Impairment of endothelium-dependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics.

BACKGROUND Endothelial injury may be an important event in the pathophysiology of pulmonary hypertension. We therefore investigated whether endothelial dysfunction occurs early in children with congenital heart defects who are at risk of developing pulmonary vascular disease. METHODS AND RESULTS In 25 children aged 3-16 years, we studied the response of the pulmonary circulation to graded infusions of acetylcholine (an endothelium-dependent vasodilator) and nitroprusside (a dilator not dependent on endothelial function). Diameter of a bronchopulmonary segment artery and pulmonary blood flow velocity were measured using quantitative angiography and intra-arterial Doppler catheters in 10 children aged 4-16 years with normal pulmonary hemodynamics (controls), seven children aged 3-12 years with left-to-right shunt lesions resulting in increased pulmonary flow, and eight children aged 3-14 years with established pulmonary vascular disease. In the controls, there was a dose-dependent increase in flow velocity in response to acetylcholine (maximal increase, 93 +/- 7%) and in response to nitroprusside (51 +/- 8%). In contrast, in patients with pulmonary vascular disease, the response of flow velocity to similar doses of acetylcholine (33 +/- 7%, p < 0.01) and nitroprusside (7 +/- 13%, p < 0.01) were impaired. In the patients with high pulmonary flow, there was an impaired response to acetylcholine (46 +/- 9%, p < 0.01), but response to nitroprusside was preserved (42 +/- 8%, p > 0.10), consistent with endothelial dysfunction. Arterial diameter was unchanged during acetylcholine infusion in all subjects and increased only modestly in response to nitroprusside (< or = 10%), indicating that the major site of action of each agent is distal to the segmental pulmonary arteries. CONCLUSIONS Endothelium-dependent pulmonary artery relaxation can be demonstrated in vivo and is impaired in young patients with increased pulmonary flow secondary to congenital heart disease. This impairment may be an important early event in the pathogenesis of pulmonary vascular disease.