Embryonic stem cell therapy show benefits in rebuilding damaged heart

Aug 18 2004

Despite improvements in earlier diagnosis and treatment, cardiovascular disease is far and away the leading cause of death in the U.S. and the world.

According to the latest posted statistics, heart disease causes 700,000 deaths in the U.S. each year, with the number of adults diagnosed with heart disease exceeding 23 million, or 11.5% of the adult population.

Previously thought of as concentrated in rich countries, ischemic heart and related cerebrovascular diseases alone caused an estimated 17 million or 23.2% of deaths globally in 2000, WHO reported.

A contributing cause of what some have called a pandemic is that in contrast to many other organs in the body, the heart has only a minimal capability for self-renewal, leaving most current therapies to address symptoms with little hope of rehabilitating the injured heart itself after a heart attack (myocardial infarction).

The regenerative potential of stem cells in relation to the muscle layer of the heart wall (or myocardium) has been recently recognized, but how this might translate into therapeutic uses to repair the heart has been limited.

Mayo Clinic team demonstrates potential for “rebuilding” damaged heart

Using embryonic stem cells, Mayo Clinic researchers transformed these master cell types into fully functional cardiac cells and transplanted them into damaged regions of the myocardium, where the cells integrated into the infarct and showed rapid and robust improvements, which were stable over an extended period post-therapy.

The study, entitled “Stable benefit of embryonic stem cell therapy in myocardial infarction,” appears in the August 2004 edition of the American Journal of Physiology-Heart and Circulatory Physiology, one of 14 peer-reviewed journals published by the American Physiological Society.

The investigative team under the direction of Andre Terzic included Denice M. Hodgson, Atta Behfar, Leonid V. Zingman, Garvan C. Kane, Carmen Perez-Terzic, Alexey E. Alekseev, and Michel Puceat, all of the Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota. In addition, Perez-Terzic is at Mayo’s Department of Physical Medicine and Rehabilitation, and Puceat is also at Centre de Recherches de Biochimie Macromoleculaire, CNRS, Montpellier, France.

Researchers took a murine embryonic stem cell line and engineered a cell clone to express fluorescent proteins so they could easily identify the location of the “newly” generated cardiac cells. They tested the cardiogenic capacity of the line and collected cells with high potential for becoming cardiomyocytes. Randomly assigned rats that had been induced with myocardial infarction were injected directly into the damaged heart area either with the embryonic stem cells or were subject to a control or “sham” protocol.

Three weeks after therapy, the cardiac contractile function of both groups was tested by echocardiography. Not only was the stem cell-treated group’s left ventricular pumping significantly stronger than the sham-treated group, but the heart beat of the stem-cell group reacted favorably to “stress test,” whereas the sham group showed no significant response at all.

Like all the other parameters, these improvements were maintained over the three-month length of the study.

On pathology, further investigation showed the extent of the positive influence of the stem-cell therapy. First, cardiac cells stayed in the heart, and didn’t spread to the brain, kidney or liver. Microscopy showed that the stem cell-derived cardiomyocytes took on the distinctive striations indicating proper development of contractile apparatus. Stem cell-treated hearts also showed normal cardiac ultrastructure, in contrast to acellular infarct areas of sham-treated hearts.

Finally, the stem cell-treated hearts showed that the wall or muscle had been “rebuilt” compared with the sham-treated hearts which remained “eaten-up”, with a decayed thin look, including formation of aneurysms, associated with a post-heart-attack liability to rupture. Conversely, the stem cell-treated hearts showed no evidence of graft rejection, electrical and/or structural abnormality, sudden cardiac death or tumor formation.

The researchers conclude that “embryonic stem cells, through differentiation within the host myocardium, can contribute to a stable beneficial outcome on contractile function and ventricular remodeling in the infarcted heart.”

Going a step further, they add that “the stable benefit of embryonic stem cell therapy on myocardial structure and function in this experimental model supports the potential for stem cell-based reparative treatment of myocardial infarction. By regenerating diseased myocardium and promoting cardiac repair, embryonic stem cells provide a unique therapeutic modality that has the potential to reduce the morbidity and mortality of this prevalent heart disease.”

Looking ahead, they noted that issues to be resolved include mechanisms of action, finding the optimum window for therapy, and determining what the long-term effect of such therapy will be.