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U of U Physician, Arizona Researchers Find Critical Clue to Congenital Heart Abnormalities

July 22, 2002 — Researchers led by a University of Utah physician have discovered a key clue in what causes one of the most common congenital heart problems-defective valves.

The problem, atrioventricular septal defects (AVSD), occurs when the polysaccharide hyaluronan (HA), one of the most common substances in the body, is absent during the early stages of heart formation, the researchers say in the July 22 edition of Nature Medicine.

The discovery changes the fundamental understanding of how hearts are formed, said John A. McDonald, M.D., Ph.D., professor of internal medicine at the U of U medical school, chief of internal medicine at the Salt Lake City Veterans Affairs Medical Center and the project leader.

“We now have the potential to look at genes in patients who have these heart defects and see if they’re abnormal,” said McDonald.

The human heart comprises four chambers. The two upper chambers, or atriums, collect blood that flows into the heart. The lower chambers, or ventricles, pump blood back into the body. Four valves control blood flow between the chambers by flapping open and closed with each heartbeat.

In AVSD, the valves cannot control blood flow, which can result in too much blood in the lungs, weakened blood vessels, high blood pressure or other problems. AVSD usually must be corrected by surgery within the first few months of life.

McDonald, who came to the U in 2001 from the Mayo Clinic in Scottsdale, Ariz., began looking into HA’s role in disease and health in 1996. His research team discovered a family of genes responsible for HA production.

Using “knockout” gene techniques pioneered at the University of Utah by Dr. Mario Capecchi, they deactivated the principal gene for HA production in mice. They found that when HA is not present, the regions that form the septum and valves were absent in developing mice hearts.

Now, the group has shown that HA communicates with a family of receptors called ErbB, to play a critical role in heart-valve genesis.

“You need both HA and the ErbB system to build a normal heart,” McDonald said. “That was really a surprise.”

The next step for the researchers, according to McDonald, is to identify precisely how HA activates the ErbB receptor family. They also want to find out if HA plays a wider role in the formation of other systems or organs in the body.

The discovery of HA’s role also has potential significance for fighting cancer. ErbB2 is present in some breast cancers, and laboratory models have shown that HA engages ErbB2 in ovarian cancers. Thus, it’s possible an HA-related reagent might be able to inhibit cancer growth.

Along with McDonald, the researchers in the project include two postdoctoral trainees, Todd D. Camenisch and Joyce A. Schroeder, both from the University of Arizona; Judy Bradley from the Mayo Clinic in Scottsdale; and Scott E. Klewer, a pediatric cardiologist at the University of Arizona School of Medicine.