What are the causes of severe pulmonary arterial hypertension (PAH) with right ventricular (RV) dysfunction in pediatric patients?

Causes of Severe PAH with RV Dysfunction in Pediatrics

Severe pulmonary arterial hypertension with right ventricular dysfunction in pediatric patients has multiple etiologies, with congenital heart disease being the most common cause, followed by developmental lung diseases, genetic mutations, and idiopathic forms. 1

Congenital Heart Disease (Most Common)

Congenital heart disease represents the leading cause of severe PAH with RV dysfunction in children, particularly lesions with left-to-right shunts. 1

High-Risk Cardiac Lesions:

• Truncus arteriosus, transposition of the great arteries, obstructed total anomalous pulmonary venous connection, and aortic origin of pulmonary artery are especially predisposed to severe PAH and RV dysfunction, particularly if repair is delayed beyond the neonatal period 1
• Large ventricular septal defects (VSDs) cause pressure overload and high flow, leading to irreversible pulmonary vascular disease if not repaired before 9 months to 2 years of age; approximately 50% develop Eisenmenger syndrome without appropriate surgery 1
• Atrioventricular canal defects, particularly in patients with Down syndrome, carry increased risk due to associated lung hypoplasia and accelerated PAH development 1
• Single-ventricle physiology after cavopulmonary anastomosis (Glenn or Fontan procedures) is vulnerable to RV failure because small elevations in pulmonary vascular resistance markedly impair cardiac performance in the absence of a subpulmonary ventricle 1, 2

Chromosomal and Genetic Associations:

• Down syndrome patients have inherent lung hypoplasia, which increases PAH risk and is accelerated by cardiac disease or intermittent hypoxia 1
• Patients with genetic syndromes, chromosomal abnormalities, or extracardiac anomalies have high incidence of lung hypoplasia and simplified pulmonary vascular beds, complicating postoperative courses 1

Developmental Lung Diseases

Developmental lung abnormalities represent a major category of severe PAH in infants and young children. 1, 3

Prenatal Causes:

• Congenital diaphragmatic hernia (CDH) causes severe pulmonary hypoplasia and is one of the most common causes of PAH in infants 1, 3
• Severe oligohydramnios, thoracic dystrophies, skeletal disorders, and neuromuscular disorders limit lung or thoracic growth in utero 1
• Alveolar capillary dysplasia with misalignment of veins is uniformly fatal and presents with severe PAH 1
• Scimitar syndrome (right lung hypoplasia, anomalous pulmonary venous return, pulmonary artery hypoplasia) presents in infancy with severe PAH, often multifactorial in origin 1, 3

Postnatal Causes:

• Bronchopulmonary dysplasia (BPD) is the most common cause in premature infants, with structural pulmonary vascular changes including medial hypertrophy and abnormal muscle extension to peripheral arteries 1, 3
• Surfactant protein dysfunction disorders (SPB deficiency, SPC deficiency, ABCA3, TTF-1/Nkx2) cause diffuse interstitial lung disease leading to PAH 1
• Giant omphaloceles may be associated with PAH due to severe pulmonary hypoplasia 1

Genetic and Idiopathic Forms

Genetic mutations in transforming growth factor-beta receptor pathways account for approximately 22% of childhood-onset PAH cases. 4

Specific Genetic Mutations:

• BMPR2 mutations (11% of pediatric cases) include partial gene deletions and nonsense mutations, often arising de novo 4
• ALK-1 missense mutations and endoglin branch-site mutations have been identified in children presenting with idiopathic PAH 4
• Familial PAH can occur but represents a minority of cases 5

Idiopathic PAH:

• One-third of pediatric PAH cases are primary/idiopathic, with the remaining two-thirds secondary to other conditions 6
• Before targeted therapies, most children with idiopathic PAH died within 1-2 years of diagnosis 1

Environmental and Altitude-Related Causes

High-altitude exposure causes severe PAH in genetically susceptible children, particularly lowland natives ascending rapidly. 1

• Symptomatic high-altitude pulmonary hypertension (SHAPH) most commonly afflicts infants and children of Han Chinese ancestry who have moved from low altitude to the Qinghai-Tibet Plateau above 3000 meters 1
• High-altitude pulmonary edema (HAPE) affects children as well as adults, with risk increased by rapid ascent 1

Postoperative and Acute Causes

Pulmonary hypertensive crises (PHCs) occur in 0.75-4% of pediatric cardiac surgery patients and carry 20% mortality. 1

Risk Factors for PHC:

• Young age at surgery, specific cardiac lesions (truncus arteriosus, TGA, obstructed TAPVC), and abnormal pulmonary vascular development predispose to acute RV failure 1
• Left atrial or pulmonary venous hypertension increases pulmonary vasoreactivity and PHC risk 1
• Triggers include pain, anxiety, tracheal suctioning, hypoxia, and acidosis, creating a vicious cycle of increased PAP, RV failure, and systemic hypotension 1

Pathophysiology of RV Dysfunction

RV adaptation to increased afterload, rather than absolute pulmonary artery pressure, determines clinical outcomes and mortality. 7, 8, 9

• RV dysfunction results from vessel loss, dysfunctional angiogenesis, metabolic derangements, and coronary perfusion impairment when RV pressure exceeds aortic pressure 8, 1
• Decreased vascular growth, increased vascular tone, and reduced alveolar-capillary surface area directly increase pulmonary vascular resistance 2

Critical Diagnostic Considerations

• Cardiac catheterization remains the gold standard for confirming diagnosis, assessing severity, and determining vasoreactivity 1, 2
• Echocardiography with assessment of tricuspid regurgitant jet velocity, RV function, and presence of pericardial effusion is essential for screening and monitoring 1, 3
• Clinical signs may be masked by respiratory disease, requiring high clinical suspicion in at-risk populations 3