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Organ Replacement Technologies: A New Frontier: Cell Transplantation to Repair or Regenerate Injured Myocardium: A New Frontier in the Treatment of Cardiovascular Disease


Cell Transplantation to Repair or Regenerate Injured Myocardium: A New Frontier in the Treatment of Cardiovascular Disease

"The field of cellular transplantation has really come of age in the last couple of years," Doris A. Taylor, PhD, of the Division of Cardiology at Duke University Medical Center in Durham, North Carolina, told Medscape (personal communication, 2/12/03). "For many years, everyone thought it was science fiction, but in the last few years, it has really exploded due to the concept of stem cells, which have the potential to become more than they were designed to be." Unlike pharmacologic treatments that make healthy myocardium work better, myoblast transplantation has the potential to repair and regenerate damaged myocardium and, using the patient's own skeletal myoblasts, sidesteps problems of immune rejection.

As the technique of "cellular cardiomyoplasty" transitions from the bench to the bedside, unresolved controversies include which specific cells should be used and at what dosages, effects on myocardial electrical activity, long-term survival of implanted cells, and even whether transplanted myoblasts can improve contractile function vs just preventing further deterioration.[8] Possible effects of transplanted cells include alteration of the mechanical properties of scar tissue, secretion of factors affecting the scar or the myocardium, fusion with existing cardiomyocytes, or engrafting to become muscle and thereby contributing to contraction.

Although research suggests that autologous skeletal myoblasts are the best first-generation cells for cardiac repair, other candidates include cardiocytes and stem cells.[9] Ensuring improved contractile and electrical function rather than just preserving remaining cells may require engineered grafts, which facilitate nutrient delivery and blood supply in infarcted regions and protect against mechanical remodeling and decompensation.

Cellular cardiomyoplasty is now in phase 1 clinical trials. In a pilot study, 10 patients each received injection of 800 million myoblasts into injured, non-revascularized myocardium. At the 2.5-year follow-up, 1 patient had died, but most exhibited improved ejection fraction and regional wall motion (personal communication, 2/12/03). Success of cellular repair immediately after myocardial infarction may be very different from the results seen in cases of end-stage cardiac dysfunction. "It's an exciting time, but we need to do it right, not to overpromise," Taylor says. "We need to do it slowly, carefully and well so we don't become another gene therapy field."

Small Blood Vessel Replacement

Tissue engineering may also help develop cardiovascular substitutes, according to Dr. Nerem. "We're about 10 years away from seeing Food and Drug Administration-approved blood vessels," he told Medscape (personal communication, 2/14/03). "It's still a tremendous challenge, but there is a lot of exciting science taking place."

Earlier applications include the endothelial-seeded endovascular graft, which is too large in diameter for coronary vessels. Polymeric scaffolds developed in Japan are useful only for venous grafts. Researchers have sought the "holy grail" -- a small blood vessel substitute -- for half a century. Ideally, a small-diameter blood vessel resembles the native vessel it replaces, both mechanically and functionally.[10] Mechanical attributes include strength, viscoelasticity, and biomechanical compatibility with the patient's vasculature. Although several substitutes have sufficient burst pressure, lack of an elastin structure has thus far prevented exact duplication of native viscoelasticity. Functionally, the engineered vessel should have an "endothelial-like" lining capable of thrombogenicity and vasoactivity.

"The critical issue is the cell source, especially for the endothelial lining," Nerem says, adding that circulating endothelial progenitor cells are the most realistic source for autologous cells. "Off-the-shelf availability is what surgeons want. Long-term, allogeneic stem cells might be good, but immunologic intervention will be needed."

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