American Heart Association Announces Top 10 Research Advances For 1998 -- Gene Therapy Among The List

December 30, 1998

DALLAS, Dec 30 -- Gene therapy to grow new blood vessels to the heart, strong confirmation that "superaspirin" IIb/IIIa receptor blocker drugs prevent blood clots, the importance of inflammation throughout the blood in cardiovascular disease, and a study on the deadly effects of smoking fewer than 10 cigarettes a day are among the top 10 research advances in heart disease and stroke during 1998, says Valentin Fuster, M.D., Ph.D., president of the American Heart Association. The list, first created in 1996, recognizes achievements in basic and clinical research that may have the greatest impact in improving the prevention and treatment of cardiovascular disease, the nation's No.1 killer.

1. Gene therapy to create a "natural" bypass to circumvent plaque obstructions in the heart's blood vessels
In the next century many people with heart disease may be routinely treated with a genetically engineered therapy that induces the growth of new blood vessels to and from the heart. These new vessels would help restore blood flow to the hearts of people whose arteries are obstructed by fat-laden plaque. By impeding blood flow, these fatty obstructions can cause severe chest pain, heart attacks and strokes. Gene therapy may become an adjunct to other therapies for heart disease, which now include low saturated fat diets, exercise, smoking cessation, and, if appropriate, medications such as cholesterol-lowering drugs and the surgical procedures of cardiac bypass surgery and angioplasty. Gene therapy to create natural bypasses is described in research published this year in Circulation: Journal of the American Heart Association. This research was also presented at the 71st Scientific Sessions, AHA's largest medical conference, in November. "At the American Heart Association's meeting in 1997, scientists described very preliminary research findings that unlocked the door to using gene therapy for heart disease," says Fuster. "This past year, researchers opened that door." In February, 1998, German scientists reported in Circulation that they had used FGF-1, a human growth factor obtained through genetic engineering, to induce new blood vessels in 20 patients with heart disease. In their three-year follow-up of the patients, the scientists reported that the treatment resulted in a two to three times more blood flow to the heart. In November at the AHA's Scientific Sessions, three groups of scientists reported preliminary findings about another growth factor, VEGF, to induce blood vessels to grow at the heart. The approach of each of the three groups differs. Boston scientists injected the gene for VEGF directly into heart tissue. The New York City researchers attach the VEGF protein to a cold virus to speed the protein's entry into heart tissue cells. In Finland, scientists paired the gene therapy with angioplasty. "This is very exciting research but much more research is needed to verify and expand on these preliminary findings," adds Fuster.

2. "Super aspirin" does super job in fighting heart attack and stroke
Like aspirin, the drugs called platelet IIb/IIIa receptor blockers keep blood platelets from clumping and forming blood clots that can trigger a heart attack or stroke. However, the platelet blockers -- sometimes called "super aspirins" and sold under the generic names of eptifibatide, tirofiban and abciximab -- are more potent than aspirin. They are also administered through an intravenous "drip," or infusion. A report recently published in Circulation: Journal of the American Heart Association analyzed 16 studies of about 32,000 heart attack patients. Participants received the platelet blocker drugs as part of their treatment for either heart attack or severe chest pain. Some individuals in the study received only the platelet blockers while others were treated with one of the three drugs plus angioplasty -- a surgical procedure that uses a balloon-tipped catheter to restore blood flow in the blood vessel. Those who received the platelet blockers had a 30 percent reduced risk of all-cause death than those who did not receive the drugs. The individuals who particularly benefited from the drugs were those who also were treated with angioplasty. In these individuals the drug was administered just as the coronary arteries were being opened by inflation of the balloon-tipped catheters used for the procedure. Studies are now underway to test the combination of platelet blockers and clot-dissolving medicines in heart attack patients.

3. Inflammation and heart attacks
The American Heart Association recommends that people at high risk for heart attack and stroke take aspirin because research studies have shown that this low-cost, over-the- counter drug helps prevent the blood clots that can trigger heart attacks and strokes. Aspirin, however, may have another benefit for people at high risk for heart attacks and stroke. Aspirin is an anti-inflammatory drug, and recent research suggests that the body's inflammatory response to an unnatural condition in the body -- a virus or other microbe, high blood cholesterol levels, or cigarette smoking --may play a role in cardiovascular disease. In recent years scientists were intrigued by research showing that the area of the blood vessel where a plaque obstruction develops can become inflamed and that the inflammation can actually weaken the surface of the plaque obstruction, making it more prone to rupture which can cause a dangerous blood clot. "This year, the 'news' is that the inflammatory response is not only localized in the blood vessel wall," Fuster says. "It also can occur not only throughout the bloodstream." Systemic inflammation may explain the development of blood clots on top of relatively stable plaque obstructions, thereby causing the occlusions in the coronary arteries that trigger heart attacks, says Fuster. "The critical issue here is that blood components that are sensitized by inflammation have a greater tendency to initiate dangerous blood clots." When the body mounts an inflammatory response, it releases a substance called C-reactive protein into the bloodstream. Because the amount of C-reactive protein in the blood possibly correlates with the extent of the body's inflammatory response, many scientists regard this protein as a marker for inflammation and as a target for research to determine the role of infection and other factors such as high blood levels of cholesterol and cigarette smoking in the initiation and progression of cardiovascular disease. At the American Heart Association's Scientific Sessions in November, researchers reported that cigarette smokers have elevated levels of C-reactive protein in their blood. Scientists also presented research results showing that individuals who were suffering a heart attack and who had high blood levels of C-reactive protein had a slower than normal response to clot-busting drugs, which are frequently the first line of treatment for heart attack In a research paper published in 1998 in Circulation: Journal of the American Heart Association, scientists reported that women with the highest levels of C-reactive protein had a fivefold increase in the risk of developing heart attack and stroke and a sevenfold increase in risk for these diseases, when compared to women with the lowest level of C-reactive protein. In 1997 the same research group reported that C-reactive protein was a potent predictor of heart attack risk in healthy men.

4. Detecting people at risk for heart attack and stroke through non-surgical imaging technology
Most heart attacks and strokes are triggered by blood clots unleashed by plaque obstructions in the blood vessels. The clots, which are formed when the plaque obstructions rupture, block blood flow to the heart and brain, thereby causing a heart attack or stroke. This year scientists described research showing how magnetic resonance imaging (MRI) can detect plaque obstructions that are prone to rupture in the carotid artery, the blood vessel in the neck that supplies blood to the brain, and the thoracic aorta, one of the largest blood vessels that carries blood from the heart to the lower body. Their preliminary findings suggest that the MRI can be adapted to freeze-frame the beating heart so that "unstable" plaque in the coronary arteries also can be detected. If this imaging technology proves effective in identifying unstable plaque obstructions in the blood vessels, it will provide a way for cardiologists to diagnose people who are at high risk of having a heart attack or stroke and to initiate treatment to help stabilize the plaque obstructions or reduce the chances that a blood clot will form if a plaque ruptures. "This technology can change our approach to patient care," says Fuster.

5. Heart cells may recover as result of left ventricular assist device
This year, two separate groups of researchers published reports in Circulation: Journal of the American Heart Association indicating that the heart tissue of people with congestive heart failure can recover some of its function. In both studies, the "treatment" was the left ventricular assist device (LVAD), which takes over the pumping action of the heart for patients with severe heart failure who are awaiting heart transplantation surgery. In the first report, scientists described how some heart muscle cells, called myocytes, had recovered their ability to contract and relax as a result of the heart's being supplemented by the LVAD. The heart cells had been obtained from patients who had been on LVADs but who were given heart transplants. In the second study, scientists describe how they had weaned five patients from the LVAD. When they were placed on the LVAD, all had diagnosed irreversible end-stage heart failure. But their heart function was dramatically modified during the LVAD treatments. As a result, they did not need a heart transplant.

6. Tobacco's deadly effects: fewer than 10 cigarettes daily dramatically increase risk of death
"One of the most persuasive studies on the deadly effects of tobacco was reported at the American Heart Association's Scientific Sessions this year," says Fuster. In the study, about 13,000 men in the United States, Europe and Japan were monitored for 25 years. The scientists found that men who smoked fewer than 10 cigarettes daily had a 30 percent higher risk of death from heart disease or lung cancer than men of the same age who did not smoke. For men who smoked 10 or more cigarettes a day, the risk skyrocketed to 80 percent.

7. Impact of diet and exercise on blood cholesterol levels
New research has helped characterize people for whom a low-fat diet often is effective in lowering high levels of "bad" cholesterol (low-density lipoprotein, or LDL). "Interestingly, the individuals who seem to benefit most from the cholesterol lowering effects of a low-fat diet are those who are at the worst risk for heart attack and stroke," says Fuster. Research in 1998 suggests that people whose high LDL levels decline with a low-fat diet typically "make up a subgroup of those at risk because of specific genetic factors," explains Fuster. Studies showed that diet effectively lowers high LDL levels in people who have inherited the E-4 variant of the apolipoprotein E , a genetic variant associated with high LDL, or who have a form of LDL that is called "pattern B." In addition, people with "pattern B" LDL typically have low levels of "good" (high-density lipoprotein or HDL) levels, which can rise to normal levels as a result of diet. About 15 percent of the population have the E-4 variant and about 25 percent have "pattern B" LDL. Because diet can be effective in so many people, especially those at particularly high risk, it generally should be tried first before initiating cholesterol-lowering drugs, says Fuster. If LDL levels can not be reduced by diet, add exercise. That's another message of research this past year. Increased physical activity can enhance the effects of low fat diet in reducing LDL levels. "Exercise and diet should be paired," says Fuster.

8. Community education campaigns get more people to the emergency room
At the American Heart Association's Scientific Sessions in November, scientists described a study that examined the influence of community campaigns in educating the public about heart attack symptoms and the need for rapid action. The long-term goal is to reduce the time people delay seeking emergency care for heart attack because the quicker that people seek treatment, the greater their chances of surviving the heart attack and reducing damage to the heart. The study was conducted in 20 medium-sized cities in five regions of the country. Half of the cities were sites of the community education campaign. In the remainder, the educational program was not conducted. In the cities where the education campaign occurred, more people with heart attack symptoms came to the emergency department. There also was a 10 to 15 percent increase in the number of people choosing to call Emergency Medical Service (EMS)/911 for transport. In most U.S. cities, one-half to two-thirds of those with possible heart attack arrive in the emergency room by other means than EMS. "This study points out the importance of education and community campaigns in persuading people not only to arrive early in the emergency room but to seek medical attention in the first place," says Fuster.

9. Epidemic of cardiovascular disease and stroke
Following the federal government's lead, the American Heart Association has updated the way it computes age-adjusted death rates from heart attack and stroke, resulting in death rates that scientists say more realistically depict the true burden of cardiovascular disease. The new death rates are published in the AHA's 1999 Heart and Stroke Statistical Update, an annual report about statistics on cardiovascular disease that was released today. According to AHA's President Valentin Fuster, M.D., Ph.D., "The good news is that the new year brings a new formula for compiling death rates for cardiovascular disease that the AHA welcomes. The bad news is that it only reinforces how immense the burden of heart disease and stroke is on the public." To describe heart disease and stroke trends, health officials calculate statistics such as number of deaths, or mortality, and death rates. The death rate is obtained by dividing the number of cardiovascular disease deaths by the United States population. But because heart disease and stroke deaths increase dramatically at older ages, the death rates need to be adjusted for the aging of the U.S. population so they don't simply reflect the effect of an increasing number of older persons over time. Age-adjustment works like a currency so that different populations can be compared, or the same populations can be compared, over time to determine trends in diseases. The new age-adjusted death rates are adjusted to the age-distribution (number of individuals in each 10 year grouping) of the U.S. population in the year 2000 replacing the old standard that was based on the age-distribution of the 1940 population. Thus, the U.S. population projected for the year 2000 has many more older people than the 1940 population did. As a result, heart disease and stroke death rates adjusted to year 2000 are much higher than those adjusted to 1940 standard. The death rate from coronary heart disease, the cause of heart attack, was 187.1 people per 100,000 in 1996, according to the new death rate calculations. The "old" calculation using the 1940 population was 86.7 deaths per 100,000. The rate of stroke was 63.2 per 100,000 based on the population of 2000 versus 26.4 per 100,000 based on the "old" calculation using the 1940 population. For total cardiovascular disease, the new rate was 377.3 per 100,000 versus the 1940 rate of 173.5 "Compared to 1940, the population of the year 2000 will include almost twice as many individuals 65 years and older, an age range when heart attack and stroke are more likely to occur. Therefore it may seem as if death rates have jumped," says Fuster. "The number of deaths has been gradually increasing as the percentage of individuals over age 65 has increased. The increase in the number of senior citizens means more Americans are dying from heart attack and stroke than has been reflected in the 1940-based statistics," he says. "Equally important is the report that developing nations, including China and India, face an epidemic of heart disease and stroke that could devastate their economies," says Fuster. The report was published this past year in Circulation: Journal of the American Heart Association. The epidemic mirrors that of the United States and other industrialized countries 30 years ago. However, the industrialized nations have had both the means and the time to cope with their epidemics of heart disease and stroke. The developing nations have neither. This projected increased in cardiovascular disease will be economically disastrous to the developing world.

10. Nobel Prize for discovery of nitric oxide: present and future implications for treating cardiovascular disease and stroke
"The discovery of nitric oxide and its function is one of the most important in the history of cardiovascular medicine," says Fuster about the awarding of the 1998 Nobel Prize in medicine to three American scientists for their discovery of nitric oxide, a colorless gas that makes blood vessels dilate by relaxing the vessels' smooth muscles. Nitric oxide is a key component to blood pressure. Levels of nitric oxide normally rise when someone is in a stressful situation. A lack of nitric oxide in the bloodstream, or a lack of reactivity by the blood vessels to nitric oxide, can narrow the vessel, thus raising the blood pressure. High blood pressure, which affects 50 million Americans, is a major risk factor for heart disease and stroke. In the June, in Circulation: Journal of the American Heart Association, researchers at the National Heart, Lung, and Blood Institute published a study that found that the blood vessels of African Americans were less likely to respond to nitric oxide, providing a possible reason for why they are more susceptible to high blood pressure. "The role of nitric oxide and its derivatives in the future of therapy to lower high blood pressure and the recent development of the nitric oxide-like drug sildenafil, or Viagra, are examples of the hopeful future of nitric oxide research in cardiovascular therapy," says Fuster.
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American Heart Association

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