IN-UTERO PLACEMENT OF AORTOPULMONARY SHUNTS - A MODEL OF POSTNATAL PULMONARY-HYPERTENSION WITH INCREASED PULMONARY BLOOD-FLOW IN LAMBS

Background The development of pulmonary hypertension and its associated increased vascular reactivity is a common accompaniment of congenital heart disease with increased pulmonary blood flow. Although the morphology of the pulmonary vascular changes is well described, the mechanisms of vascular remodeling and increased reactivity remain incompletely understood. Methods and Results To elucidate these mechanisms, we established an accurate and reliable experimental model of pulmonary hypertension with increased pulmonary blood how. An aortopulmonary shunt was created with an 8.0-mm expanded polytetrafluoroethylene vascular graft in 11 late-gestation fetal lambs. At 1 month of age, shunted lambs had a pulmonary-to-systemic blood flow ratio of 2.2+/-1.2. Compared with 11 age-matched control lambs, mean pulmonary arterial pressure (44.8+/-11.7 versus 16.2+/-2.9 mm Hg) and the ratio of pulmonary to systemic arterial pressure were significantly increased (P<.05). Pulmonary vascular resistance was not significantly increased. The pulmonary vasoconstricting response to the infusion of U46619 (a thromboxane A(2) mimic) or acute alveolar hypoxia also was augmented in the shunted lambs. Morphometric analysis of the barium-filled pulmonary artery bed revealed medial hypertrophy, abnormal extension of muscle distally into the walls of the intra-acinar arteries, and increased numbers of barium-filled intra-acinar arteries. Conclusions In utero placement of aortopulmonary shunts reproduces the aberrant hemodynamic state of children with congenital heart disease with left-to-right shunts; postnatal pulmonary hypertension, increased pulmonary blood flow, and vascular remodeling. In addition, the lambs have a unique paradoxical increase in pulmonary vascular volume that attenuates an increase in pulmonary vascular resistance. This experimental preparation provides a useful and consistent model for the study of the pathogenesis of pulmonary hypertension.