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Tiny bits of RNA give window into adult congenital heart disease in Stanford study

MicroRNA in the blood holds clues to heart problems in adults born with tetralogy of Fallot, a type of congenital heart disease, Stanford research shows.

Measuring tiny bits of genetic material in blood can provide a unique view into the development of heart failure in a specific group of patients, according to new Stanford Medicine research.

The technique also has the potential to help scientists identify new targets for drugs that treat problems with the muscle on the right side of the heart, which existing heart medications do not help.

The study, published recently in PLOS ONE, focused on adults with tetralogy of Fallot, a form of congenital heart disease. Born with a combination of four structural heart defects, these patients generally receive cardiac repair surgeries early in childhood. Though very effective, the surgeries are not perfect. Years later, many tetralogy of Fallot patients experience heart problems that can lead to a failing heart and damage to other organs if not caught early.

"Because of the amazing success of surgical interventions and catheterization techniques, it's now expected that tetralogy of Fallot patients will live to adulthood," said Chad Weldy, MD, PhD, the study's first author and a fellow in cardiovascular medicine at Stanford. "But then they're facing a whole new world of other complexity."

Heart failure in early adulthood

As adults, patients with tetralogy of Fallot continue to need ongoing monitoring, such as that provided by Stanford's Adult Congenital Heart program. By their twenties, 40% of these patients have problems in their heart's right ventricle, the pumping chamber that sends blood through the lungs, Weldy said. This is often caused by malfunction of the pulmonary valve at the exit of the right ventricle.

When the pulmonary valve malfunctions, patients may experience enlargement of the right ventricle and develop such symptoms as shortness of breath, poor exercise tolerance, swelling in their legs and feet, and liver and kidney damage.

Current monitoring techniques such as echocardiograms are less than perfect, Weldy said. What's more, if not detected early, right heart failure is more difficult to treat. When the right ventricle fails, existing heart medications -- which target the left side of the heart -- don't help.

"The right ventricle is a different system," Weldy said, noting that experts have discovered important biological differences between the muscle cells on the two sides of the heart.

Clues from microRNA

In the new study, Weldy and his colleagues measured tiny pieces of genetic material called microRNA in patients' blood, in an effort to secure more information about the development of problems in the right ventricle. MicroRNAs help regulate gene activity. The blood samples came from 20 adults with surgically repaired tetralogy of Fallot, all of whom also had heart echocardiograms performed at the time of the study.

From the echocardiograms, the researchers classified four participants as having normal-sized right ventricles, 11 as having mild to moderate enlargement of the right ventricles, and 5 as having severe enlargement.

The patients' microRNA profiles correlated with the amount of right ventricular enlargement. The profiles also gave more granular information than echocardiograms, suggesting different degrees of severity among patients who were classified by echocardiogram as having mild-to-moderate ventricular enlargement.

This is exciting because patients in this category currently fall into a diagnostic grey area, and it would be helpful for them to have more information about how quickly their hearts might fail, Weldy said.

"If we're trying to decide, say, when a patient should go through surgery for pulmonary valve replacement and the microRNA profile suggests something concerning is happening, we would maybe intervene sooner," Weldy said. Larger studies to validate the concept are needed, he noted.

Insights into the heart

The microRNA profiles also held clues as to which metabolic pathways go awry in patients whose right ventricles fail, a hopeful sign for scientists who want to better understand the mechanics of this type of heart disease.

For instance, the new data showed that molecular pathways that regulate how the right ventricle processes fatty acids were not working correctly, perhaps implying that the failing heart muscle is not using fuel efficiently.

The molecular changes could provide a starting point for designing new drugs that target right ventricular problems, Weldy said, concluding, "It's exciting that, through a noninvasive test, we now have a potential method that could give insight into biology of what's going on in someone's heart."

Photo by Cathal Mac an Bheatha

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