Silent Time Bombs
The 'public health threat no one knows about'
Sixteen thousand times each year, someone in the U.S. dies suddenly and violently
when a bulge in the wall of their aorta — the major artery carrying blood from
the heart to the lower half of the body — rips open. Doctors call it a ruptured "triple-A," for
abdominal aortic aneurysm. Eighty percent of these aneurysms occur in men,
and the risk increases with age. While only 20 percent of AAAs occur in women,
they are more likely to die from a ruptured aneurysm or from complications
after surgery.
Vladimir Grigoryants, Derek Woodrum, Gilbert
Upchurch and Kevin Hannawa Photo: Martin Vloet |
The good news about aortic aneurysms is that they take years to develop and,
if detected before they become too large, can be repaired. The bad news is
that there are usually no symptoms or warning signs, and they aren't easy to
detect during a routine physical exam. Aneurysms are most often discovered
when they show up on a CAT scan or during an ultrasound exam for an unrelated
medical condition.
Gilbert Upchurch, M.D., an assistant professor of surgery in the U-M Medical
School, calls ruptured aortic aneurysms the "public health threat no one knows
about." "Only one in five patients with a ruptured AAA will live," Upchurch
says. "Fifty percent of them die before they even make it to a hospital. There
is no medical therapy. The only way to treat an aneurysm is to catch it early
and perform an elective repair."
The U-M Cardiovascular Center is a major referral center for repair of aortic
aneurysms. Depending on the size and location, the damaged area of the aorta
can be repaired with a conventional open abdominal operation or a less invasive
endovascular procedure where the physician threads a polyester tube, called
a stent-graft, through blood vessels to reinforce the damaged area of the aorta
from the inside.
When he's not in the operating room repairing aneurysms, Upchurch is in the
laboratory directing research aimed at finding answers to the many questions
about this dangerous condition. One of the biggest mysteries is what causes
aortic aneurysms in the first place.
"An aneurysm is an inadequate response to injury," Upchurch explains. "Something
happens to damage elastin fibers in the blood vessel wall and, for some reason,
the immune system's normal healing response doesn't work. Instead, the immune
system increases production of destructive enzymes called metalloproteinases
or MMPs. They eat away at smooth muscle cells in the wall of the aorta until
it starts to fall apart."
The constant stress of blood pounding against the bulging arterial wall is
a contributing factor, and people with high blood pressure are at increased
risk. Genetics plays a role, too. Aneurysms tend to run in families and, for
reasons scientists don't understand, women are more likely than men to pass
on the genetic mutations involved to their children.
Scientists working in Upchurch's lab have found an intriguing relationship
between a particularly nasty cell-digesting enzyme called MMP-9 and nitric
oxide — a molecule produced by cells lining the inside of blood vessels that
makes them relax to increase blood flow. In studies with laboratory animals,
U-M scientists found that reducing the amount of nitric oxide in the animal's
aorta caused levels of MMP-9 to increase. Giving extra nitric oxide made MMP-9
levels go down and prevented the formation of aneurysms.
"There's clearly a relationship here, even if we don't yet completely understand
it or know how to translate it to the human condition," Upchurch says. He is
currently testing an antibiotic called doxycycline, which also inhibits MMP-9s,
as a potential medical therapy to reduce the growth of aortic aneurysms in
humans. In future research, Upchurch also hopes to evaluate use of nitric oxide
as a possible treatment.
"If we can find a way to slow the growth of the aneurysm by 50 percent, that
could increase the length of time before the aneurysm must be repaired by three
to seven years," Upchurch says.
-SFP
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