Various methods of myocardial regeneration are now under investigation, including the use of cardiomyocytes, bone marrow, and embryonic stem cells, and in this series, the patient's autologous skeletal muscle myoblasts. Some of the problems in obtaining and using these other types of cells are avoided: autologous skeletal myoblasts can be easily obtained, extracted from a muscle biopsy, and then expanded in culture, and finally reinjected into an area of myocardial infarct.

Preclinical studies, such as those done by Dr Doris Taylor (Duke University Medical Center, Durham, NC), have shown the myoblasts do differentiate into cells that resemble myocytes and that they form fibers, induce angiogenesis to provide a blood supply, and improve function and contractility within infarcted tissue.1

Questions remain though, Siminiak noted, about how the cells couple with surrounding cardiomyocytes, and there is no evidence of the formation of gap junctions.

After phase 1 clinical results on a series of 10 patients were reported by a French group led by Dr Phillipe Menasché (Hôpital Bichat, Paris, France), Siminiak and colleagues undertook a phase 1 clinical study of their own in 10 patients with previous MI. As Menasché's group had done, the Polish researchers injected the cells directly into scarred tissue while the patient's chest was open during bypass surgery, choosing an area of the infarction that would not be revascularized by the procedure.

Injected segments had been shown to be either akinetic or dyskinetic on dobutamine stress echo. Patients at relatively low risk were purposely selected, and each received about 20 million cells.

Siminiak reported 1 death that occurred 7 days postoperatively. Autopsy revealed a new site of infarction in a part of the left ventricle that had previously been normokinetic. "This gives us and our ethical authorities the hope that this is not related to the procedure," he said.

Arrhythmia is 1 theoretical problem with this intervention, Siminiak said, and in fact, their first 2 patients experienced sustained ventricular fibrillation (VF) postoperatively. Both were treated with oral amiodarone, which was discontinued by 5 months. After these cases, they began using a prophylactic infusion of amiodarone in all further patients, and there were no subsequent episodes of arrhythmia, he said.

Follow-up dobutamine stress echo showed an increase in contractility in several injected segments, he said. While an assessment of efficacy was clearly not the aim of this study, Siminiak confessed he was "unable to resist" showing a slide illustrating that ejection fractions have risen in all 9 surviving patients.

The invited discussant for the paper was Menasché, whose group reported the first use of this approach in humans in 2000 and last year reported results in their first 10 patients at the American Heart Association Scientific Sessions 2001.

Menasché congratulated Siminiak on this series but addressed 3 points of concern. The first, he noted, was the fact that about half of the segments injected were only dyskinetic, while in these preliminary experiments, the most appropriate target is probably the akinetic fibrous scar.

"Because CABG is still required ethically, we must make sure there is no mixing of the effect of revascularization," he said. He also advised that more cells be injected. About 90% of cells die almost immediately. Such a small number of surviving cells would be unlikely to affect function. In a new phase 2 trial, Menaschésaid, patients are being randomized to a "low dose" of 400 million cells and a "high dose" of 800 million cells.

Finally, Menasché discussed the arrhythmias seen in the Polish series, noting that the occurrence of sustained VF postoperatively "matched exactly our experience."

"I think we must be honest about these cases, and some are probably related," to the treatment, he said.

Some investigators have put forward the idea that all patients receiving these transplants should also have an ICD implanted, he noted, but if the results of MADIT-2 are widely adopted, many of these patients will have ICDs anyway.

Nevertheless, with the caveat about arrhythmia, the technique is safe, Menasché concluded, and asserted that "the time has come for a randomized trial, which is scheduled to begin in the next week and will hopefully give us some answers as to whether or not skeletal myoblast transfer can or cannot improve function," for these patients.

Target enrollment for the trial is 300 patients, he said. Siminiak also noted they will shortly begin a phase 2 trial.