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Doernbecher Children's Hospital Patients Help UCSD Find Genetic Time Bomb in Heart

   Portland, Ore.


Each year, thousands of children undergo corrective surgery for congenital heart malformations that improve the immediate function of the heart. However, surgical correction of certain forms of congenital heart disease may not fix the underlying molecular trigger that drives progressive heart failure and sudden death later in life, according to new research from the University of California, San Diego (UCSD) School of Medicine. Over time, a genetic time bomb that causes structural abnormalities at birth, continues to degrade vital heart systems, eventually disrupting the electrical impulses that control the heartbeat.

Now, researchers have determined where and how this progressive heart failure occurs in patients with familial forms of congenital heart disease called atrial septal defects, even after the malformation is surgically corrected. The researchers believe that their findings could, potentially, apply to other forms of congenital heart disease, as well.

In a study published in the April 30 edition of the journal Cell, the investigators used mouse and human subjects to determine that genetic defects in a gene called Nkx2-5, which is critical for embryonic heart formation, continue to exert their detrimental effects over time by degrading the electrical wiring of the heart, in particular, the heart's atrioventricular (AV) node (which normally conducts electrical impulses between the upper and lower chambers of the heart), and by encouraging excessive overgrowth of heart tissue.

According to the March of Dimes, congenital heart defects, which are structural problems present at birth, are the most common birth defect in newborns. Atrial septal defects are sometimes called holes in the heart. A defect between the heart's two upper chambers (the atria) occurs in the septum, the wall that separates the heart's left and right sides. The most common treatment has been surgery to close the hole.

"People have thought that congenital heart disease is cured by surgery, which is true for the short term," said the study's senior author, Kenneth Chien, M.D., Ph.D., professor of medicine and director of the Institute of Molecular Medicine at UCSD. "If a child is born with a hole in the heart, it can be patched. However, as these patients survive, it is now clear that there is an intrinsic, progressive problem with the heart that makes them get late stage heart failure and in certain cases, sudden death due to cardiac electrical problems."

One of these patients was Dennis Appel of Vancouver, Washington who was born with an atrial septal defect in 1970. Although surgery at age 5 repaired the structural defect, he experienced irregular heartbeats in his 20s and had a pacemaker implanted when he was 22. Unexpectedly in 2001, at the age of 31, he suffered from a severe arrhythmia, or irregular heart rhythm.

According to his wife, Vicki, "he seemed fine. Then, he moaned and slumped forward on his stomach. When the paramedics came, they tried CPR because they heard a rhythm. But it turned out to be the pacemaker, which was working fine. Dennis was dead."

Appel was a member of a large Oregon family where multiple generations had inherited atrial septal defects, causing advanced AV node malfunction, and in some of the family, unexpected death. Heart tissue samples from affected family members who had a known defect in the Nkx2-5 gene were studied by researchers at Oregon Health & Science University (OHSU) in Portland and the Imperial College and Royal Brompton Hospital in England, in conjunction with the UCSD research team. A characteristic pattern of disease in the electrical system of the heart was found.

"This family almost uniformly had surgeries to correct the structural defects," said Michael Silberbach, M.D., a Doernbecher Children's Hospital cardiologist, OHSU Heart Research Center scientist and one of the authors of the paper in Cell. "Then, over a period of several years, they developed problems with the conduction system - the electrical system in the heart."

Silberbach and another co-author, Siew Yen Ho, Ph.D., were able to compare the human-patient results with the studies in mice by Chien and his team. The UCSD mice, which were created without Nkx2-5 in specific compartments of the heart, were shown to have significant deterioration of their AV nodes. This included an under-formed AV node and disorganized cellular tissue, as compared to normal mice. Similar AV node deterioration was seen in the human patients. Also similar in both mice and humans was a progressive, massive overgrowth of cardiac muscle as they aged.

"With these studies, we learned that Nkx2-5 is critical not only for heart formation, but also for maintenance of heart function," Chien said. "It also showed us that our mouse model closely resembled the human disease and therefore was an ideal experimental animal model for studies of this form of congenital heart disease caused by the Nkx2-5 mutation."

To determine what was causing the excessive overgrowth in the hearts of Nkx2-5-deficient humans and mice, the UCSD researchers began a search for genes changed by the deficiency. They utilized DNA microarrays, which track the expression - the turning on and off - of thousands of genes in a single, high-speed test, and used computer technology to compare the results to large 30,000 gene databases that were generated from multiple other forms of heart muscle disease. What they found was a growth-factor gene called BMP-10 that was expressed 500 times higher in Nkx2-5-deficient mice, as compared to normal mice, and the gene was unique to this specific form of congenital heart disease. Normally, BMP-10 is only active during fetal heart development, not later in life.

The team went on to engineer animals that have high levels of BMP-10 growth factor in the heart and observed the same form of heart disease found in Nkx2-5 deficient mice and in patients that harbor mutations in this gene.

Because the AV node is under-formed in the Nkx2-5-deficient mice, when the animal grows and there is excessive expansion of the heart muscle due to BMP-10 expression, the small AV node is unable to keep up with the growth. The result is a mismatch between the AV node electrical switch and the surrounding cardiac muscle, causing the AV node to deteriorate.

"Because a major portion of the muscle defect is due to BMP-10, we will conduct further tests to see if blocking the persistent expression of this single growth factor will have an effect on the late stages of cardiac dysfunction, including the excessive overgrowth of the heart and the potentially deadly arrhythmias," Chien said.

He added that there are other forms of congenital heart disease, with other mutated genes, that are linked to late stage arrhythmias in heart failure, in spite of surgical corrections.

"We think we may have uncovered, conceptually, the mechanistic paradigm for this important form of human heart failure," Chien said. "Further work is ongoing to determine whether it may hold to be true for other forms of congenital heart disease, and to see if blocking the activity of the BMP-10 growth factor might have a therapeutic effect in halting the onset of the massive cardiac over-growth and associated conduction system disease."

In addition to Chien and Silberbach, the study was conducted by co-first authors Mohammad Pashmforoush, M.D., Ph.D. and Jonathan T. Lu, M.D., Ph.D., both with the UCSD Institute of Molecular Medicine; and by Hanying Chen, Ph.D. and Weinian Shou, Ph.D., Indiana University of Medicine; Tara St. Amand, Ph.D., Richard Kondo, Ph.D., Sylvain Pradervand, Ph.D., Sylvia M. Evans, Ph.D., James R. Feramisco, Ph.D., Wayne Giles, Ph.D., UCSD Institute of Molecular Medicine; Bob Clark, Ph.D., University of Calgary, Canada; Siew Yen Ho, Ph.D., Imperial College and Royal Brompton Hospital, London, England; and D. Woodrow Benson, M.D., Ph.D., University of Cincinnati, Ohio.

The study was funded by the National Heart, Lung and Blood Institute.

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