October 7, 1999
Sleuths Identify Prime Suspect: Inflammation of Artery.
Body's Efforts to Repair Irritated Lining of Vessel Can Backfire Disastrously
Plaques Burst Like Popcorn
mechanism of most heart attacks, in the popular view, is pretty clear. A
coronary artery is gradually narrowed by a buildup of crud as in a corroded
pipe, until finally, when the artery is, say, 80% closed, a small clot gets
stuck in it and shuts off blood flow to the heart. The more the artery is
narrowed, the greater the risk from a clot.
the popular view is wrong.
fact, about 70% of heart attacks are caused by much smaller obstructions, which
narrow the artery by perhaps only a third or so -- too small to cause symptoms
or to be detected by an X-ray angiogram. This is one reason for a dismayingly
common phenomenon: Someone comes out of a heart checkup with a clean bill of
health, and soon afterward has a severe or fatal heart attack.
in a flurry of new discoveries, some just emerging from academic and corporate
laboratories, researchers are beginning to explain why this happens. In the
process, they are unlocking secrets about the biological forces that ravage the
coronary arteries and producing new insights that could eventually transform
treatment of the West's deadliest disease.
entire understanding of what causes coronary atherosclerosis
is changing right before our eyes," says Paul Ridker
at Harvard Medical School.
hypotheses from these scientists are startling, and none more so than this: The
body's defense system -- there to protect it from harm -- is a key culprit in
heart attacks. It can cause small arterial deposits to suddenly rupture like
popcorn kernels, choking off the blood supply to the heart.
this could be so involves a concept that is at the center of the new research:
inflammation. Researchers believe that coronary-artery disease is an
inflammatory process, characterized by a decades-long cycle of irritation,
injury, healing and reinjury to the inside of the
certain circumstances, "the body's defense mechanism turns into a
betrayal," says Valentin Fuster,
director of cardiovascular research at Mount Sinai School of Medicine in New York.
notions have propelled research into the biology of atherosclerosis,
as heart scientists try to understand what makes plaques rupture and find ways
to identify and treat them before they do. It "isn't just sludge caking up
on the vessel wall," says Peter Libby, chief of cardiovascular medicine at
Harvard Medical School and Brigham and Women's Hospital.
"There is an inflammatory response," he says, that "alters the
biology of the artery wall and can make the plaque susceptible to rupture."
new research doesn't detract from well-known risk factors. On the contrary, it
bolsters arguments for controlling blood pressure and cholesterol, avoiding
smoking and adopting a healthier lifestyle. But the inflammation thesis is
opening up tantalizing new approaches to prevention and targets for treatment.
approaches would certainly be welcome. For all the progress that has been made,
heart disease kills nearly a million Americans every year, far more than any
other disease. About 1.5 million suffer heart attacks. Bypass surgery and
artery-opening technology such as angioplasty balloons and stents
-- anchors of a $200 billion industry to treat heart disease -- are very
effective in relieving its chief symptom, the severe chest pain called angina.
But they do almost nothing to arrest the disease itself.
the past decade, cholesterol-lowering drugs called statins have emerged as a
powerful weapon, with proven ability to prevent heart attacks, reduce the need
for bypass surgery and angioplasty, and save lives. But statins don't save
everyone. And in terms of knowing who is most at risk,
a cholesterol test, though a strong predictor, is far from perfect: Half of the
people who suffer heart attacks have "normal" cholesterol. In fact,
up to one-third don't seem to have any of the accepted risk factors.
new research could help. Dr. Ridker's work, for
instance, suggests that a test for signs of inflammation, if added to routine
cholesterol screenings, would greatly improve doctors' ability to detect heart
disease well before it reaches harmful advanced stages.
be sure, it's a long way from insight to proven hypothesis in medicine. And
while inflammation is the hot topic in cardiology, what it means is the subject
of contentious debate. One key question: Does the presence of inflammation
truly point to new treatment targets, or just reflect the effects of such
already-known risks as high cholesterol and smoking?
researchers wonder if more benefit might be gained by investigating causes of
the arterial injury rather than the body's response. In addition to
cholesterol, smoking and high blood pressure, potential culprits include
certain bacteria, viruses and high levels of a protein constituent called
the inflammation hypothesis is gaining influential converts. The pharmaceutical
industry is hunting for agents that might attack key steps in the body's
inflammatory response to artery irritation. And in just the past few months,
doctors at the renowned Cleveland Clinic have begun checking some heart
patients more aggressively for markers of inflammation that may indicate
heightened risk of more trouble.
most prominent in making the case for inflammation include teams led by
Harvard's Dr. Libby, Mount
Sinai's Dr. Fuster, and Russell Ross, a researcher at the University of Washington in Seattle, who was a longtime champion of the
concept until his death early this year.
picture that emerges from their labs as well as others is of a disease that
begins as early as adolescence with an initial irritation to the artery's inner
wall, called the endothelium. This sets off alarms summoning the immune system
and the broader inflammatory response, dispatching cellular soldiers to fight
the invaders and fix the damage.
the injury is a one-time event, this is no problem. The immune-system players
retreat, and the inflammatory response that accompanied their efforts recedes as well. But over decades, with persistent
irritation such as from high blood cholesterol or exposure to cigarette smoke,
this becomes chronic, and the body's repair machinery begins to run amok.
a smoldering process," says Dr. Libby. As it proceeds, "the normal
defense mechanisms get turned against you." For instance, an irritated
cell in the lining produces molecules that act like flypaper to attract the
beneficial repair crews. But over time, these stuck molecules become the
seedbed for eventual cholesterol deposits called plaques.
plaques grow slowly, probably through a helter-skelter series of small fissures
that rupture and heal over again and again. They amount to scar tissue on the
artery wall. And they house pools of cholesterol, which become covered by a
as these plaques mature, they may fill 70% or more of the blood vessel.
Obstructions this extensive are readily detected on an angiogram, and the
restricted blood flow may cause angina. But these plaques typically stabilize
and pose little risk of a major rupture.
contrast, younger plaques are soft, covered by a thinner fibrous cap and
contain a particularly rich lode of cholesterol, making them volatile. They may
narrow the artery by only 30% or 40%, and cause no symptoms. Because the vessel
wall often accommodates them by expanding outward, they also may go unnoticed
on an angiogram.
they rupture, however, they trigger massive, sudden clots that can fill up the
entire artery and cause a life-threatening heart attack. For patients, says Dr.
Ridker, the issue boils down to this: "Everyone
has atherosclerosis. The question is, do you have an
inflammation comes in again. One function of the body's repair system is to
clear cholesterol from the cells lining the artery wall, a role that falls to
cellular garbage trucks called macrophages. They swoop in and suck up the
cholesterol from the plaque and haul it away.
in a particularly fatty plaque, the immune-system macrophages can become
engorged with so much cholesterol that they can't do their job. They turn into
what scientists call foam cells -- because they become so laden with fat they
to perform their duties, they die. As they die, they add their contents to the
cauldron of plaque bubbling under the fibrous cap. And they release toxic
substances that lay the groundwork for the plaque to rupture.
of the toxic culprits they release, identified by Dr. Libby and his colleagues,
is a group of enzymes that attack the fibrous cap covering the plaque, chewing
up structural components and destabilizing it. That appears to make it
vulnerable to some other event -- like a stressful argument or strenuous
snow-shoveling -- that raises blood pressure and causes the plaque to break
open, spilling its clot-causing contents into the blood stream.
At Mount Sinai, Dr. Fuster
and his colleagues found that macrophages can do even more damage. It turns out
that they release another toxic substance in their death throes, called tissue
factor, which increases the tendency of blood to clot.
teamed up with Juan Jose Badimon, another scientist
in his lab, who invented a chamber that mimics conditions in which blood flows
through diseased arteries. When they used it to expose blood to plaque
specimens that were rich in tissue factor, they found the blood was
hyper-susceptible to clotting. Then they added to the blood an agent designed
to neutralize the tissue factor and ran it through the chamber again. "The
clot didn't take place," Dr. Fuster says.
results point to one of many targets that research into inflammation is
identifying for potential treatment to avoid heart attacks. They also
underscore a daunting challenge: Any new drugs will have to attack the harmful
effects of inflammation while preserving its important benefits.
of this offers a provocative hypothesis for how 70% of heart attacks happen.
But what about the other 30%?
the past two years, Dr. Fuster's group has devoted
some of their attention to this problem, and they are investigating whether
inflammation is at work here as well.
know that the high velocity of blood squeezing through narrowed arteries can
strip away the artery's lining, leaving nothing but hard tissue. For a clot to
form there, Dr. Fuster reasoned, the problem has to
be in the blood itself, not the vessel wall.
1997, he heard a report from Renu Virmani
of the Armed Forces Institute of Pathology in Washington, who had found that most victims of
fatal heart attacks not involving a ruptured plaque either were smokers or had
high cholesterol. Dr. Fuster decided to check whether
cholesterol or smoke in the bloodstream could prompt clotting. His team ran
blood from patients with high cholesterol through the Badimon
chamber. "It began to clot in 10 seconds," Dr. Fuster
Fuster thinks some interaction between certain cells
that are present in inflammation and the blood from these patients switches on
a clotting mechanism. As the blood moving through the artery hits the section narrowed
by a mature and stable plaque, it backs up and a clot forms, causing the heart
he and his colleagues found, when blood from the same patients was tested again
after they had taken statin drugs, very little
problem for both doctors and patients is that all of this
action takes place beginning years before symptoms appear. "The
Holy Grail of this field is to prevent the first heart attack from occurring at
all," says Harvard's Dr. Ridker. He and his
colleagues set out to use the inflammation research to find new indicators that
might widen the net for patients at risk.
problem for both doctors and patients is that a lot of this action takes place
beginning years before symptoms appear. "The Holy Grail of this field is
to prevent the first heart attack from occurring," says Harvard's Dr. Ridker. He and his colleagues set out to use the
inflammation research to find new indicators that might widen the net for
patients at risk.
way to answer this question resided in a basement underneath a Thai restaurant
on Boston's Commonwealth Avenue. There, stored in 60 stainless-steel
cylinders at 170 degrees below zero Fahrenheit, were blood samples taken in the
early 1980s from more than 22,000 doctors. This "Physicians' Health
Study" had already produced a landmark finding: that a low daily dose of
aspirin greatly reduced one's risk of a heart attack.
the preserved blood samples enabled Dr. Ridker and
his colleagues to travel back in medical time. They checked samples from 543
doctors who they knew eventually had heart attacks or strokes, to see what
their levels of C-reactive protein had been about eight years earlier. Another
543 were picked as controls.
a test much more sensitive than those currently on the market, they found that
men whose levels had been in the highest 25% when the study began were nearly
three times as likely to have a heart attack as those who had the lowest
levels. Moreover, those with high levels who also were taking aspirin -- which
happens to be an anti-inflammatory drug -- benefited more from this aspirin
than did men whose blood showed less sign of inflammation.
raised new questions: Can C-reactive protein be lowered with treatment, and
would lowering it mean that inflammation and heart-attack risk had also been
again Dr. Ridker looked to frozen samples, this time
from a study Bristol-Myers Squibb did to find out whether its statin drug, Pravachol, reduced
heart attacks and heart-related deaths (it did). Dr. Ridker
found that C-reactive protein declined 38% over five years in people given Pravachol. And those who started with the highest levels of
the protein showed the biggest reduction in heart attack risk.
effect was independent of any changes in cholesterol, suggesting that statins
have an anti-inflammatory effect that is protective, over and above their role
in lowering cholesterol.
Ridker says his work suggests that by combining a
sensitive test for C-reactive protein with standard cholesterol screening,
"you could do a very good job predicting over the next 10 years who is
going to have a stroke or heart attack." Maybe, he adds, "there is a
rationale for much more aggressive primary prevention based on evidence of
are doubters. Thomas Kottke of the Mayo Clinic warns
against thinking that just because certain patients have nice low levels of
C-reactive protein, they are less vulnerable to high cholesterol, smoking, lack
of exercise and a poor diet. "Those behaviors are associated with death --
I don't care what their C-reactive protein is," Dr. Kottke
Merck & Co., which sells two statin drugs, is so
intrigued that it has put an expert on inflammation in charge of its quest to
find the next big heart drug. And Bristol-Myers, in seeking ways to broaden use
of its own statin drug, is looking at arterial
inflammation and at C-reactive protein as a sign of it.
heart patients at the Cleveland Clinic are tested for the protein now.
"Once we started looking for it, we couldn't get over how frequent it
was," says Eric Topol, chairman of cardiology.
"We have all these patients with angiograms that
look benign and cholesterols that are normal. But they have high
Topol is trying to persuade the makers of the hot new
class of arthritis drugs called COX-2 inhibitors to test them in heart
patients. The drugs -- Celebrex from Monsanto Co.'s Searle unit, and Vioxx from Merck -- are anti-inflammatory
drugs that behave somewhat like aspirin but in a more targeted way. Officials
at Searle and Merck are interested but say that not
enough is known yet to warrant a trial.
other questions about inflammation need answers as well, and finding them is
likely to be a dominant theme of heart research for years to come. The case for
inflammation is "not fully proven," Dr. Topol
says. "But there's nothing more promising and exciting as the next
frontier in cardiology than this."
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