Research information of Dr. Rick Barr, left, Dr. Marshall Summar, and Lynn Hall, research assistant, appeared in the Journal of Pediatrics in January. (photo by Anne Rayner Pollo)
VUMC team studies risk factors after congenital heart surgery
What began as a thesis for a Master’s in Clinical Investigation for Dr. Frederick Barr, assistant professor of Pediatric Critical Care, has evolved into a study published in the January issue of The Journal of Pediatrics.
The purpose of the study, titled the “Effect of Cardiopulmonary Bypass on Urea Cycle Intermediates and Nitric Oxide Levels after Congenital Heart Surgery,” is to determine risk factors for developing a complication called pulmonary hypertension after surgical repair of a congenital heart defect.
Approximately 40,000 infants are born with congenital heart defects in the United States every year and a large majority of these infants require open-heart surgery, which can lead to complications.
Post-operative pulmonary hypertension, or increased blood pressure in the arteries supplying the lungs which subsequently doesn’t allow enough blood flow to the lungs and causes decreased oxygen levels, is one complication physicians typically see in newborns. Development of postoperative pulmonary hypertension can translate into longer ICU stays, longer hospital admissions, and even death if untreated.
Barr’s studies have looked at nearly 300 children with various congenital heart abnormalities but the publication focused on patients at highest risk for postoperative pulmonary hypertension, such as those undergoing repair of an atrioventricular septal defect (AVSD).
“We initially found that the stress of cardiopulmonary bypass and surgery caused a dramatic decrease in the amino acid arginine, which is the precursor to nitric oxide, an extremely important molecule in controlling pulmonary artery blood pressure,” said Barr. “We also found that infants who developed postoperative pulmonary hypertension have lower postoperative arginine levels compared to other infants.”
The next step was to figure out why.
Arginine is supplied by the urea cycle, which is a complex set of biochemical reactions — with the most important step being catalyzed by an enzyme called carbamyl phosphate synthetase I (CPSI). One of Barr’s collaborators, Dr. Marshall L. Summar, associate professor of Pediatrics and Molecular Physiology and Biophysics, had previously found that one particular change called a single nucleotide polymorphism in the sequence of the CPSI gene appeared to affect arginine and nitric oxide production.
“We next looked at each infant’s genotype at this polymorphism (called T1405N) to determine if it was a genetic risk factor for post-operative pulmonary hypertension,” said Barr. “We found postoperative arginine levels were different among infants depending on their genotype and that infants with one particular genotype appeared to be protected against pulmonary hypertension.”
According to Barr, the next step is to give infants undergoing congenital heart surgery another amino acid called citrulline to see if postoperative pulmonary hypertension can be prevented. Citrulline is converted in the body to arginine.
“We hope to begin our citrulline trial in the coming weeks to see if it is a useful treatment to increase arginine and nitric oxide production post-operatively,” Barr said. He expects to have some answers roughly a year after the study starts.