Mechanisms underlying early development of pulmonary vascular obstructive disease in Down syndrome: An imbalance in biosynthesis of thromboxane A₂ and prostacyclin

Abstract

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) A(2) and prostacyclin (PGI(2)) in four groups of infants, cross-classified as shown below, by measuring the urinary excretion levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha): 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-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) 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-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) was higher in the presence of DS (P < 0.001), independently of the presence of PH (P = 0.297). The predominant biosynthesis of TXA(2) over PGI(2), leading to vasoconstriction, 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.

Efficacy and safety of oral sildenafil in children with Down syndrome and pulmonary hypertension

“…This is also consistent with previous studies that have documented reduced endothelium-dependent vasodilation in DS patients compared with age-matched healthy individuals [25] and an imbalance in the synthesis of the vasoconstrictor thromboxane A2 compared with the vasodilator prostacyclin in children with DS [10]. In addition, children with PAH-CHD and DS are less responsive to inhaled nitric oxide than children with PAH-CHD but without DS [26].…”

Down syndrome patients with pulmonary hypertension have elevated plasma levels of asymmetric dimethylarginine

“…Some of the molecular factors that may cause PH in this population have been evaluated; however, the results have been mixed [6,10]. In this study, ADMA, a NO synthase inhibitor, was found to be significantly higher in DS patients with PH than in those DS patients without PH.…”

What people with Down Syndrome can teach us about cardiopulmonary disease

“…In persons with Down syndrome and CHD with a left-right shunt, there is an imbalance in vasoactive mediators which favours vasoconstriction, platelet aggregation and cell proliferation in the pulmonary vasculature [54]. Infants with Down syndrome have a high rate of PAH that is disproportionate for their age [55][56][57], and ∼30% of adults with Down syndrome have septal defects and higher associated mortality compared to those without Down syndrome [58].…”