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.

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