Gene Therapy
Researchers gained insights in 1998 into a powerful new weapon against heart disease. They are using gene therapy to promote the growth of new blood vessels to bypass diseased ones in a process called angiogenesis. They have also evaluated gene therapy as a way to reduce the failure rate of cardiac bypass surgeries. The results are exciting.

Last year, Dr. Jeffrey Isner and his team at St. Elizabeth's Medical Center in Boston used gene therapy to grow new blood vessels in the legs of nine patients to bypass those obstructed by atherosclerosis. The scientists have since treated 20 more patients, with good results. Even more exciting, they used this technique to treat 14 men who suffer severe chest pains, called angina, because the blood vessels feeding their heart are choked due to plaque obstructions caused by atherosclerosis. All but one experienced a dramatic decrease in chest pain and required less angina medication. Many have been able to resume activities, such as swimming, that were impossible before treatment.

Gene therapy to grow new blood vessels in the heart. [Courtesy Dr. Jonathan Marmur, Mount Sinai School of Medicine].

In this experimental treatment, the researchers surgically inject copies of a special gene into the patient's heart muscle at the site of the blocked vessel. The gene "instructs" the heart cells to make a protein called vascular endothelial growth factor (VEGF). This protein makes new blood vessels grow to bypass the blockage.

Researchers in Germany are using a protein produced by genetic engineering to grow new blood vessels in the heart. Dr. B. Schumacher and colleagues at the Fulda Medical Center are injecting a growth factor called FGF-I into the heart muscle near the blocked coronary artery. In a study involving 20 patients, the researchers saw evidence that new blood capillaries (tiny, thin-walled blood vessels) had grown and were delivering more blood to the heart within four days of treatment. As a result, the patients' hearts grew stronger and were able to pump more blood to the body. All 20 patients were alive three years after treatment. At the present time, in a number of institutions in the United States and Europe, various forms of VEGF and FGF are being delivered via catheter directly into the coronary arteries without requiring any surgical intervention. The results of this simple delivery approach will be available within one year.

Up to half of all coronary artery bypass surgeries fail. In these surgeries, portions of veins are surgically inserted to bypass clogged blood vessels to the heart. Gene therapy shows promise of reducing this failure rate. Drs. Victor Dzau and Michael Mann at Brigham and Women's Hospital in Boston have developed a gene therapy technique that may prevent the growth of new cells lining the inside of these grafted blood vessels. The new cell growth is a fertile ground for the growth of the plaque obstructions that characterize atherosclerosis.

Thus far, the Boston researchers have investigated the gene therapy approach in preventing the growth of new cells in vessels grafted to bypass obstructed vessels in the legs of patients. Their next step is to evaluate this approach to reduce the failure rate of coronary bypass surgeries. Their gene therapy approach involves soaking the blood vessel prior to grafting with a short segment of DNA that blocks the genetic machinery needed to form the new cells.

Identifying Vulnerable Plaques
The coronary arteries (blood vessels feeding the heart) of most people develop some fatty deposits known as plaques. Plaques become a major concern when they grow large enough to obstruct blood flow to the heart, brain or other organs, or become fragile and prone to rupture. Plaques that rupture form blood clots that can break off and clog a vessel that feeds the heart or brain, resulting in a heart attack or stroke. Over the last few years, we have learned much about how plaques cause blood clots.

Not all plaques are equal. The most dangerous ones are soft and consist largely of a pool of cholesterol covered by a thin fibrous cap. The stress of blood flow can tear the caps and cause a blood clot. These plaques are often inflamed and the inflammation can further weaken the thin cap. However, the harder, more stable, calcium-rich plaques can also trigger a stroke or heart attack by blocking the flow of blood so much that blood pools behind it. Stagnant blood is more likely to clot.

Researchers at the Stanford University School of Medicine recently showed the importance of combining physical activity with a low-fat diet in the treatment of elevated LDL cholesterol levels.

Another common genetically influenced condition that determines how well individuals respond to a lower-fat diet is called "LDL subclass pattern B." About one in three adult men and one in five to six postmenopausal women have this trait.

LDL in the blood of people with this trait is transported in small, dense particles. These people also have elevated blood levels of triglycerides-fats in the blood that come from food. They also have lower levels of the protective cholesterol called high-density lipoprotein (HDL), which helps the body get rid of LDL cholesterol. People with LDL subclass pattern B are at higher risk for developing diabetes and heart disease. However, patients with pattern B respond much better to low-fat diets than do patients who have the larger, less dense LDL particles (pattern A trait).

Researchers at the Stanford University School of Medicine recently showed that a low-fat, low-cholesterol diet failed to lower LDL cholesterol levels in some men and women with high-risk LDL levels unless they also engaged in regular aerobic exercise. This finding highlights the importance of combining physical activity with a low-fat diet in the treatment of elevated LDL cholesterol levels.

Recent animal and human studies have identified genes-called the obesity genes and the diabetes genes-that are helping us understand the causes of and possible treatments for obesity. Leptin, a by-product created by one of the obesity genes, is a hormone that regulates food intake and body weight. A diabetes gene codes for the protein that forms cell receptors for leptin. Defects in the production of either protein may lead to a tendency toward weight gain and obesity.

These findings show that obesity-which is a major risk factor for heart disease, diabetes and other illnesses-often results from an inherited condition rather than from the patient's lack of willpower. Further research may lead to effective treatments for preventing and treating obesity.

How Low to Go
There is no longer any question about the health benefits of lowering high levels of LDL cholesterol through diet, exercise or drug therapy. But how low is low enough? Can LDL cholesterol be lowered too much?

An analysis of recent studies suggests that people who have heart disease should work with their physician to lower their LDL level to 100 mg/dl. Reducing it any further will not offer increased protection against heart attacks. Future studies, however, may show that lower LDL levels might provide increased benefits for some groups of people.

The Role of Inflammation
Evidence accumulated over the past year suggests that inflammation in the circulating blood may play an important role in triggering heart attacks and strokes by activating blood-clotting mechanisms, which in turn can slow down or stop blood flow. Inflammation is the body's natural response to injury and blood clotting is often part of that response.

During the inflammatory process, a substance-C-reactive protein-is produced in the blood. By measuring blood levels of C-reactive protein, researchers now have an important tool for studying the role of inflammation in heart attacks and strokes, since the amount of inflammation can be measured by the C-reactive protein.

A study this year by Dr. Paul M. Ridker and colleagues at Brigham and Women's Hospital showed that measuring C-reactive protein levels can help predict the risk of heart attack in postmenopausal women. Last year, the researchers showed that C-reactive protein was an excellent way to gauge the heart attack risk in a group of middle-aged men.

Inflammation can limit the effectiveness of clot-busting drug therapy, which is the first line of treatment for patients suffering a heart attack. Dr. Agha W. Haider at Boston's Massachusetts Veterans Research Center and colleagues at Hammersmith Hospital in London showed that heart attack patients with high levels of C-reactive protein respond more slowly to treatment with clot-busting drugs called thrombolytics.

The longer that blood flow to the heart muscle is cut off, the greater the damage to the heart. This study suggests that anti-inflammatory drugs may improve the effectiveness of anticlotting treatment in patients with high levels of C-reactive protein.

HEARTBEAT: A Heart Health Update
Page 3

Lives can be saved by
educating the public about
the need to seek prompt
emergency care at the
first signs of a heart attack.

Studies done in our laboratory, and in other laboratories, have shown that high cholesterol levels can cause an inflammatory response in the circulating blood. People who smoke cigarettes have elevated levels of C-reactive protein. Having increased inflammation in their blood may one of the reasons smokers are at a much higher risk of death from heart disease and stroke than nonsmokers. One the most remarkable findings reported at the American Heart Association's Scientific Sessions last year was from a University of Minnesota study of nearly 13,000 men in Europe, Japan and the United States. The study followed the men for 25 years and found that those who smoked fewer than 10 cigarettes a day had a 30 percent higher risk of death from heart disease or lung cancer than nonsmokers. Those who smoked 10 or more cigarettes a day had a whopping 80 percent higher incidence of death from these diseases. This is one of the most convincing studies to date measuring the deadly effects of tobacco.

Education Saves Lives
Another study conducted at the University of Minnesota showed that lives can be saved by educating the public about the need to seek prompt emergency care at the first signs of a heart attack.

The REACT study compared two communities, one of which had been exposed to an educational campaign about how to identify the first signs of a heart attack. Although the study was designed to compare the time it took for heart attack victims to seek emergency care, the researchers found little difference in the response time between the two communities. It did find that people in the educated community were much more likely to seek lifesaving care when they had a heart attack than people in communities with a lower degree of education. This study shows that teaching people about heart attacks can save lives.™

Dr. Fuster is director of the Cardiovascular Institute at Mount Sinai School of Medicine, New York, N.Y., and president of the American Heart Association.
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