Increased pulmonary vascular tone (PVT) can complicate the postoperative course after 6 specific surgical procedures for congenital heart defects. These include the unrestrictive ventricular septal defect (VSD) repair, the atrioventricular septal (AVSD) repair, the arterial switch procedure for transposition of the great arteries (TGA), and the Norwood I, bidirectional Glenn shunt, and Fontan procedures for single ventricle lesions. PVT is partially controlled by nitric oxide (NO). Arginine, the precursor to NO, is a product of the urea cycle. In the preliminary data section of this application, we present data on 169 infants and children who have undergone one of these 6 surgical procedures. We specifically found that urea cycle function and plasma arginine levels were significantly decreased in all patients. Furthermore, patients with increased PVT had significantly lower arginine levels compared to patients with normal PVT. Finally, a genetic single nucleotide polymorphism (SNP) in the rate limiting urea cycle enzyme, carbamyl phosphate synthetase I (CPSl T1405N), appeared to affect postoperative plasma arginine levels and pulmonary vascular tone. The hypothesis of this study is that genetic polymorphisms in the rate limiting urea cycle enzyme CPSl and other important enzymes in the urea cycle influence the availability of nitric oxide precursors and that perioperative enhancement of urea cycle function with the key urea cycle intermediate, citrulline, will increase plasma arginine and NO metabolites and prevent elevations in PVT. Specific Aims: 1. In an observational study in infants and children undergoing one of 6 congenital heart surgeries test the hypothesis that genetic polymporphisms in the urea cycle enzymes carbamyl phosphate synthetase I (CPSl), ornithine transcarbamylase (OTC), argininosuccinate syntheatse (ASS), argininosuccinate lyase (ASL), and enodothelial nitric oxide synthase (eNOS) influence arginine and NO availability and postoperative pulmonary vascular tone 2. In a phase 1/11clinical trial, determine the pharmacokinetics and safety profile of 3 doses of intravenous citrulline in children undergoing cardiopulmonary bypass for correction of congenital heart defects. 3. In a phase III randomized clinical trial of infants and children undergoing one of 6 congenital heart surgeries test the hypothesis that intravenous citrulline increases postoperative arginine and NO metabolite levels and prevents increased postoperative PVT.

R01HL073317

2003-12-01

2009-11-30