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Introduction: Idiopathic Pulmonary Arterial Hypertension (iPAH) is a fatal lung disease characterized by remodeling of the lung vasculature leading to a 5-fold increase of the pulmonary vascular resistance (PVR). Quantitative information on vascular remodeling is limited to assessments of increased wall thickness, and the extent of internal diameter decrease and thus the contribution to PVR increase, is unknown. Therefore, we quantified the number of affected arteries and their internal diameter to estimate the PVR increase using an anatomy based model. Methods: Internal and external diameters of resistance arteries (external diameter of 13 to 500 μm) were measured in 5 controls and 6 iPAH subjects. The vessels were classified in Strahler orders, and number fraction of narrowed vessels and their relative internal diameter decrease in iPAH were determined. To predict arterial resistance increase as a result of diameter decrease, the arterial bed was modeled as a tree, using Poiseuille9s Law, and data on diameters, lengths, and numbers. Results: Only 30 to 50% of the resistance arteries in iPAH patients were narrowed. Their internal diameters decreased to approximately 50 to 70%. This remodeling resulted in an arterial resistance increase of only 3 times in iPAH. Conclusions: In iPAH, narrowing of resistance arteries is heterogeneous: not all arteries are narrowed, and internal diameters vary largely. Diameter changes cannot fully explain the increased PVR seen in iPAH. Therefore, future experiments should determine numbers and sizes of vessels in control and iPAH subjects to gain further insight into the possible role of arterial rarefaction and venous changes in iPAH.

Introduction: Recent reports have shown that mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene cause autosomal recessively inheritable pulmonary veno-occlusive disease (PVOD) in familial and a subset of sporadic cases. The pathophysiology evolving from EIF2AK4 mutations remains still to be elucidated. Aim and objective: We sought to differentiate histopathological characteristics between EIF2AK4 mutation-carriers and non-carriers with PVOD. Methods: Histology of lung samples obtained after transplantation of EIF2AK4 mutation-carriers (n=9) and non-carriers (n=9) displaying clinical PVOD were systematically analyzed and scored in a blinded fashion, using quantitative semi-automated morphometry. Results: EIF2AK4 mutation-carriers were significantly distinctive from non-carriers regarding several patterns: a) intimal fibrosis (more severe) and media hypertrophy (less severe) of pulmonary arteries; b) diffuse interstitial fibrosis (less frequent) and patchy hemangiomatosis-like foci (more frequent) within the parenchyma. A trend to heavier remodeling of interlobular septal veins was observed. Conclusion: Histology of bi-allelic EIF2AK4 mutation-carriers can be differentiated from non-carriers due to arterial and interstitial remodeling patterns. Whether the severe arterial remodeling is of primary or secondary nature in the setting of heritable PVOD requires further insight into EIF2AK4 biology.