Clinical characteristics of pulmonary arterial hypertension associated with Down syndrome

Abstract

The genetic abnormalities associated with Down syndrome (DS) are still being identified. Few studies have examined the roles of CRELD1 and GATA4 in cardiac abnormalities or their association with pulmonary artery histopathology. Children with DS have an elevated risk of pulmonary arterial hypertension (PAH). This increased risk is likely mainly due to genetic background, the structural characteristics of the pulmonary vascular wall, and certain heart diseases and partly due to pulmonary hypoplasia, upper and lower airway obstructive diseases, chronic infection, and neuromuscular underdevelopment. Exposure to increased left-to-right shunt flow increases sheer stress on endothelium and may induce endothelial dysfunction followed by irreversible remodeling of pulmonary arteries. Pathologic changes include endothelial cell proliferation and thickening of the pulmonary arterial wall due to mechanical responses to the thinner medial smooth muscle cell layer, which includes underdevelopment of alveoli. Production of prostacyclin and nitric oxide is diminished in DS, but endothelin-1 and thromboxane are elevated. Perioperatively, patients with DS may experience pulmonary hypertensive crisis after intracardiac repair and prolonged PAH, and have a poorer response to nitric oxide inhalation. To better manage DS, it is crucial to systematically evaluate the systemic complications of DS. Cardiac catheterization data, particularly those regarding pulmonary arterial resistance, are essential in assessing severity and response to vasodilating agents, preventing postoperative crisis, and evaluating the possibility of intracardiac repair. Advanced therapy with pulmonary vasodilating agents appears effective. Operative risk is similar for individuals with and without DS, except among patients with a complete atrioventricular canal defect.

What people with Down Syndrome can teach us about cardiopulmonary disease

“…Persistent pulmonary hypertension of the newborn, another group 1 PAH disease, is quite prevalent in Down syndrome [59][60][61]. The combination of upper respiratory tract malformations, alveolar capillary dysplasia, hypoxia and hypercapnia may collectively promote development of pulmonary hypertension [62,63]. Importantly, there have been no randomised controlled trials in Down syndrome with PAH examining response to vasodilator therapy [64,65].…”

“…Progress has been made with regard to biomarkers of paediatric PAH [113,114], but not PAH in the setting of Down syndrome, (DS-PAH), and there are no animal models specific for DS-PAH. Many factors such as chronic hypoxia, sleep apnoea, recurrent respiratory infection, low birthweight and transient myeloproliferative disease probably contribute to DS-PAH or pulmonary hypertension in Down syndrome [63]. Atherosclerotic disease is the leading cause of death in Europe and worldwide (∼30% of all deaths worldwide) [115].…”

El niño con Síndrome de Down en la Unidad de Cuidados Intensivos

“…Dentro de los mecanismos asociados, se atribuye un rol a la alteración del desarrollo de la vasculatura, polimorfismo genéti-co que afectaría la producción de óxido nítrico y otros mediadores de la resistencia vascular pulmonar, entre otras causas 23,29,30 .…”

“…Como se señaló previamente la incidencia de HP es mayor en niños con SD 29,30 , donde la alta prevalencia de cardiopatía congénita es un contribuidor significativo.…”

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

“…Children with DS have a higher risk for developing PH due, in part, to these congenital heart defects [5]. Other factors that may play a role in the higher risk for PH in children with DS include upper airway obstruction, lung hypoplasia, gastroesophageal reflux, abnormal pulmonary vascular function, obstructive sleep apnea (OSA) [6–8], and an imbalance in mediators, such as nitric oxide, thromboxane A2, and prostacyclin [9–11], which have been implicated in the development of PH [12]. Despite the increased risk for PH in children with DS, the response to treatment with targeted therapies for PH in these patients is not well characterized.…”