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Damaged heart? Grow around it!

Damaged heart? Grow around it!

(This article is scheduled for release in the January, 2005 issue of the Harvard Heart Letter. For more information or to order, please go to http://health.harvard.edu/heart.)

Researchers are racing to heal injured hearts by using stem cells from outside the heart, and maybe even ones inside it.

An idea that was mere fantasy just a few years ago - growing new tissue to replace damaged or diseased heart muscle - is now one of the hottest areas of on-the-horizon cardiology research. Teams around the world are trying to mend broken hearts by injecting or infusing primitive stem cells or muscle cells into the heart or by rousing the heart to repair itself.

Whether these efforts will pay off is anyone's guess. The researchers must work their way over daunting scientific, technical, and sometimes ethical hurdles. Despite the occasional scientist's overenthusiastic statement that such new therapy will be routinely used in five years, it isn't likely to get beyond clinical trials any time soon.

It is easy to see why researchers, cardiologists, and some businesspeople get excited about the possibility of growing new, healthy heart tissue. Take heart failure as a good initial application of this effort. Dead muscle and scar tissue left behind by a heart attack weaken the heart's pumping ability, making it difficult for the heart to deliver enough blood to meet the body's demands. About five million Americans have heart failure (23 million people worldwide), half of whom die within five years. In the U.S. alone, treating heart failure costs $40 billion a year.

Drugs and devices can ease symptoms and prevent heart attacks or sudden death by reducing the heart's workload, regulating its electrical signals, and even assisting with some of the pumping. What they don't do is reverse the damage. In theory, growing new, healthy tissue could give the heart the extra kick it needs and eliminate some expensive and not always effective treatments.

Salamander tricks

A number of so-called lower animals are able to repair serious damage or sprout new parts. Dice a flatworm, let the pieces grow, and you'll soon end up with dozens of identical flatworms. Salamanders that lose a tail or leg grow a new one. They can even replace a damaged or partially amputated heart. The zebrafish, a striped, 2-inch denizen of many fresh-water aquaria, can do the same neat trick.

Humans aren't nearly so plastic. To be sure, most cuts and scrapes heal perfectly. That's a simple but effective form of tissue regeneration. Our bodies can also repair damaged liver, bone, and muscle tissue. Blow out your heart, though, and your body could no more repair it than your car could fix its own flat tire.

Yet studies beginning in the early 1980s indicated that the heart may have some capacity for regrowth. This set off a trickle of research that has turned into a torrent of exploration.

Regenerating heart muscle

Adding stem cells

Stem cells (A) taken from bone marrow, thigh muscle, or the blood are infused or injected into damaged heart tissue. They take up residence (B) and grow into healthy heart muscle (C).

Waking up stem cells

Growth factors, hormones, or other substances (A) are infused or injected into damaged heart tissue. They stimulate dormant cardiac stem cells (B) to multiply and grow into healthy heart muscle (C).

Stem cells to the rescue?

Each of us begins life as a single cell. That cell becomes 2, then 4, 8, 16... At first, these cells are identical, and each has the potential to grow into a fully formed child. Gradually, though, small clusters of cells set off down separate paths, morphing into the 200 or so different cell types that make us "us". This process of specialization is known as differentiation.

Small populations of cells remain partially unspecialized. These are called stem cells. Given the right chemical and genetic signals, stem cells can develop into many different cell types. Some live in bone marrow. Others circulate in the bloodstream. And tantalizing research suggests that some sit quietly inside the heart.

Now that scores of animal experiments have shown that stem cells can be introduced into the heart, researchers have moved on to trials in humans. To date, more than 400 people have received stem cell injections or infusions (see figure). In general, the procedure improves the heart's ability to provide the body with oxygenated blood, and it may reduce the zone of dead or inactive tissue after a heart attack.

Immature muscle cells called myoblasts may be an alternative to stem cells captured from bone marrow or blood. Myoblasts are harvested from a marble-sized chunk of thigh muscle and allowed to grow and divide for a few days to increase their number. When injected into the heart, they adopt the characteristics of heart cells and begin to act like them.

Adding stem cells or myoblasts to the heart isn't entirely without risk. Even though they take up residence in the heart, they may not fit seamlessly into its precise architecture. This could interfere with the mustn't-fail electrical connections that keep the heartbeat steady. In fact, serious heart rhythm problems have developed in a few people who received stem cells or myoblasts.

Ethics and embryos

The most flexible type of stem cell comes from a fertilized egg that has divided a few times. All of the cells in this pinhead-sized ball, called a blastocyst, have the remarkable ability to form any tissue in the body. Because harvesting stem cells destroys the embryo, research involving embryonic stem cells has become entangled in the abortion debate.

The embryos used in this line of research come from fertility clinics, which create more fertilized embryos than can safely be implanted. The unused ones are stored in case the couple chooses to try to have another baby. Opponents say that the use of embryonic stem cells destroys human life. Supporters say that instead of discarding unused embryos, those donated by couples for stem cell research should be used instead to help cure a variety of debilitating diseases.

Grow yo ur own

Instead of injecting stem cells or myoblasts into the heart, a handful of teams are pursuing an even wilder idea - forcing the heart to repair itself.

Biologists and cardiologists have long believed that muscle cells in the heart, like nerve cells, don't divide and can't repopulate a zone of stressed, damaged, or dead tissue. Researchers have been chipping away at that notion for the past 20 years. We now know that nerves in the brain can divide and grow, and there is mounting evidence that heart cells can, too.

If there are, indeed, cardiac stem cells scattered through the heart, it may be possible to prod them into churning out legions of healthy cells that are programmed to live and work in the heart (see figure). Researchers are looking for drugs, growth-factor cocktails, and other chemical signals that might awaken dormant cardiac stem cells.

Another self-repair strategy revolves around an even more radical idea: coaxing some heart cells to regress to a stem-cell-like state and then stimulating them to make millions of young, healthy heart cells. Dr. Mark Keating, a cardiologist and molecular biologist at Harvard-affiliated Children's Hospital, and his colleagues turned back the clock for mouse muscle cells by bathing them in fluid extracted from regenerating leg of newt. The muscle cells lost their characteristic shape and properties and became like stem cells.

This approach isn't nearly as far along as stem cell therapy. But it could avoid some of the risks seen with implanted stem cells or myoblasts. That process is like "sending a chic urbanite to live with a primitive tribe in the Amazon - even if he managed to survive and adapt, he would always stand out," says Dr. Keating.

Trial time

Heart failure certainly isn't the only condition that might benefit from stem cell therapy. The approach is being tested for diabetes, Parkinson's disease, spinal cord injuries, Alzheimer's disease, and others. In the cardiovascular realm, researchers are trying to create personalized replacement heart valves covered with an individual's own stem cells. Stem cell injections are also being tested as a way to grow new blood vessels around blocked coronary arteries.

The field of cardiac repair is in its infancy. Early tests suggest that it's feasible to use stem cells or myoblasts to heal a damaged heart. What's needed now are long-term tests to show how safe and effective these strategies are, and whether it's possible to harness the heart's own regenerative powers.

Several clinical trials are already under way, and more are in the works. California's controversial initiative to fund a decade of stem cell research with $3 billion in state money will undoubtedly help spur this research forward.