Shunt-type plexiform lesions identified in the Sugen5416/Hypoxia rat model of pulmonary arterial hypertension using SPµCT

We recently described four distinct types of plexiform lesions in human idiopathic and familial pulmonary arterial hypertension (PAH) [1], visualising the three-dimensional lesion structure using synchrotron-based phase-contrast micro-CT (SPµCT). Two types, 1 and 2, are shunt-type lesions that connect pulmonary arteries to the bronchial circulation: type 1 to the vasa vasorum, and type 2 to peribronchial vessels. Type 3 lesions are found peripherally in the lung as spherical structures abruptly terminating the distal pulmonary artery/arteriole, and type 4 are characterised by recanalization of an occluded artery/arteriole. Our observation of type 1 and type 2 lesions in PAH supports previous work which demonstrated intrapulmonary bronchopulmonary anastomoses (IBAs) connected to plexiform lesions in human PAH, suggesting that shunting of blood can occur within lesions in the setting of supra-systemic pulmonary arterial pressure [2]. Further hemodynamic studies of distinct subtypes of plexiform lesions have been hampered by the lack of available animal models with plexiform lesions representative of the full range of lesion types found in human disease. Plexiform lesions have previously been described in the Sugen5416/Hypoxia rat model of pulmonary hypertension when time until sacrifice following hypoxia is extended to 13–14 weeks. Initially plexiform lesions were identified within the lumen as well as outside the vessel as aneurysm-like lesions [3], and recently the latter type was shown to form in supernumerary arteries [4]. However, neither study observed plexiform lesions communicating with the bronchial circulation, possibly because of methodological limitations of the histological analysis. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Christian Westöö declares a regional salary grant for medical resident researchers from ALF Forskningsutrymme för ST-läkare. Till Dreier declares an industrial PhD salary from Excillium AB, and payment to their institution from the Swedish Foundation for Strategic Research SSF) in connection with the present manuscript. Maya E Kumar declares American Heart Association Scientist Development Grant AHA 16SDG30030006, Stanford Pediatrics startup funds 1246483-200-JHAJH, Stanford Spectrum Child Health Research Institute 1170805-100-GHEBG, Stanford Maternal and Child Health Research Institute Pilot Grant 1220318-108-JHACT, Vera Moulton Wall Center for Pulmonary Vascular Research grant 1144545-401-GHDCK and a Bravo Family Endowed Faculty Scholarship, in connection with the present manuscript. Edda Spiekerkoetter declares that they have a research scholarship from Vera Moulton Wall Center for Pulmonary Vascular Disease, in connection with the present manuscript; and that they have received grants from the National Institutes of Health (National Heart, Lung and Blood Institute grants R01HL158868 and R01 HL128734) and Department of Defense (grants PR161256 and PR 181774) in the 36 months prior to manuscript submission; and that they receive royalties from Stanford University for Method of use patent “Use of FK506 for the treatment of Pulmonary Arterial Hypertension”; that they have a provisional US patent for “Enzastaurin and Fragile Histidine Trial (FHIT) Increasing Agents for the Treatment of Pulmonary Hypertension”; and that they are chair of the American Heart Association 3CPR Early Career Committee, and a member of the Stanford University Institutional Review Board. Karin Tran-Lundmark declares funding from the Swedish Heart-Lung Foundation, the Crafoord Foundation, the Swedish Society of Medicine, the Knut and Alice Wallenberg Foundation and the Skåne County Council, in connection with the present manuscript; as well as roles as American Thoracic Society (ATS) Pulmonary Circulation Program Committee member (unpaid); American Heart Association (AHA) 3CPR Early Career Committee (unpaid) and Association for European Paediatric and Congenital Cardiology (AEPC) Councillor in the Working Group for Pulmonary Hypertension, Heart Failure and Transplantation (unpaid). All other authors declare no competing interests.