Ovine Models of Congenital Heart Disease and the Consequences of Hemodynamic Alterations for Pulmonary Artery Remodeling.

The natural history of pulmonary vascular disease (PVD) associated with congenital heart disease (CHD) depends upon associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop PVD more commonly than patients exposed to increased PBF alone. To investigate the effects of these differing mechanical forces on physiologic and molecular responses, we developed two models of CHD utilizing fetal surgical techniques: 1) left pulmonary artery (LPA) ligation primarily resulting in increased PBF; and 2) aortopulmonary shunt placement resulting in increased PBF and PAP. Hemodynamic, histologic, and molecular studies were performed on control, LPA, and shunt lambs as well as pulmonary artery endothelial cells (PAECs) derived from each. Physiologically, LPA, and to a greater extent, shunt, lambs demonstrated an exaggerated increase in PAP in response to vasoconstricting stimuli compared to controls. These physiologic findings correlated with a pathologic increase in medial thickening in pulmonary arteries in shunt, but not control or LPA lambs. Further, in the setting of acutely increased afterload, the right ventricle of control and LPA, but not shunt, lambs suffers ventricular-vascular uncoupling and adverse ventricular-ventricular interactions. RNA Sequencing revealed excellent separation between groups via both principal components analysis and unsupervised hierarchial clustering. In addition, we found hyperproliferation of PAECs from LPA, and to a greater extent, shunt lambs, with associated increased angiogenesis and decreased apoptosis in PAECs derived from shunt lambs. A further understanding of mechanical force-specific drivers of pulmonary artery pathology will enable development of precision therapeutics for PH associated with CHD.