What is the Best Way to Deliver Stem Cells to the Heart?

Three main techniques have been used to deliver stem cells to the heart. The simplest technique to introduce stem cells intravenously and hope that they will home to the heart and stay there. A more technically demanding way to introduce stem cells to the heart is to inject them into the wall of the heart. This method is called transendocardial cell injection, and it requires electromechanical mapping guidance (NOGA) in order to direct the surgeon to the site where the stem cells should be injected. Finally, stem cells are introduced to hearts by means of intracoronary delivery. Intracoronary delivery takes advantage of angioplasty technology to deliver stem cells through the coronary arteries where they move across the blood vessels and enter the heart.

Stem cell delivery by means of intravenous introduction has been shown in several studies to be extremely inefficient. The vast majority of the stem cells end up in the lungs, liver and the spleen and only a tiny, insignificant fraction goes to the heart.

The transendocardial injection method is the most difficult of the three methods, but it is also the most direct, since it deposits the stem cells directly into the cardiac muscle . This method requires special equipment and also increases the risk of rupture of the heart wall.

The intracoronary method was adapted from the same procedure that cardiologists use to implant stents. This procedure, known as percutaneous infusion (PCI), uses an over-the-wire technique to inflate the coronary artery nearest the damage, and then deposits the stem cells into the artery (see this video here). Because PCI has been used so much recently and because the technique has been greatly refined, stem cell delivery with this technology is second nature to many cardiologists. However, it does have some risk of causing narrowing of the artery (stenosis).

Which technique is better, transendocardial injection or intracoronary delivery? While some papers have compared the two procedures, there has been no randomized comparison with blinded endpoint analysis of the two techniques; until now.

In a paper published in the Journal of Cellular and Molecular Medicine by a Dutch lab at the University of Utrecht in the Netherlands, these two techniques were used to deliver stem cells to the hearts of pigs that had suffered heart attacks. The number of stem cells delivered in both cases were exactly the same, and the outcomes were compared and statistically compared. The stem cells were also labeled with a low-energy radioactive isotope so that they could be easily visualized in imaging experiments.

The results showed that both sets of pigs, which were given the stem cell treatments four weeks after the heart attack, improved about the same. Also the retention of stem cells in the heart was the same for both groups. The only difference was that the cells delivered by transendocardial injection tended to be clustered near the border of the infarct, but in the case of intracoronary delivery, the cells were spread throughout the heart muscle.

Also the safety profiles of both techniques were about the same, with the exception that the intracoronary delivery technique was easier and did not show the variation of the transendocardial technique, which is a much more difficult technique.

The authors conclude that both of these delivery techniques are feasible and safe. Furthermore, the conditions and cost of the techniques should determine which is used, since the safety and efficacy of the two is essentially the same.

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.”