Last year the American Heart Association reported the good news that the
death rate from heart attack, stroke and other cardiovascular diseases had
dropped 20 percent in the past decade-thanks to advances in research and
remarkable progress in the treatment and prevention of these diseases. Despite
this progress, heart attacks remain the number-one killer of Americans, strokes
the number-three killer. The World Health Organization predicts heart disease
will be the leading cause of death and disability worldwide by the year
2020. Gene Therapy 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. 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. 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. New medical imaging techniques for finding vulnerable plaques-those prone to
rupture and form a dangerous blood clot-may soon be available. Patients who have
been diagnosed as having vulnerable plaques are treated to reduce the changes
that blood clots can form, if indeed their plaques rupture. My colleagues and I at the Mount Sinai Medical Center found that strokes can
be triggered by soft plaques in the aorta, the main artery in the chest. It was
already known that strokes can result when the carotid arteries-the blood
vessels in the neck that transport blood to the brain-become so large that they
vibrate in the turbulent blood flow. When the turbulence and vibrations become
severe enough, a tear in the artery can occur. That tear can launch a blood clot
to the brain. Our own research has shown that magnetic resonance imaging (MRI)-a diagnostic
technique that can create detailed images of the body without surgery-can
painlessly distinguish the most vulnerable plaques in the aorta. MRI allows us
to see not just the size but also the composition of the plaques. We may soon be
able to do the same for arteries that supply the heart. The great challenge for
looking at coronary arteries with MRI has been to freeze the motion of the
beating heart. We have developed techniques that for the first time have allowed
us to see coronary artery plaques with MRI. Researchers elsewhere are testing other imaging techniques for detecting
vulnerable plaques. For example, Dr. James E. Muller at the University of
Kentucky in Lexington is testing an infrared (heat-seeking) sensing device on
the end of a catheter for analyzing the chemical composition of plaques. The
method is a variant of a technique that NASA scientists used to analyze rocks on
Mars. Understanding Genes, Physical
Exercise and Diet 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 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 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. Lives can be saved
by 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 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.
by Valentin Fuster,
M.D., Ph.D.
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.
Gene
therapy to grow new blood vessels in the heart. [Courtesy Dr. Jonathan
Marmur, Mount Sinai School of Medicine].
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.
Figure 1 (left): Magnetic
resonance coronary images obtained without any dye injection, shows a
blockage (arrow) in the left coronary artery. Figure 2 (right): Magnetic
resonance images of the aorta which is the main artery that carries blood
from the heart to the body. The high resolution images of the top portion
of the aorta, reveal the makeup of the plaque (arrow) such as cholesterol
deposits, calcium, and blood clots or thrombus (T). [Courtesy Dr. Zahi A.
Fayad, Mount Sinai School of Medicine].
We have begun to unravel the
mystery of why some people with elevated blood cholesterol levels seem to be
helped by eating a low-fat diet, while others do not. For many, the differences
appear to be inherited. About one in seven people in the United States have a
gene that makes a variant of the protein apolipoprotein E (apoE), which is a
"ferry service" for transporting fat through the bloodstream. Individuals with
this protein tend to have elevated levels of low-density lipoprotein (LDL, or
the "bad cholesterol") and are at increased risk of developing heart disease.
Those with this gene variant respond well when they consume a low-fat diet.
However, people who have the "normal" gene variant, called apoE3, show much less
reduction in LDL levels when they adhere to a low-fat diet.
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.
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?
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.
educating the public about
the need to seek prompt
emergency care at
the
first signs of a heart attack.
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.