Lung function, inflammation, and endothelin-1 in congenital heart disease-associated pulmonary arterial hypertension

BACKGROUND: Breathlessness is the most common symptom in people with pulmonary arterial hypertension and congenital heart disease (CHD-APAH), previously thought to be caused by worsening PAH, but perhaps also by inflammation and abnormalities of lung function. We studied lung function and airway inflammation in patients with CHD-APAH and compared the results with controls.

METHODS AND RESULTS: Sixty people were recruited into the study: 20 CHD-APAH, 20 CHD controls, and 20 healthy controls. Spirometry, gas transfer, whole body plethysmography and lung clearance index, 6-minute walk distance, and medical research council dyspnea scoring were performed. Inflammatory markers and endothelin-1 levels were determined in blood and induced sputum. The CHD-APAH group had abnormal lung function with lung restriction, airway obstruction, and ventilation heterogeneity. Inverse correlations were shown for CHD-APAH between medical research council dyspnea score and percent predicted peak expiratory flow (r=-0.5383,P=0.0174), percent predicted forced expiratory flow rate at 50% of forced vital capacity (r=-0.5316,P=0.0192), as well as for percent predicted forced expiratory volume in 1 s (r=-0.6662,P=0.0018) and percent predicted forced vital capacity (r=-0.5536,P=0.0186). The CHD-APAH patients were more breathless with lower 6-minute walk distance (360 m versus 558 m versus 622 m,P=0.00001). Endothelin-1, interleukin (IL)-β, IL-6, IL-8, tumor necrosis factor α, and vascular endothelial growth factor were significantly higher in CHD-APAH than controls. Serum endothelin-1 for CHD-APAH correlated with airflow obstruction with significant negative correlations with percent predicted forced expiratory flow rate at 75% of forced vital capacity (r=-0.5858,P=0.0135).

CONCLUSIONS: Raised biomarkers for inflammation were found in CHD-APAH. Significant abnormalities in airway physiology may contribute to the dyspnea but are not driven by inflammation as assessed by circulating and sputum cytokines. A relationship between increased serum endothelin-1 and airway dysfunction may relate to its bronchoconstrictive properties.