Authors: Nicholas Fawley, DO - Children’s Hospital Los Angeles
A 21-year-old female with Trisomy 21, who underwent complete atrioventricular canal (CAVC) repair as an infant, presents with fatigue and progressive dyspnea on exertion. A transthoracic echocardiogram demonstrates an estimated right ventricular systolic pressure of 64 mmHg. Which of the following medications improves exercise capacity in adults with Trisomy 21 and pulmonary hypertension?
Children with Trisomy 21 (T21) have an increased incidence of pulmonary hypertension (PH). There are a variety of risk factors that contribute to the development of pulmonary hypertension in these patients, including congenital heart disease. However, there are other genetic, pulmonary, vascular and metabolic factors that also contribute to the overall risk of developing PH. The most frequent congenital heart defects found in patients with T21 include atrioventricular septal defects and ventricular septal defects. Both defects are associated with left-to-right intracardiac shunting of blood, leading to increased pulmonary blood flow, increased pulmonary arterial pressure and increased arterial wall shear stress. Ultimately, over time, the result is endothelial dysfunction, altered vasoactive mediator expression, and vascular remodeling. Progressive endothelial intimal fibrosis leads to arterial narrowing and further shear stress. The vascular remodeling associated with increased pulmonary blood flow is a key component in the timing of corrective surgery. Although early surgical repair can prevent continued hemodynamic stress on the pulmonary vasculature, elevated pulmonary arterial pressures may persist after repair. There is some evidence to suggest intrinsic endothelial dysfunction is present in patients with T21. This is supported in this patient population with evidence of elevated endothelial vasoconstrictors such as endothelin-1, impaired production of nitric oxide, and an imbalance of vasoactive eicosanoid to prostacyclin ratios. Furthermore, upregulation of proinflammatory genes in patients with T21 contributes to endothelial dysfunction and impaired nitric oxide production.
Respiratory disorders are prevalent in children with T21 and may contribute to the development of PH. Functional and anatomic upper airway obstruction, obstructive and central sleep apnea, chronic aspiration, and recurrent lower airway infections can lead to increased pulmonary vascular resistance secondary to hypoxic pulmonary vasoconstriction. Small studies in children with T21 provide evidence of pulmonary hypoplasia with reduced vascular surface area and impaired microvascular development. Pulmonary hypoplasia contributes to hypoxemia during periods of increased oxygen demand. Additionally, pulmonary vein stenosis may be underdiagnosed in this population, which results in pulmonary venous hypertension and upstream pulmonary arterial hypertension. Early identification of respiratory disorders, with intervention, can potentially circumvent the development of PH. Despite early resolution, subsequent respiratory disease can cause recurrence of PH later in life.
Pharmacologic treatment of PH in infants and children with T21 may be accompolished through targeted monotherapy or combination therapy. In 2023, Hopper and colleagues studied data from patients with T21 in the Pediatric Pulmonary Hypertension Network Registry and found that prescribing practices are similar for pediatric patients with and without T21. Unfortunately, there are few studies comparing the efficacy of PH pharmacotherapies in pediatric patients with T21. Due to upregulated endothelial vasoconstrictors and endothelial dysfunction in T21, there may be particular benefit of endothelin receptor antagonists (ERAs), such as bosentan. In adults with T21 and PH, D’Alto and colleagues found that bosentan improved WHO functional classification, exercise capacity, and pulmonary hemodynamics.
Other targeted PH pharmacotherapies include phosphodiesterase type V inhibitors (sildenafil), prostacyclins (treprostinil), calcium channel blockers, and selective prostacyclin receoptor agonists (selexipag). Sildenafil is a widely prescribed therapy in infants and children with PH and has been studied in the STARTS-1 and STARTS-2 trials. However, a STARTS-1 trial sub-analysis by Beghetti and colleagues demonstrated that when comparing children with T21 compared to those without T21, sildenafil was well-tolerated but did not lead to meaningful improvements in pulmonary vascular resistance or mean pulmonary pressure. There is a lack of strong evidence-based recommendations for prostacyclin therapy in children with T21, but reduced prostacyclin production in patients with T21 suggests a possible role in pharmacotherapy. In guidelines from the American Heart Association and American Thoracic Society (AHA-ATS) on pediatric pulmonary hypertension, prostacyclin pharmacotherapy is recommended for pediatric patients with higher-risk disease severity of PH, defined by the following features: clinical evidence of right ventricular (RV) failure, WHO functional class of III & IV, recurrent syncope, significant RV enlargement/dysfunction by echocardiography, pulmonary vascular resistance index > 20 WU.m2 , cardiac index of less than 2.0 L/min/m2, pulmonary vascular resistance/systemic vascular resistance ratio > 1, significantly elevated brain natriuretic peptide, shorter 6-minute walk distance, and peak VO2 < 15 ml/kg/min. Bosentan is approved for pediatric patients aged 3 to 17 years, while sildenafil is approved for ages 1 to 17 years by the Federal Drug Administration for the treatment of pulmonary arterial hypertension.
Although studies of targeted PH therapy in children and adults with Trisomy 21 are lacking, D’Alto and colleagues demonstrated that bosentan improves WHO functional classification, exercise capacity, and pulmonary hemodynamics in adults with PH and Trisomy 21.
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