New insight into pulmonary hypertension in infants may lead to novel treatment

Susan Jeffrey

June 13, 2001

Wed, 13 Jun 2001 21:00:00

Boston, MA - New insight into the biochemical events leading to pulmonary hypertension (PH) in infants points to a potential new - and cheap - treatment for these tiny patients. In a report appearing in the June 14, 2001 issue of the New England Journal of Medicine, researchers describe an unexpected link between abnormalities in the urea cycle - responsible for disposal of nitric oxide (NO) - and the failure in newborns to produce sufficient NO to allow a normal transition from maternal to cardiorespiratory circulation at birth.

Researchers led by Drs DeLinda L Pearson and Marshall L Summar (Vanderbilt University Medical Center, Nashville, TN) found infants with pulmonary hypertension had low concentrations of both precursors and metabolites of NO, implicating inadequate NO production the pathogenesis of pulmonary hypertension.

"Our preliminary observations suggest that the genetically predetermined capacity of the urea cycle - in particular, the efficiency of carbamoyl-phosphate synthetase - may contribute to the availability of precursors for nitric oxide synthesis," the authors write.

Inhaled NO is already used as an effective treatment for PH, Summar told heart wire in an interview, but costs about $4000 per day to administer, when the costs of intensive care once PH has developed are calculated. "It turns out that the things they're missing, (NO precursors L-arginine and citrullene) are dirt cheap," he said, at about $5-10 per day. They hope to begin a trial in the fall, orally supplementing children with citrulline and L-arginine as soon as they begin to show distress, to see whether PH can be prevented.

PH: Life-threatening in first moments of life

As an infant takes its first breath, the vascular beds of the lungs open, and the child makes the transition from maternal to cardiorespiratory circulation. A key element required for this transition is a "burst" of NO, Summar noted. Some children are not able to make the transition and PH results: Pulmonary vascular resistance is elevated and an extrapulmonary left-to-right shunting of blood across the patent ductus arteriosus or foramen ovale results in hypoxia in the infant. PH occurs in 1.9 per 1000 newborns, and mortality is estimated at about 11%.

Summar's research interest historically has been the urea cycle, the pathway responsible for catabolism of NO, "which has nothing to do with pulmonary hypertension, or so we thought," he said. The potential connection between the development of PH and the urea cycle came from the observation that byproducts of the cycle, L-arginine and citrulline, are required by endothelial cells to generate NO.


We wondered if kids who had a less well-developed urea cycle would . . . go on to develop pulmonary hypertension, and that's exactly what we found.


"We wondered if kids who had a less well-developed urea cycle would be the ones who go on to develop pulmonary hypertension, and that's exactly what we found," Summar said.

Further, they reasoned that the supply of these precursors might be driven genetically, and investigated whether one polymorphism in particular, T1405N - which is known to affect the function of carbamoyl-phosphate synthase (CPS), the rate-limiting enzyme controlling the urea cycle - might be more common in children who developed PH than among those who did not.

In the current study, they assessed plasma concentrations of NO, as well as its precursors in 65 near-term infants with respiratory distress, some of whom had developed pulmonary hypertension and others who had not. NO metabolites were measured in a subgroup of 10 infants. Frequencies of CPS genotypes were also determined.

They found that the children with PH (n=31) had significantly lower mean plasma concentrations of L-arginine and NO metabolites compared to those without PH in this sample.

NO precursors and metabolites


Pulmonary hypertension

NO pulmonary hypertension

p value

20.2 + 8.8
39.8 + 17.0
< 0.001
18.8 + 12.7
47.2 + 11.2
To download table as a slide, click on the slide logo below

Genetically driven?

The investigators had hypothesized that infants with PH would have a different distribution of T1405N genotypes than those without PH. Instead, they found that this study population of infants with respiratory distress had overall, a skewed distribution of CPS genotypes for this polymorphism: "One possible explanation for the similarity between the group with pulmonary hypertension and the group without pulmonary hypertension is that all infants with transitional respiratory problems may have some degree of pulmonary hypertension; our definition of elevated pulmonary arterial pressure may have identified the most severely affected infants along this continuum."

That these ill infants had a skewed distribution of T1405N genotypes compared to the general population supports the possibility that the functional status of CPS has a role in the cardiorespiratory transition at birth, the authors note.

The presence of this polymorphism is not sufficient in and of itself to cause PH, Summar added, since it is actually quite common in the population. "At least typically, it needs to be in combination with an environmental stress, such as partial birth asphyxia or meconium aspiration, something like that," he said.

Summar's group is actually studying other high-stress events that may result in respiratory distress or pulmonary hypertension in small patients with these genetic underpinnings. "We're looking at the postcardiac surgery population," he said. "Pulmonary hypertension is a fairly common event after pediatric cardiac surgery, and in looking at amino acids and genotypes, so far it looks very similar to what we saw in the newborns," Summar concluded.


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