Impact of Carbamoyl-Phosphate Synthetase Gene Polymorphism on Increased Susceptibility to Persistent Pulmonary Hypertension in Neonates

Abstract

ailure of the transition to a cardiorespiratory circulation at birth results in persistent pulmonary hypertension of the newborn which is characterized by elevated pulmonary vascular resistance with extrapulmonary right-to-left shunting of blood across the patent ductus arteriosus or the foramen ovale . Persistent pulmonary hypertension can cause life-threatening hypoxemia in newborn infants . Transitional pulmonary hypertension occurs in 1.9 of every 1000 newborn infants and is associated with a mortality rate of 11 percent. PPHN can be easily triggered in newborns by hypoxic lung diseases such as meconium aspiration syndrome, respiratory distress syndrome and pneumonia. Administration of inhaled nitric oxide can be an effective treatment for persistent pulmonary hypertension in newborn infants. Endogenous nitric oxide is critical in the transition to a pulmonary circulation at birth and in the regulation of pulmonary vascular resistance. Cells generate nitric oxide from the precursor l-arginine , an amino acid supplied by the urea cycle. Theoretically, therefore, a link exists between nitric oxide production and the urea cycle. We hypothesized that low concentrations of arginine would correlate with the presence of persistent pulmonary hypertension in newborns and that the supply of this precursor would be affected by a functional polymorphism (the substitution of asparagine for threonine at position 1405 [T1405N]) in carbamoyl-phosphate synthetase, which controls the rate-limiting step of the urea cycle.