Early Efforts at Avoiding Permanent Left Ventricular Remodeling Cover Story
Though reperfusion agents and balloon angioplasty help restore cardiac blood flow in the critical hours following myocardial infarction, there is still often residual tissue damage that can prevent full recovery of ventricular function. And for those who miss this 12-hour therapeutic window, the pathologic remodeling of the heart is well under way within a week, and well established within a month.
To try and reduce, and ideally reverse, such tissue damage in the first few days or weeks following MI, Cleveland Clinic cardiologists are now beginning to test several stem cell-based strategies. One of these, the RECOVER trial, is a phase I clinical trial that is testing whether injections of a drug, which causes a mobilization of stem cells from the bone marrow into blood, is safe and can lead to improved LV function following major heart attack. The other, which is still in pre-clinical testing, is looking at this same mobilization drug in combination with injections of myoblasts that have been genetically altered to overproduce the signaling protein that guides stem cells to damaged heart tissue. “Since restoring blood flow is not enough, we need to explore new strategies for achieving full cardiac recovery,” says Stephen G. Ellis, M.D., Director, Sones Cardiac Catheterization Laboratory at The Cleveland Clinic, and principal investigator of the RECOVER trial.
“Though stem cell mobilization occurs naturally after injury, for unknown reasons, the response following MI is underwhelming, with little functional impact,” says Dr. Ellis. “Our goal in the RECOVER trial is to amplify this weak response.”
Stephen G. Ellis, M.D.
In this ongoing, double-blinded study, patients who’ve had a large heart attack (LV ejection fraction less than 40%) within the last 48 hours are given subcutaneous injections of either placebo or granulocyte colony stimulating factor (GCSF), a mobilizing agent that increases the level of circulating stem cells by a factor of five within two days.
The patients are followed for one year, with their heart function assessed by echocardiography at 30 days and 12 months. Previous animal studies, as well as a European clinical trial (FIRST LINE) in which GCSF was administered to 26 patients with MIs, showed that such mobilization can lead to modest improvement in left ventricular function.
Just how stem cells may mediate this improvement is not well understood. Dr. Ellis and other investigators are considering additional mobilizing agents that may recruit a different subpopulation of stem cells, and are beginning to unravel the signaling cascade that directs stem cells to the infarct zone, as well as helps them transform or attract the other cells needed in the regenerative process.
One of those researchers is Marc S. Penn, M.D., Ph.D., a colleague of Dr. Ellis in the Clinic’s Department of Cardiovascular Medicine and Cell Biology. Dr. Penn has identified the gene that codes for one of the signaling proteins (SDF-1) that helps guide stem cells to damaged heart tissue. Unfortunately, after an MI, this gene is expressed for less than a week, and the homing signal it creates quickly fades.
Dr. Penn (right) and fellow Zhongmin Zhou, M.D.
In his pre-clinical studies, Dr. Penn has found a way to turn this homing signal back on. As described in his publication (Lancet, August 30, 2003), he takes myoblasts from leg muscle, genetically engineers them to overexpress this homing protein, then cultures those cells for four weeks until he has millions of them. Eight weeks after heart attack, those engineered cells are re-injected in controlled dosage with or without injections of the mobilizing agent, GCSF.
Animals receiving such treatment showed significant improvement in cardiac function (up to 90%) as well as neovascularization in the infarct zone. Dr. Penn is hoping to begin a phase I clinical trial of this novel therapy in the next year or so. Besides SDF- 1, Dr. Penn has recently identified two other families of genes that seem to play a role in creating the homing signal of damaged myocardial tissue. Pre-clinical studies of these new gene candidates lie ahead.
By better understanding how stem cells get recruited into the blood and directed towards damaged heart tissue, Drs. Ellis, Penn and others are beginning to find a way to extend the therapeutic window following MI, and more fully restore normal ventricular function.
Increased number of blood vessels (red-bordered objects) in the zone of damaged heart tissue after treatment with SDF-1 expressing cells. Treatment occurred two months after the heart attack. Heart function in the treated group was on average 83% better than untreated.
Area of damaged heart tissue five weeks after heart attack showing the presence of engineered stem cells that were infused one day after the heart attack. This picture also shows that these cells express proteins that allow for electrical conduction across the scarred tissue. Heart function in the treated group was on average 208% better than untreated.
For more information, call Dr. Ellis at 216/445-6712 or Dr. Penn at 216/445-1932.
