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Common Drug Found to Repair Aortic Disorder

The discovery marks a breakthrough for those with Marfan syndrome. Human tests will begin.

April 07, 2006|Jia-Rui Chong | Times Staff Writer

A drug commonly prescribed for high blood pressure may be able to save lives by blocking the formation of lethal aneurysms in patients with Marfan syndrome, according to a report today in the journal Science.

Although the research was conducted in mice, it was so promising that the team will begin testing it in babies and children with the genetic disorder within a few months.

"This is a landmark discovery," said Dr. Alan C. Braverman, who heads the Marfan Syndrome Clinic at Washington University in St. Louis.

The drug, called losartan, prevented the abnormal growth that enlarges and stresses the walls of the aorta, the main artery leading away from the heart.

The enlargement leaves the aorta vulnerable to tears. Olympic volleyball player Flo Hyman and "Rent" playwright Jonathan Larson, among others, died when their Marfan-weakened aortas burst.

Researchers were excited because the drug not only stopped the abnormal growth of the aorta, but also repaired the fragmented structure, they said.

"This represents a potentially curative therapy, which is very different from saying, 'My patients won't get as bad as fast,' " said Dr. Craig T. Basson, director of cardiovascular research at Weill Medical College at Cornell University in New York.

The results could also apply to other diseases involving the aorta because many of them share the same biological mechanism, Basson said.

"I think this is one of the most important studies that has been published in the past, say, 10 years for individuals with aortic aneurysm disease," he said.

Marfan syndrome, an inherited disorder, affects 1 in 10,000 to 1 in 5,000 people worldwide. It weakens tissue that holds together skin, muscles and organs and is marked by tall stature, enlarged hands and feet, impaired vision and weakened arteries.

Left untreated, people with Marfan rarely live beyond their 30s. About 70% to 90% require surgery on their aortas at some point.

Surgery has helped Marfan patients live into their 70s, but it has not solved all their problems. Other parts of the aorta may enlarge, tear or rupture. When an aortic valve is replaced with an artificial valve, patients have to begin a lifelong regimen of anticoagulants, which can cause serious complications.

Many doctors now prescribe beta blockers, another heart medication, to treat some of the symptoms of Marfan. But though beta blockers slow the rate of aortic growth, they only delay the need for surgery.

The idea of using losartan (trade-named Cozaar) was spurred by the discovery about 15 years ago of the defective gene that causes Marfan, said Dr. Hal Dietz, a cardiologist and geneticist at Johns Hopkins University who led the current study.

Researchers engineered mice with the defective gene and discovered that the mutation also affected the regulation of a protein known as transforming growth factor beta, Dietz said.

This growth factor tells cells when to divide, where to migrate and when to die.

Researchers found that preventing the growth factor from binding to its target blocked many symptoms of Marfan in mice, and they suspected that losartan, which had already been shown to be safe in humans, could do so.

To test their hypothesis, Dietz and his colleagues observed three groups of mice with Marfan and one group without the disease.

One group with Marfan consumed losartan in drinking water. A second group was given beta blocker, and the third received a placebo.

The aortas in mice given losartan stopped growing and after six months were identical in size to aortas of the disease-free mice. Microscopic examination of the treated aortas showed that their walls had the same thickness and structure as those of healthy mice.

Beta blockers helped slow the growth and degradation but were less effective.

Losartan also affected other organs, improving the structure of the lungs in some mice and preventing emphysema-like symptoms.

Doctors cautioned patients against using the drug until the results were confirmed in a clinical trial.

But Dr. Reed Pyeritz, a medical geneticist at the University of Pennsylvania who has been following Dietz's research, said he had recently prescribed the drug to older patients who had already had heart surgery.

"They needed to be on blood pressure medicine anyway," he said. "And given a choice of blood pressure medication, why not choose losartan?"

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