Mechanisms underlying early development of pulmonary vascular obstructive disease in Down syndrome: An imbalance in biosynthesis of thromboxane A ₂ and prostacyclin

Patients with Down syndrome (DS) and a left-to-right shunt often develop early severe pulmonary hypertension (PH) and pulmonary vascular obstructive disease (PVOD); the pathophysiological mechanisms underlying the development of these complications are yet to be determined. To investigate the mechanisms, we evaluated the biosynthesis of thromboxane (TX) A₂ and prostacyclin (PGI₂) in four groups of infants, cross -classified as shown below, by measuring the urinary excretion levels of 11-dehydro-TXB₂ and 2,3-dinor-6-keto-PGF_1α: DS infants with a left-to-right shunt and PH (D-PH, n=18), DS infants without congenital heart defect (D-C, n=8), non-DS infants with a left-to-right shunt and PH (ND-PH, n=12), and non-DS infants without congenital heart defect (ND-C, n=22). The urinary excretion ratios of 11-dehydro-TXB₂ to 2,3-dinor-6-keto-PGF_1α in the D-PH, D-C, ND-PH, and ND-C groups were 7.69, 4.71, 2.10, and 2.27, respectively. The ratio of 11-dehydro-TXB₂ to 2,3-dinor-6-keto- PGF_1α was higher in the presence ofDS (P<0.001), independently of the presence of PH (P=0.297). The predominant biosynthesis of TXA₂ over PGI₂, leading to vaso-constriction, was observed in DS infants, irrespective of the presence/absence of PH. This imbalance in the biosynthesis of vasoactive eicosanoids may account for the rapid progression of PVOD in DS infants with a left-to-right shunt.