Highly Regarded Cochrane Library Study Shows that Bone Marrow Treatments Help Heart Attack Patients

A whole gaggle of stem cells treatments for heart attack patients have been completed. Some patients are definitely helped, but others are not. Some clinical trials have shown a definitively positive effect from stem cell infusions in combination with standard care. Other trials, however, have failed to show any positive benefits to combining stem cell infusions with standard care. What do these clinical trials as a whole tell us?

This question is the realm of “meta-analyses.” While several clinical trials that have given stem cell treatments on heart attack patients have been subjected to meta-analyses, more stem cell trials have been completed, and further analyses are necessary. Meta-analyses take data from separately published studies that were conducted at different times and places and combine these data into a giant database that is subjected to rigorous statistical analysis. One organization that excels at meta-analyses, and has a solid reputation in the field is the Cochrane Library. The Cochrane Library has just completed a systematic meta-analysis of the data generated in 33 different clinical trials that used adult stem cells to treat the hearts of heart attack patients. The Cochrane Library’s analysis revealed that heart function definitely improves after stem cell treatments. However, these same analyses showed that the data are limited by the predominance of small trials and larger clinical trials are necessary to more rigorously demonstrate if the benefit of stem cell treatments in the heart actually means that the treated patients will benefit from a longer and healthier life.

Heart attacks are caused by blocked coronary arteries that prevent life-giving oxygen from flowing to heart muscle. This lack of oxygen causes the demanding heart muscle cells to die, and this cell death damages the heart and leads to the production of a scar that does not contract or conduct electrical impulses. Clinical trials have used adult stem cells from the patient’s own bone marrow to repair and reduce this damage. Although, unfortunately, this treatment regime is only available in facilities that have close links to medical research facilities.

The Cochrane Library authors (David M Clifford and colleagues), cobbled together data from as many clinical trials that used bone marrow stem cells to treat heart attack patients as they could find. In 2008, Cochrane reviewed 13 clinical trials to address this very question. However, since that time, 20 more clinical trials have been completed, and this year, 33 clinical trials that treated 1,765 patients were analyzed. Since the earlier trials continued patient follow-up, there are new data points from many older clinical trials that were also included. These data provide a more precise indication of the effects of stem cell therapy several years after completion of stem cell treatment.

In the analyzed trials, all 1,765 patients had already undergone angioplasty, which is a conventional treatment for heart attack patients. Angioplasty uses an inflatable balloon that is fed into the coronary artery by means of a fine catheter. This catheter is inserted into a large vein and guided by imaging methods to the blocked coronary arteries. Once in place, the balloon is slowly inflated to push the obstructing material to the sides of the artery. This opens up the blocked artery and allows the flow of blood to the heart muscle. To keep the blood vessel open, sometimes a stent is inserted into the blocked vessel. If angioplasty is combined with bone marrow stem cell treatments, the Cochrane reviews finds that such treatments can produce moderate long-term improvement in heart function that is sustained for up to five years. Unfortunately, there was not enough data to reach firm conclusions about increases in survival rates.

Senior author of this review, Enca Martin-Rendon, from the Stem Cell Research laboratory at the John Radcliffe Hospital in Oxford, UK, said, “This new treatment may lead to moderate improvement in heart function over standard treatments. Stem cell therapy may also reduce the number of patients who later die or suffer from heart failure, but currently there is a lack of statistically significant evidence based on the small number of patients treated so far.”

Will such treatments become part of the treatment for a heart attack? At this point it is difficult to say with any certainty. It is simply too early to establish guidelines for standard practice, since several labs have used differing transplantation and cell isolation and storage methods. According to the Cochrane Review, further work is required to properly standardize the procedure. For instance, there is little agreement on the dosage of cells for the heart, even though several studies have shown a dose-specific effect. Secondly, a standardized protocol for when after the heart attack treatment should be given, and what methods most accurately measure heart function must be constructed before such a procedure is universally offered to patients. Martin-Rendon noted, “The studies were hard to compare because they used so many different methods. Larger trials with standardized treatment procedures would help us to know whether this treatment is really effective.

A larger trial is already in the works, since the task force of the European Society of Cardiology for Stem Cells and Cardiac Repair received a recent, sizable grant from the European Union Seventh Framework Programme for Research and Innovation (EU FP7-BAMI) to initiate such a large trials. The Principal Investigator for this trial (called BAMI) who is also a co-author of this review, Anthony Mathur, said, ”The BAMI trial will be the largest stem cell therapy trial in patients who have suffered heart attacks and will test whether this treatment prolongs the life of these patients.”

Mouse Heart-Specific Stem Cells Potentially Offer Hope For Heart Attack Patients

Biomedical researchers from the University of California, San Francisco (UCSF) have published a stem cell experiment in mice that might provide another way to fix damaged heart muscle in heart attack patients. If these results pan out, they could potentially could increase heart function, minimize scar size, promote the growth of new blood vessels around the heart, and doo all this while avoiding the risk to tissue rejection.

Sounds too good to be true? It was published in PLoS ONE. You can read about it here.

To summarize the experiments, researchers isolated a new heart-specific stem cell from the heart tissue of middle-aged mice. When cultured in a laboratory dish, the cells had the ability to differentiate into heart muscle cells that beat in the culture dish. However, these same cells could also become blood vessels, or smooth muscle, which surrounds blood vessels and regulates the diameter of the vessels. All of these tissues are essential for the heart to work and properly function.

After showing that these cells could be grown in the laboratory in converted into heart-specific cell types, this research group examined the ability of these cells to do the same thing inside a living organism. After expanding the cells in culture, they transplanted them into the hearts of sibling mice that had the same genetic lineage as the mice from which the heart stem cells had been isolated in the first place. This prevented the possibility of the immune system of the recipient mice from attacking and rejecting the implanted cells. The implanted stem cells made blood vessels and also formed smooth muscle. The increased blood flow improved heart function.

Even more exciting, these heart specific stem cells are found in all four chambers of the heart. The “cardiosphere-derived cells” (CDCs) that have been used in other clinical trials are only found in the upper chambers of the heart (atria), and express slightly different cell surface proteins. When grown in culture, these cells grow into spheres of cells that are known as “cardiospheres.”  These new heart-specific stem cells are more widely located in the heart, which means that it is possible to isolate them from patients’ hearts by doing ventricular or atrial biopsies. Biopsies of the right ventricle are among the safest procedures for procuring heart cells from live patients. This procedure is relatively easy to perform and does not adversely affect the patient.

The paper’s first author, Jianqin Ye, PhD, MD, senior scientist at UCSF’s Translational Cardiac Stem Cell Program, said, “These findings are very exciting . . . we showed that we can isolate these cells from the heart of middle-aged animals, even after a heart attack. . . we determined that we can return these cells to the animals to induce repair.”

Senior author Yerem Yeghiazarians, MD, director of UCSF’s Translational Cardiac Stem Cell Program and an associate professor at the UCSF Division of Cardiology, agreed with Ye’s assessment: “The finding extends the current knowledge in the field of native cardiac progenitor cell therapy. Most of the previous research has focused on a different subset of cardiac progenitor cells. These novel cardiac precursor cells appear to have great therapeutic potential.”

Yeghiazarians hopes that those patients who have suffered severe heart failure after a heart attack or have enlargement of the heart (cardiomyopathy) could still be treated with their own heart-specific stem cells to improve their overall health and heart function. Because these cells would come from the patients, there would be no concern of cell rejection after therapy.

These heart-specific stem cells are also known as Sca-1+ stem cells. Sca-1 is a small cell surface protein that is involved in cell signaling. These heart-specific Sca-1+ cells also express a transcription factor called Islet (Isl-1). These cells are known to play an important role in heart development. Most of the previous research on heart stem cells has examined different subset of cells known as “c-kit” cells. Sca-1+ cells, like the c-kit cells, are located within a larger clump of cells called cardiospheres.

To isolate the Sca-1+ cells, Yeghiazarians’ group devised ways to separate the Sca-1-expressing cells that were also expressing high levels of Isl-1. Sca-1 is rather easy to use for isolation, since it is a cell surface protein, but Isa-1 is a nuclear protein and is less useful for isolation purposes.

Yeghiazarians proposed that the co-expression of these two molecules that are also made during heart development suggests a strategy for heart therapy: “Heart disease, including heart attack and heart failure, is the number one killer in advanced countries. It would be a huge advance if we could decrease repeat hospitalizations, improve the quality of life and increase survival.” By giving the heart cells that are extremely similar to those cells that help construct it during development; those same cells could reconstruct the heart when it starts to fail.

More studies are on the board for the future, and these animal studies might lead to future clinical trials.