Battle of the Bulge
School of Medicine surgeons pioneered minimally invasive treatment of aortic aneurysms. But could drug therapy prevent them entirely?
“ Early on, Dr. Sicard recognized and fully embraced the potential of this ‘crazy idea’ of sliding a new lining into the aorta. If it wasn’t for his foresight, we would be caught way behind the curve .”
Brian G. Rubin, MD
“In 1976, I told my chief I was developing a new system that could eventually be used under local anesthesia to replace the huge, stressful repair operation. Initially, the idea wasn’t taken seriously at all, and after my first presentations, I was verbally attacked.”
Juan C. Parodi, MD
WHEN THE AORTA , the body’s central lifeline, weakens and swells dangerously, this aneurysm can grow life-threatening. If it bursts, the circulatory system will drain within minutes. The patient has only a 20 percent chance of reaching the hospital alive; half of those who receive treatment will survive.
The School of Medicine’s section of vascular surgery, directed by Gregorio A. Sicard, MD, head of the division of general surgery, has advanced a technique called endovascular repair for preventing these aortic ruptures. Researchers also are investigating whether drug treatments could one day prevent aortic aneurysms.
Endovascular repair offers a far less invasive alternative to open surgery, and the surgeons of the vascular surgery section are leaders in its use.
“Endovascular treatment of aortic aneurysms is one of the greatest innovations in vascular surgery in the last 30 years,” says Sicard.
The technique uses a collapsible synthetic graft that is threaded into the aorta from the iliac arteries of the legs. Once in place, the graft is deployed, expanding to the width of the healthy aorta and bridging the distended portion. Because the aneurysm is accessed through the iliac arteries, the procedure requires only small incisions near the groin.
“Early on, Dr. Sicard recognized and fully embraced the potential of this ‘crazy idea’ of sliding a new lining into the aorta,” says Brian G. Rubin, MD, associate professor of surgery, who practices in the vascular surgery section. “If it wasn’t for his foresight, we would be caught way behind the curve.”
Before endovascular repair came on the scene, surgeons had to open patients’ abdomens or chests to replace aneurysmal sections of the aorta with sewn-in grafts. But in 1990, Juan C. Parodi, MD, treated the first patient with the new approach in Buenos Aires, Argentina.
Parodi met with great resistance when he first proposed the technique because it was a radical departure from established procedure.
“In 1976, I told my chief I was developing a new system that could eventually be used under local anesthesia to replace the huge, stressful repair operation,” Parodi says. “Initially, the idea wasn’t taken seriously at all, and after my first presentations, I was verbally attacked. But then I met Greg Sicard who said, ‘Continue with it. I think it is going to have a big future.’”
Parodi, now a vascular surgeon on the Washington University faculty, was vindicated in clinical trials, and endovascular devices were FDA approved in 1999. Parodi’s endovascular system is used to treat 80 percent of patients at the School of Medicine with aneurysms large enough to pose a danger. Instead of open surgery with its risks and long recovery period, patients can go home the day following treatment.
Ninety percent of aortic aneurysms occur in the lower abdominal section of the aorta. Much of this section lies below the point where smaller arteries branch off to carry blood to the kidneys. So most endovascular repairs use a fairly simple graft having a large “body” section for the aorta and two smaller “legs” that extend down into the iliac arteries.
But recently it has become possible to apply endovascular repair to parts of the aorta higher in the abdomen and even up into the thorax.
“The newest endovascular devices allow us to work further and further up the aorta where it has branches that go to the kidneys, thorax, arms, heart, neck and head,” says Luis A. Sanchez, MD, associate professor of surgery. “It’s important not to cover the branches with the grafts, so these new grafts have complex sets of fenestrations and tubes to accommodate the upper regions.”
Because of the number of branches in this region of the aorta and the structural differences between patients, it takes detailed imaging studies and careful planning to create custom grafts for upper abdominal and thoracic aortic aneurysms. Now the next wave of physicians, including Sanchez, is training to use these grafts to repair aneurysms in the upper aorta.
On another front, physicians hope to do away with grafting by preventing aneurysms or halting their expansion while too small to do harm. They are studying the molecular mechanisms involved in destruction of the aortic wall.
One of the most important of these components is elastin, the most abundant protein in the aortic wall. As its name suggests, elastin allows the aorta to stretch and return to its original shape with each heartbeat.
“There’s a loss of elastin in normal individuals as they age,” says Robert W. Thompson, MD, professor of surgery. “But in aneurysms the loss of elastin becomes more accelerated and more severe.”
Enzymes that break down elastin have been found in abnormally high amounts in aneurysms. One in particular, an enzyme called matrix metalloproteinase-9 (MMP-9) has emerged as a major subject of study.
Work by Thompson and John A. Curci, MD, assistant professor of surgery, showed that the antibiotic doxycycline, a member of the tetracycline family of drugs, inhibits the activity of MMP-9 in mice and humans and suppresses the formation of aneurysms in mice. Preliminary human studies have shown promise in reducing the rate of aneurysm expansion.
Even at this early point, however, as information about the effect of doxycycline has spread, many doctors are already prescribing the drug to aneurysm patients in hopes of stopping progression of their disease.
Doxycycline also may increase the effectiveness of endovascular repair grafts, which can shift position if the aorta dilates over time. The researchers are now completing the first study testing this hypothesis.
“Expansion of the neck of the aneurysm where the graft touches it may be related to the same process that caused the aneurysm to grow in the first place,” Thompson says. “So Dr. Curci and I are studying whether systemic as well as local delivery of doxycycline could stabilize aneurysm growth. That could lead to a doxy-cycline-eluting graft that would prevent future aortic expansion.”
Thompson is also investigating other promising treatments for the prevention of aneurysms including statins, frequently used to treat atherosclerosis and high cholesterol, and curcumin (turmeric), the anti-inflammatory ingredient in curry.
Yet one of the best known ways for people to decrease the risk of developing an aneurysm is to not smoke. Smoking dramatically increases the incidence of aneurysms, and Curci is looking into the cause.
“The puzzle is what’s the connection between what’s inhaled in the lungs and what’s happening in the aorta,” Curci says. “In my lab, we are trying to sort out what change occurs as the result of smoking that leads to aneurysmal degeneration.”
Curci also leads a research project that investigates why smooth muscle cells decrease in number in aneurysmal tissue. Evidence suggests that aneurysms contain their own unique subtype of smooth muscle cells that contribute to the disease.“At the School of Medicine, we are on the front lines of dealing with aortic aneurysms,” Curci says. “We can treat them with surgical and endovascular techniques. But because we also conduct research, we can bring clinical practice and research together to create really interesting new ways of considering the disease and its treatment.”