BETHESDA — It may be time for a retrenching in basic science when it comes to the use of stem cells to treat heart disease, prominent researchers said at a National Heart, Lung, and Blood Institute–sponsored symposium.
Dr. Stephen G. Ellis, section head of invasive/interventional cardiology at the Cleveland Clinic Lerner College of Medicine, reviewed a series of human trials in acute myocardial infarction and congestive heart failure. “The initial results are somewhat mixed, but they are promising,” Dr. Ellis said. The stem cells—technically, bone marrow–derived mononuclear cells—that were used in the studies have shown some utility in acute MI, but not as much in heart failure, Dr. Ellis said at the Symposium on Cardiovascular Regenerative Medicine.
In the acute MI trials, patients who improved most had left ventricular ejection fractions below the median at baseline, he said. And the improvement may even be sustainable over 5 years, Dr. Ellis said. There was a consistent reduction in the clinical end points of death, reinfarction, and heart failure in patients who had the bone marrow–derived cells injected into the myocardium. A meta-analysis of the published data showed an aggregate ejection fraction benefit of about 3.5%, compared with placebo.
The method of cell isolation and the timing of injections may influence results. Ongoing studies are comparing delivery times: several days post infarction versus several weeks, he said.
The unknowns are even greater when it comes to using the cells to treat heart failure, he said. First, the homing signal is weak at best, leaving little likelihood that the stem cells will reach the target cells. Even with acute MI, homing signals are present only for a week or two. Results of studies so far show that improvement in perfusion may be possible, but little is known about the best possible target population, the best cells to use, the optimum delivery method, possible side effects, and whether concomitant improvement in left ventricular function is possible, Dr. Ellis said.
Even so, “rather than calling a halt to clinical trials, we need to learn from one another.” Researchers should use animal models and basic models to come up with initial therapeutic impressions, and then move on to human phase I and II studies. But there should be careful reflection on those results and refinement of that knowledge before there is a move toward large-scale trials, he said.
Dr. Joshua M. Hare, director of the Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine, said that there are a lot of data yet to emerge from a slew of ongoing studies in various delivery methods and different cell types. “It is essential to continue with the clinical testing in parallel with the basic science testing. That's where we'll get the greatest bang for the buck,” he said.
Some researchers complained that trials are continuing with little basic knowledge about the various cells and with little characterization of what cells are actually being used. In many studies, the injections are a heterogeneous mix, not a homogeneous, pure therapy.
Dr. Martin Friedlander, a professor in the department of cell biology at the Scripps Research Institute in San Diego, was “flabbergasted” that thousands of patients had been enrolled in studies with “no clear rationale” and a lack of clarity on what cell types were being used. He suggested that scientists take a step back and determine more about the cells and their microenvironments, as well as further define the therapeutic goals.
Dr. Valentin Fuster, director of Mount Sinai Heart, New York, urged his colleagues to do more thinking. He said he would put more resources first into basic understanding, then into large animal studies, and finally into human trials.
But for Dr. Ellis, human trials are a public health imperative. “Whether it's a stem cell therapy or not, I think our patients deserve a trial to define whether or not there's benefit,” he said
Dr. Ellis disclosed that he had consulting arrangements with multiple companies, including Abbott Laboratories. No other researcher reported conflicts.