Dr. Marshall Summar and colleagues have discovered a link between the ability to generate the compound nitric oxide and development of PPHN. (photo by Dana Johnson)
Newborn pulmonary hypertension linked to nitric oxide production
The transition to life outside the womb doesn’t always go smoothly. Complications during birth can send an infant into respiratory distress, which can worsen to a severe condition called persistent pulmonary hypertension of the newborn (PPHN). The condition is common, affecting about one in 500 newborns, said Dr. Marshall L. Summar, associate professor of Pediatrics in the division of Medical Genetics.
Summar, Dr. DeLinda Pearson, a fellow in Neonatology, and colleagues have now discovered a link between the ability to generate the compound nitric oxide and development of PPHN. Their findings, reported June 14 in the New England Journal of Medicine, suggest strategies to prevent the life-threatening pulmonary hypertension in at-risk newborns.
At the center of the story is nitric oxide, a compound that reduces blood pressure and is used to treat infants with PPHN. In the body, nitric oxide is synthesized from the amino acid arginine. Summar theorized that low supplies of arginine and its precursor citrulline would result in low supplies of nitric oxide, and that these conditions might predispose an infant to PPHN.
His reasons for wondering about the effects of low arginine supplies were rooted in over 12 years of research focused on the urea cycle, a metabolic pathway that rids the body of waste nitrogen. Arginine is an intermediate product of the urea cycle, and Summar and colleagues had identified genetic variants in the urea cycle enzyme carbamyl phosphate synthetase I (CPSI) that reduce the amount of arginine produced. PPHN, he thought, represented a condition where the genetic changes might make a difference.
Summar and Pearson collaborated with Dr. William F. Walsh, professor of Pediatrics and director of Nurseries, Dr. Brian W. Christman, associate professor of Medicine, and Sheila Dawling, Ph.D., associate professor of Pathology, to test this idea. They enrolled 65 near-term newborns with respiratory distress in the study, which assessed blood amino acid and nitric oxide metabolite levels and determined the genetic form of CPSI. Of the 65 infants, all patients in the Neonatal Intensive Care Unit at Vanderbilt Children’s Hospital, 34 developed PPHN and the remaining 31 served as controls.
The investigators found that infants suffering from PPHN had lower levels of citrulline, arginine and nitric oxide metabolites compared to infants with respiratory distress who did not develop PPHN. Genetic variants of the CPSI enzyme differed in the entire group of infants, relative to the general population and specifically for patients who developed PPHN.
“The ability to generate nitric oxide seems to be dependent on what kind of capacity these infants have in their urea cycle, which in turn depends on a genetic change that affects the function of the cycle,” Summar said. “It’s a change that isn’t going to cause a problem during everyday wear-and-tear. But under the severe stress conditions of the newborn period, these infants can’t process enough material through the urea cycle, can’t make as much nitric oxide as they need, and go on to develop pulmonary hypertension.”
There is likely a threshold level of nitric oxide required to make the transition from fetal circulation to normal circulation, Summar said, and infants who develop PPHN don’t make that threshold. “It’s probably due to several factors, one of which is the urea cycle not working quite right.”
In fact, he added, the data suggest that genetic variation that affects the urea cycle might predispose infants to respiratory distress in general. The investigators will broaden their study to include infants who have risk factors for respiratory distress – things like lack of oxygen during birth and inhalation of meconium waste – but do not develop any lung disease.
In a new set of studies, Summar and colleagues will supply urea cycle intermediates like citrulline and arginine to at-risk infants to “see if we can block the development of pulmonary hypertension in these babies,” he said. In addition to the health benefits for the infants, the cost savings could be significant. Citrulline and arginine would cost only a few dollars per day compared to $3000 or more per day for nitric oxide treatment.
The relationship between urea cycle function and nitric oxide “has opened up a really new field,” Summar said. He and Christman also are studying patients undergoing high dose chemotherapy for bone marrow transplantation. The complication of hepatic veno-occlusive disease appears to relate to nitric oxide levels and urea cycle function, Summar said.
With Dr. Rick Barr, assistant professor of Pediatrics and Anesthesiology, Summar is studying children who develop pulmonary hypertension following cardiac surgery. “It looks like the same phenomenon is happening here as well,” he said.
“It’s like macroeconomics in a biological system,” Summar said. “It’s supply and demand – if you don’t have a supply of materials to make nitric oxide when you have the demand for it, you run into trouble.”
Other collaborators on the NEJM article are Jonathan L. Haines, Ph.D., Amy Bazyk, and Nathan Scott. The research was supported by the National Institutes of Health.