By Jennifer
Kahn
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Photographs by
Robert Clark
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As heart
disease reaches epidemic proportions
worldwide, researchers are moving away from
the old "clogged-pipes" model to search for
triggers lurking in our genes. |
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Cheeseburgers, smoking, stress, the rise of
the couch potato: These are the usual
suspects on the list of risk factors for
heart disease, a malady reaching global
epidemic proportions. Now discoveries about
genetic triggers may help us spot trouble
before it starts.
Gloria Stevens is lying on her back, sedated
but alert, staring at an image of her own
beating heart. Metaphorically, Gloria's
heart is the very core of her emotional
self—not to be worn on the sleeve, much less
displayed on an overhead monitor. More
literally, it is a blood-filled pump about
the size of a clenched fist whose rhythmic
contractions have kept Gloria alive for 62
years, and with a little tinkering will keep
her going for an indeterminate number more.
At this moment, her doctor is threading a
thin catheter up through her femoral artery
from an incision in her groin, on into the
aorta, and from there into one of the
arteries encircling Gloria's heart. At the
tip of the catheter is a small balloon. The
doctor gently navigates the tip to a spot
where plaque has narrowed the artery's
channel by 90 percent. With a quick,
practiced movement he inflates the balloon
to push back the artery wall, deflates the
balloon, then inserts an expandable stent—it
looks like a tiny tube of chicken wire—that
will keep the passage open. As Gloria
watches on the monitor, the crimp in her
artery disappears, and a wide laminar flow
gushes through the vessel, like a river in
flood.
The procedure is over. It has lasted only
half an hour. In all likelihood, Gloria will
be able to go home the next day. So will a
few thousand other patients in the United
States undergoing such routine
angioplasty—more than a million of them a
year. Pipe fixed, patient cured, right?
Wrong.
Because of her treatment, Gloria's quality
of life will likely improve. She'll breathe
easier and maybe live longer. But she is
hardly cured. Her coronary atherosclerosis—a
hardening and narrowing of the arteries that
supply the heart with oxygen-rich
blood—still leaves her vulnerable to future
blockages and coronary heart disease.
Although hearts suffer many maladies—valves
leak, membranes become inflamed—coronary
heart disease, which can lead to heart
attack and ultimately to heart failure, is
the number one killer of both men and women
in the United States, where 500,000 die
annually. Worldwide, it kills 7.2 million
people every year. Exacerbated by the export
of Western lifestyle—motorized transport,
abundant meat and cheese, workdays conducted
from the comfort of a well-padded
chair—incidence of the disease is soaring.
To help stem this lethal tide, cardiologists
can prescribe such cholesterol-lowering
drugs as statins to help keep arteries
clear. They can advise patients to change
their habits, or they can operate to fix an
immediate problem. Angioplasty is one
procedure, and surgery to bypass the
diseased arteries is another—each year more
than 400,000 bypasses are performed in the
U.S. Transplants can replace severely
damaged hearts, and artificial ones can keep
people alive while they wait for a donor
heart. But in the face of an impending
global epidemic, none of these stopgap
measures addresses the essential question:
Who gets heart attacks and why?
The human heart beats 100,000 times a day,
propelling six quarts of blood through
60,000 miles (97,000 kilometers) of
vessels—20 times the distance across the
U.S. from coast to coast. The blood flows
briskly, surging out of a ten-ounce (0.3
kilograms) heart so forcefully that large
arteries, when severed, can send a jet of
blood several feet into the air. Normally
the relentless current helps keep blood
vessels clean. But where an artery bends,
tiny eddies form, as in a bend in a river.
This is where bits of sticky, waxy
cholesterol and fat can seep into the artery
wall and oxidize, like butter going rancid.
Other matter piles up too. Eventually, the
whole mass calcifies into a kind of arterial
stucco, or plaque.
Until recently, cardiologists approached
heart disease as a plumbing problem. Just as
mineral deposits restrict the flow of water
through a pipe, an accretion of plaque
impedes the flow of blood through an
arterial channel. The more crud in the
system, the greater likelihood that a dammed
artery will trigger a heart attack. Doctors
now dismiss this "clogged-pipes model" as an
idea whose time has passed. It's just not
that simple.
Most heart attacks are caused by plaque
embedded within the artery wall that
ruptures, cracking the wall and triggering
the formation of a blood clot. The clot
blocks the flow of blood to the heart
muscle, which can die from lack of oxygen
and nutrients. Suddenly, the pump stops
pumping.
Contrary to the clogged pipes model, heart
attacks generally occur in arteries that
have minimal or moderate blockage, and their
occurrence depends more on the kind
of plaque than on the quantity. Scientists
have been struggling to figure out what type
is most responsible. Paradoxically, findings
suggest that immature, softer plaques rich
in cholesterol are more unstable and likely
to rupture than the hard, calcified, dense
plaques that extensively narrow the artery
channel. But understanding the root cause of
the disease will require much more research.
For one thing, human hearts, unlike plumbing
fixtures, are not stamped from a mold. Like
the rest of our body parts, they are
products of our genes.
Don Steffensen was putting duck-hunting
decoys out on a small lake one fall
afternoon in southwestern Iowa when his
heart attack hit. The infarction was massive
and unexpected. It's likely that Steffensen
survived only because a buddy was carrying
nitroglycerin tablets and quickly slipped
one under his friend's tongue. Nitroglycerin
is used to make dynamite; in the body, a
heavily diluted form releases nitric oxide,
which signals the smooth muscle cells in
veins and arteries to relax, dilating the
vessels.
The Steffensen clan is enormous: more than
200 relatives spread over three generations,
many of the youngest are now dispersed from
Iowa to New York and beyond. Although heart
trouble is common in the family, it had
never struck anyone as unusual. "I
attributed it to diet," shrugs Tina, a slim
38-year-old and the family's only
vegetarian.
It was a reasonable conclusion. The
Steffensens were raised on the kind of farm
food that the state is famous for—ham balls,
meatloaf, pie, macaroni and cheese—and still
popular even as careers have moved indoors.
Driving north through cornfields to meet
some of the family in Buffalo Center, I
dined at a restaurant offering deep-fried
sandwiches. A single ham and cheese
hoagie—dunked in hot fat and served
sizzling—seemed capable of stopping a heart
all on its own.
But could the high incidence of heart
trouble among the Steffensens be related to
something else besides high-fat diets?
Eleven years after Don's attack, his wife,
Barbara, happened to overhear a doctor
describing a study about the genetics of
heart attacks.
Curious, Don and 20 of his relatives each
sent a vial of blood to the Cleveland
Clinic, where the research was being
conducted. Eric Topol, a cardiologist and
genetics researcher at the clinic, spent a
year studying their DNA. Each person's
genome comes with millions of individual
variations, but Topol was looking for
something distinctive—and shared only by the
members of the clan with heart trouble. The
mutation he and his team finally spotted, in
a gene called MEF2A, produced a
faulty protein. "We knew we had something,"
Topol says. "But the question was: How does
this sick protein, present at birth, lead to
heart attacks 50 years later in life?"
Topol himself is as lean as a greyhound and
weathered in a cowboyish way. He talks
slowly and eats minimally: salads for dinner
and high-fiber cereal for breakfast. He
doesn't eat lunch at all. Like almost every
cardiologist I've talked to, he takes
statins preventively, and his cholesterol
count is a low 135. His children, 22 and 25,
also eat uncommonly well for their ages.
"People have looked at the cadavers of men
in their 20s who died in car accidents or as
casualties of war, and nearly all had
arterial cholesterol deposits," Topol said
as we walked to his lab. "This disease
starts much earlier than people realize."
Using endothelial cells (which line the
inside of the artery wall) grown in culture,
Topol set about figuring out what the
MEF2A mutation does. He and his
coworkers created some cells carrying the
Steffensen variant, and others with the
normal form of the protein. Both cell
proteins were tagged fluorescent green so
their locations could be visualized on a
computer screen. The resulting images
revealed a striking difference.
In a normal cell, all the MEF2A
protein was inside the nucleus; on the
screen, the cell resembled a fried egg with
a fluorescent green yolk. But in the cells
carrying the mutated version, the nucleus
did not glow; instead the cell membrane was
edged by a thin, luminous green line: a
layer of MEF2A protein, trapped where
it cannot serve its usual purpose. Topol
believes that this defect affects the
integrity of the coronary artery walls,
rendering them more vulnerable to cracking
when the plaque embedded in them ruptures.
And each crack brings an increased chance of
a heart attack.
Since this discovery, the Steffensens have
become famous, appearing on shows like 60
Minutes II. Their mutant gene turns up
in a Robin Cook novel titled Marker,
about a health insurance company in New York
that secretly screens patients for the
MEF2A mutation and then kills them to
preempt future medical-care payouts. Lively
reading, but the Steffensen gene is an
unlikely target for an insurance company, in
part because it is an uncommon genetic
defect.
Topol's study did find that although
dysfunctional MEF2A is very rare, the
chance of heart disease in those carrying it
may approach 100 percent. Most other genetic
variations identified thus far increase the
risk by much less. As it turns out, Topol
himself carries a bum gene: apoE4,
which affects inflammation in the arteries.
Unlike MEF2A, it is common; every
fourth person has it.
"Heart disease is not a one- or two-gene
problem," says Steven Ellis, a Cleveland
Clinic cardiologist who oversees a
10,000-person genetic study known as
GeneBank that collects DNA samples from
patients who enter hospitals with
atherosclerosis. Ellis, like most cardiac
researchers, suspects that dozens of genes
end up contributing to a predisposition:
Some affect arterial integrity, others
inflammation (which both causes and
exacerbates arterial cracks), and still
others the processing of lipids (the fats
and cholesterol that turn into plaques). Of
the several dozen genes, each may contribute
just one percent to a person's total risk—an
amount that may be compounded, or offset, by
outside factors like diet. As one doctor
told me, any person's heart attack risk is
"50 percent genetic and 50 percent
cheeseburger."
The point of tracking down all these small
mutations, Ellis explains, is to create a
comprehensive blood test—one that could
calculate a person's genetic susceptibility
by adding up the number of risky (and,
eventually, beneficial) variables. Combined
with other important factors, such as
smoking, weight, blood pressure, and
cholesterol levels, doctors could decide
which patients need aggressive treatment,
such as high-dose statins, and which ones
are likely to benefit from exercise or other
lifestyle changes. Some genes already can
predict whose cholesterol level will respond
strongly to dietary changes and whose won't.
Assessing risk is crucial, Ellis says,
because heart disease is often invisible. In
fact, 50 percent of men and 64 percent of
women who die of heart disease die suddenly,
without experiencing any previous symptoms.
Although standard tests can detect
atherosclerosis, they aren't foolproof. They
may reveal plaques, but give no indication
whether or not they are life-threatening.
Tests like angiography, for example, where
doctors inject a dye into the bloodstream
and track it with x-rays, can show how much
blood is flowing through an artery, but not
discern the plaques embedded inside the
artery wall—often the culprit in a heart
attack.
Researchers have been working to solve this
problem with scanners that provide pictures
of the arterial wall itself, but it's a
tricky task. Normal cardiac artery walls are
about a millimeter thick. Coronary arteries
move with every beat of the heart, 70 times
a minute. It's tough to get a clear image of
something so small in constant motion.
Difficult, but not impossible. As I walk
through the basement of the Cleveland
Clinic, I pass a room containing a large,
blue, plastic doughnut as tall as I am, with
a woman's legs sticking out of the middle.
The doughnut is a computed tomography (CT)
scanner, a kind of three-dimensional x-ray
machine that's also used for imaging tumors.
The scanner, aided by medications that
reduce a patient's heart rate and an
injectable dye that highlights the arteries,
can produce startlingly clear pictures.
Scrolling through images on his computer
monitor, Mario Garcia, the clinic's director
of cardiac imaging, retrieves one that looks
like a black-and-white landscape
photographed from a plane, with a single,
large river running through it. As Garcia
zooms in on the river, a series of white
lumps appears on the bank—hard plaques
bright with calcium. But there is also a
tiny black smudge. "That's the type we
believe causes a heart attack," he says with
satisfaction, pointing to the smudge of soft
plaque. "It's a rare opportunity to see
that."
As compelling as the CT scan is, it's still
an imperfect tool for predicting heart
disease. It's expensive, for one, and the
dose of radiation from the x-rays makes it
ill suited for use in healthy-patient annual
exams. And although it sees arterial
plaques, even soft plaques inside arterial
walls, it can't reveal whether those plaques
are likely to crack and cause a heart
attack.
Until there are tests, genetic or otherwise,
that give a clearer measure of risk,
everyone would be advised to exercise, watch
their diet, and take statins for elevated
cholesterol—the same advice doctors gave
when the clogged-pipes model of heart
disease reigned unchallenged.
At the Cleveland Clinic, cardiologist
Stephen Nissen has conducted several studies
on statins such as Lipitor, which reduce the
amount of LDL ("bad" low-density
lipoprotein) cholesterol made by the liver.
Nissen is an advocate of lowering
cholesterol by any means necessary. Does he
take a statin? "You bet!" he says. "I have
no intention of dying of the disease I
treat." His LDL level is a paltry 51. Of
eight cardiologists I spoke with, all but
one were taking the medication. (Some
studies now seem to show that lowering even
normal cholesterol levels has a protective
effect.) HDL ("good" high-density
lipoprotein) cholesterol is another story.
Nissen calls it the "arterial-wall garbage
barge" because of its ability to remove
cholesterol from clogged arteries. Not all
HDL can do this; some is dysfunctional. But
tests have shown that raising the HDL level
in genetically engineered lab mice can
shrink their arterial plaques.
A drug that could raise functional HDL
levels in humans would likely become the
next multibillion-dollar blockbuster, and a
few are in various stages of testing.
However, the trial of a Pfizer drug called
torcetrapib ended in failure. Torcetrapib
had been shown, in combination with Lipitor,
to raise HDL levels 44 to 66 percent with a
once-a-day pill. But the increase was not
necessarily in functional HDL, and the drug
was also associated with elevated blood
pressure. In December, when data showed a 60
percent higher death rate in patients taking
torcetrapib with Lipitor than in those
taking Lipitor alone, Pfizer abruptly ended
the trial.
It's not clear whether the problem lay with
one drug or an entire class of drugs. Until
further research is completed, the several
different statins on the market will remain
the most prescribed class of drugs in the
world, with 11.6 million prescriptions
filled monthly in the U.S. alone. Pfizer's
Lipitor may be the best-selling drug ever
made, with 12 billion dollars in annual
worldwide sales.
But statins, like any drug, carry the risk
of side effects: Muscle aches are a
well-known effect, and periodic blood tests
to check liver function are recommended. The
fact is, many of us just like to eat
cheeseburgers, watch television, and get
around in cars. And it's hard, says Leslie
Cho, director of the Cleveland Clinic's
Women's Cardiovascular Center, for a person
to worry about a disease that hits ten years
down the road—particularly since heart
patients, unlike cancer patients, can't
easily observe the progress of their
disease. "You've done damage over years, and
it will take years to undo that damage," she
says. "That's a very hard thing to sell to
Americans. We do what we can, but then
people go home."
The good news is that genetic research
continues to thrive. Should we want to, we
will soon be able to know the state of our
hearts—and our genes—in ever growing detail.
That knowledge, and what we do with it,
could make the difference between dying at
65 and living until 80. The choice,
increasingly, will be ours. |
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