pump, will be conducted at the beginning and end of the study as a measure of heart function. Conclusive results will only be available when and if Phase II and Phase III clinical trials proceed.
The Hopkins team expects that after injection, the adult stem cells will migrate to the damaged areas of the heart muscle, responding to chemical signals released by the heart after an infarct that triggers a repair response from the bone marrow.
Related clinical research under way in China also uses adult stem cells, but they come directly from the patient, and no universal donor is used as in the Hopkins study.
It remains unclear from earlier animal studies how or why the adult stem cells develop into new and healthy heart tissue, or exactly how long their healing effects last.
Adult stem cells are being used because they are readily available from the bone marrow, where they are plentiful. A special kind of bone marrow stem cell, called a mesenchymal stem cell, was separated from other kinds for use in this study. While their precise biological action is not known, mesenchymal bone marrrow stem cells are known to give rise to a variety of cell types, including bone, cartilage, fat, and other kinds of connective tissue cells such as those in tendons, as well as muscle, such as the heart. A stem cell is a special type of body cell that gives rise to other types of specialized cells.
"Using mesenchymal stem cells also avoids potential problems with immunosuppression, in which every human's immune system might attack stem cells from sources other than itself," notes Hare. "Because they remain in an early stage of development, mesenchymal stem cells do not trigger an immune response, unlike what would happen if more developed stem cells were used.
"While the bone marrow adult stem cells do not have the same potential to develop into different organ tissues as do embryonic stem cells, the use of adult stem cells in this study shows their tremendous potential in developing effective therapies for heart disease, and avoids the controversy surrounding destruction of embryos to obtain the embryonic variety," he adds.
"Among its many benefits are that adult stem cells are readily available from a number of donors, and grow in large quantities in the lab. In our experiment, the treatment regimen is relatively simple, requiring only injection."
Funding for the study is provided by Osiris Therapeutics, which developed the process for preparing the adult mesenchymal stem cell product in use in the study. Additional funding comes from Hopkins' General Clinical Research Center, its Institute for Cell Engineering, and the Donald W. Reynolds Cardiovascular Clinical Research Center at Johns Hopkins. Other investigators in this research are Stuart Russell, M.D.; Ilan Wittstein, M.D.; Gary Gerstenblith, M.D.; Alan Heldman, M.D.; João Lima, M.D.; and Kathy Wu, M.D.
According to the latest statistics from the American Heart Association, in 2002, there were an estimated 565,000 new cases of heart attack in the United States, plus an additional 300,000 cases of recurrent heart attack. Almost 180,000 of all heart attacks were fatal. The AHA also estimated that 7,100,000 Americans had suffered at least one heart attack. People who have had a heart attack have a sudden death rate that is four to six times greater than in the general population. About two-thirds of heart attack patients do not make a complete recovery; however, 88 percent of those under age 65 are able to return to work.
Study Inclusion Criteria: