RenKe Li MD PhD Richard D Weisel MD and Donald AG Mickle MD

Department of Surgery and Laboratory Medicine and Pathology University of Toronto Toronto, Ontario, Canada

AN ESTIMATED 465,000 PA-/%tients In the United States are diagnosed with congestive heart failure each year. For those patients with mild heart failure, medicine can often relieve their symptoms and improve their quality of life. However, for patients with severe heart failure, medicine may be insufficient, and heart transplantation may offer the potential for a better, longer life. Unfortunately, there is a limited supply of donor hearts, and less than 10 percent of patients needing a heart transplant will actually receive one.

This dilemma — what to do for patients with severe heart failure who are unable to receive heart transplants — stimulated our interest in heart cell transplantation, an exciting new field with the potential to improve the quality of life and lengthen the lives of patients who suffer from heart failure. We hope we can begin the first trials of heart cell transplantation in human patients within the next two years.

Ren-Ke Li

So far, our research group has succeeded in growing animal and human heart cells in cell culture, outside the body. It is a very painstaking and exacting process that was previously thought to be impossible. However, over the course of ten years, we have developed techniques that permit these cells to grow and reproduce in a culture dish while retaining most of the characteristics of heart muscle cells.

When transplanted into rat hearts that have been scarred by injury to the heart's main pumping chamber, the transplanted cells formed a block of muscle tissue within the scar tissue that can be easily identified under a microscope. Consequently, hearts that had been injected with the cultured muscle cells had better pumping function than those injected with only the solution the cells were grown in but not the cells themselves.

On the basis of this finding, we realized that injecting cultured heart muscle cells into an injured heart had the potential to restore function. However, we also found that the rats developed an immune response to the transplanted cells, which were taken from a different rat, and the cells were gradually destroyed over about six months.

To avoid this immune response, we have taken heart muscle cells from one animal, grown them in the laboratory, and transplanted them back into the same animal. These cells, because they are recognized by the animal as its own cells, do not cause an immune response and are not destroyed. Again, these transplanted heart muscle cells improved heart function and blood flow to that area of the heart.

Within the next one to two years, we hope we will be able to use a similar approach in human patients undergoing heart surgery. At the time of their heart catheterization, patients with poor heart function would have a very small amount of heart muscle tissue removed. This tissue would be grown in the laboratory over several weeks to obtain a much greater number of cells. Then, during heart surgery, the cultured heart cells would be transplanted back into the patient's heart. The resulting improved heart function will hopefully result in a greater exercise capacity, better quality of life, and longer life expectancy.

This form of therapy does not apply only to heart muscle cells. We have also examined the role of muscle cells from other parts of the body, the cells responsible for making fibrous tissue, and the cells that form blood vessels. When blood vessel cells were transplanted into the scar tissue, we found that the number of blood vessels in the area tripled.

Our research suggested that a combination of heart muscle cells, to improve heart function, and blood vessel cells, to improve blood flow to the heart, might be the best solution for failing hearts with inadequate blood flow. This is exactly the situation seen in many patients with advanced atherosclerosis.

We are also using our experience in culturing heart muscle cells to build a graft material that could be used to repair heart defects in children with congenital heart disease. The graft materials currently available for repair of these defects have no living cells and therefore do not grow after implantation. Inevitably, the child outgrows the graft and usually requires a second or third operation to replace it. Each successive operation carries a greater risk.

A graft that grows with the child and does not require additional operations would be a significant advance. We have been able to grow heart muscle cells in a three-dimensional mesh, which is gradually dissolved by the body, leaving only the cells. When this mesh is seeded with heart muscle cells and implanted into the legs of rats, the graft can be seen to beat rhythmically just like normal heart muscle.

We hope to someday build a graft that can be used to repair heart defects and that will grow with the child. Although much more work is necessary to develop this kind of graft, our initial results have been very encouraging.

Heart cell transplantation is an exciting new technology with the potential to improve heart function and blood flow in patients with advanced heart failure and extensive atherosclerosis. It may also lead to the development of living graft materials that can be used to repair heart defects in children, avoiding the need for second or third operations.

Sinoatrial Node

Right Atrium

Atrioventricular Node

The heart is composed of a special type of muscle fiber that is sensitive to electrical impulses, which cause it to contract. These impulses are generated in the sinoatrial node, then they travel to the atrioventricular node and then to the heart's ventricles. Disruptions in the heart's electrical system can be corrected with a variety of approaches.

Left Atrium

Bundle of His

Fig. 12.1

Right Ventricle

Left Ventricle

CHAPTER TWELVE

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