If further animal studies and human clinical trials prove equally successful, the Hopkins researchers believe this could be a new, widely applicable treatment to repair and reverse the damage done to heart muscle that has been infarcted, or destroyed, after losing its blood supply. Nearly 8 million Americans alive today have suffered at least one heart attack and so are at greater risk for chronic heart failure or another, potentially fatal, heart attack.
"Current treatments for cardiovascular disease prevent heart attack from occurring and/or alleviate its after-effects, but they do not repair the damaged muscle that results, leaving sizably dead portions of heart tissue that lead to dangerous scars in the heart," said cardiologist Joshua Hare, M.D., professor of medicine at The Johns Hopkins University School of Medicine and its Heart Institute, and lead author of the study to be presented at the American Heart Association's Scientific Sessions 2004 on Nov. 9.
"Damage done by a heart attack to heart muscle is really the cause of all the serious complications of the disease: Disturbances of heart rhythm can lead to sudden cardiac death and decreased muscle pumping function can lead to congestive heart failure," said study co-author and interventional cardiologist Alan Heldman, M.D., assistant professor of medicine at Hopkins, who performed the injection procedures. "Our aim is to find a way to repair the damage done to the heart muscle and prevent these complications."
In a controlled study of 14 pigs (whose circulatory systems are similar to humans), seven received therapy and another seven did not. The researchers found that injections of bone marrow, or "adult," stem cells directly into heart muscle, recently damaged by a heart attack, produced a nearly full recovery after a relatively short period of time, two months.
Recovery was measured for the seven treated animals as full restoration of heart muscle contraction to levels existing prior to infarction. Indeed, dead scar tissue nearly disappeared after therapy, which produced mostly healthy, normal-looking heart tissue and left only a small trace of the heart attack, the researchers said.
In contrast, for the seven animals in the control group that did not receive therapy but were injected, instead, with placebo, no recovery was observed and the animals' condition worsened, leading to the development of congestive heart failure within two months after heart attack.
In order to thoroughly cover the area of damaged heart muscle - approximately the size of a one-dollar coin - researchers gave every treated animal between 12 and 15 microscopic injections of adult stem cells, each injection containing nearly 200 million cells.
The cells were injected directly into the heart muscle using a specialized catheter inserted through a tiny puncture in an artery, a procedure similar to other cardiac catheterization techniques. Use of this catheterization technique was shown to be safe and effective. Its use increases the options for delivering stem cell therapy in the future; most existing studies use intravenous injections.
It remains unclear how or why the adult stem cells developed into new and healthy heart tissue, or exactly how long their healing effects last.
Adult stem cells were 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 and used 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 cell in the body from which all others grow and derive into the major specialized cell types of the body.
Using mesenchymal stem cells also avoided potential problems with immunosuppression, in which each animal's immune system might have attacked stem cells from sources other than itself. 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," added Hare.
"Among its many benefits are that adult stem cells are readily available, meaning they can be extracted from the patient, no donor is required, and the cells can be simply reproduced if more are needed. In our animal experiment, the treatment regimen was relatively simple, requiring only injection to the damaged tissue. The therapy was extremely effective, allowing for almost complete recovery, with no serious complications, such as immunosuppression, which is a problem in organ transplantation. Now, we need to see how it works in people."
According to the latest statistics from the American Heart Association, in 2001, 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 185,000 of all heart attacks were fatal. The AHA also estimated that 7,800,000 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.
This two-year study was funded by the Johns Hopkins Institute for Cell Engineering, the National Institutes of Health, and the Donald W. Reynolds Johns Hopkins Cardiovascular Center, and the National Institutes of Health. Further assistance came from Osiris Therapeutics, which developed a process for preparing mesenchymal stem cells and provided both funding and the lines of adult stem cells used for each animal involved in the study. Injection catheters were provided by Biocardia Inc.
Other investigators in this research, conducted solely at Johns Hopkins, were Luciano Amado, M.D.; Marcus St. John, M.D.; Anastasios Saliaris, M.D.; Jin-Sheng Xie, M.D.; Stephen Cattaneo, M.D.; Daniel Durand, B.S.; Torin Fitton, M.D.; Jin Qiang Kuang; Garrick Stewart, M.D.; Jeff Brawn, V.T.; Virginia Eneboe, V.T.; Stephanie Lehrke, M.D.; William Baumgartner, M.D.; and Bradley Martin, Ph.D.
Note to Broadcasters: A video news release is also available.
Distribution time: 2:45 p.m. ET, Friday, Nov. 5, 2004
Via Satellite: IA-5 (formerly Telstar 5), C-Band; Transponder: 23V; Channel 23
Audio: 6.2 & 6.8; Downlink frequency: 4160 MHz
(Abstract oral sessions: Regenerative therapies in ischemic and failing myocardium, Rooms 294-296, Ernest N. Morial Convention Center.)
Johns Hopkins Heart Institute: