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In pulmonary arterial hypertension, plexiform lesions are associated with severe arterial obstruction and right ventricular failure. Exploring their structure and position is crucial for understanding the interplay between hemodynamics and vascular remodeling. The aim of this research was to use synchrotron-based phase-contrast micro-CT to study the three-dimensional structure of plexiform lesions. Archived paraffin-embedded tissue samples from 14 patients with pulmonary arterial hypertension (13 idiopathic, 1 with known BMPR2 -mutation) were imaged. Clinical data showed high-median PVR (12.5 WU) and mPAP (68 mmHg). Vascular lesions with more than 1 lumen were defined as plexiform. Prior radiopaque dye injection in some samples facilitated 3-D rendering. Four distinct types of plexiform lesions were identified: 1 ) localized within or derived from monopodial branches (supernumerary arteries), often with a connection to the vasa vasorum; 2 ) localized between pulmonary arteries and larger airways as a tortuous transformation of intrapulmonary bronchopulmonary anastomoses; 3 ) as spherical structures at unexpected abrupt ends of distal pulmonary arteries; and 4 ) as occluded pulmonary arteries with recanalization. By appearance and localization, types 1-2 potentially relieve pressure via the bronchial circulation, as pulmonary arteries in these patients were almost invariably occluded distally. In addition, types 1-3 were often surrounded by dilated thin-walled vessels, often connected to pulmonary veins, peribronchial vessels, or the vasa vasorum. Collaterals, bypassing completely occluded pulmonary arteries, were also observed to originate within plexiform lesions. In conclusion, synchrotron-based imaging revealed significant plexiform lesion heterogeneity, resulting in a novel classification. The four types likely have different effects on hemodynamics and disease progression.

The natural history of pulmonary vascular disease associated with congenital heart disease (CHD) depends on associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop pulmonary vascular disease 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 using 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 with controls. These physiologic findings correlated with a pathologic increase in medial thickening in pulmonary arteries in shunt lambs but not in control or LPA lambs. Furthermore, in the setting of acutely increased afterload, the right ventricle of control and LPA but not shunt lambs demonstrates ventricular-vascular uncoupling and adverse ventricular-ventricular interactions. RNA sequencing revealed excellent separation between groups via both principal components analysis and unsupervised hierarchical clustering. In addition, we found hyperproliferation of PAECs from LPA lambs, 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 pulmonary hypertension associated with CHD.

Objective: To determine the consequences of an early catheter-based intervention on pulmonary artery (PA) growth and right ventricular (RV) myocardial function in an animal model of branch PA stenosis., Background: Acute results and safety profiles of deliberate stent fracture within the pulmonary vasculature have been demonstrated. The long-term impact of early stent intervention and deliberate stent fracture on PA growth and myocardial function is not understood., Methods: Implantation of small diameter stents was performed in a pig model of left PA stenosis at 6 weeks (10 kg) followed by dilations at 10 (35 kg) and 18 weeks (65 kg) with intent to fracture and implant large diameter stents. Hemodynamics, RV contractility, and 2D/3D angiography were performed with each intervention. The heart and pulmonary vasculature were histologically assessed., Results: Stent fracture occurred in 9/12 and implantation of large diameter stents was successful in 10/12 animals with no PA aneurysms or dissections. The final stented PA segment and distal left PA branch origins equaled the corresponding PA diameters of sham controls. Growth of left PA immediately beyond the stent was limited and there was diffuse fibro-intimal proliferation within the distal left and right PA. RV contractility was diminished in the intervention group and the response to dobutamine occurred uniquely via increases in heart rate., Conclusions: Early stent intervention in this surgically created PA stenosis model was associated with improved growth of the distal PA vasculature but additional investigation of PA vessel physiology and impact on the developing heart are needed., (© 2018 Wiley Periodicals, Inc.)

Objective: To determine whether prominent intrapulmonary anastomotic vessels (IPAVs) or bronchopulmonary "shunt" vessels can be identified in lungs from infants with fatal congenital diaphragmatic hernia (CDH)., Study Design: We performed histology with immunostaining for CD31 (endothelium) and D2-40 (lymphatics), along with high-precision 3-dimensional (3D) reconstruction on lung tissue from 9 patients who died with CDH., Results: Each patient with CDH required mechanical ventilation, cardiotonic support, and pulmonary hypertension (PH)-targeted drug therapy. All patients were diagnosed with severe PH by echocardiography, and 5 received extracorporeal membrane oxygenation therapy. Death occurred at a median age of 24 days (range, 10-150 days) from refractory hypoxemia with severe PH, pneumonia, or tension pneumothorax. Histology showed decreased alveolarization with pulmonary vascular disease. In each patient, prominent IPAVs were identified as engorged, thin-walled vessels that connected pulmonary veins with microvessels surrounding pulmonary arteries and airways in lungs ipsilateral and contralateral to the CDH. Prominent anastomoses between pulmonary arteries and bronchial arteries were noted as well. The 3D reconstruction studies demonstrated that IPAVs connect pulmonary vasculature to systemic (bronchial) vessels both at the arterial and venous side., Conclusion: Histology and 3D reconstruction identified prominent bronchopulmonary vascular anastamoses in the lungs of infants who died with severe CDH. We speculate that IPAVs connecting pulmonary and bronchial arteries contribute to refractory hypoxemia in severe CDH., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers. MPAs were isolated from control and PPHN fetal sheep model and were tested by planar biaxial testing to measure stiffness in circumferential and axial vessel orientations. Test specimens were fixed for histological assessments of the vascular wall ECM constituents collagen and elastin. MPAs from PPHN sheep had increased mechanical stiffness (P < 0.05) and altered ECM remodeling compared with control MPA. A constitutive mathematical model and histology demonstrated that PPHN vessels have a smaller contribution of elastin and a greater role for collagen fiber engagement compared with the control arteries. We conclude that exposure to chronic hemodynamic stress in late-gestation fetal sheep increases proximal PA stiffness and alters ECM remodeling. We speculate that proximal PA stiffness further contributes to increased right ventricular impedance in experimental PPHN, which contributes to abnormal transition of the pulmonary circulation at birth., (Copyright © 2014 the American Physiological Society.)

Failure to develop antibodies to nonself A and B blood group antigens is well described after infant ABO-incompatible heart transplantation and suggests that exposure to incompatible ABO antigens early in life may lead to tolerance rather than immunogenicity. If this finding is also true following ABO-incompatible cryopreserved homograft implantation, then such patients who require transplantation may be able to accept certain ABO-incompatible organs. In this study, we measured anti-A and -B antibody titers (isohemagglutinins) and allosensitization to human leukocyte antigens (HLA) in 21 patients after homograft placement (12 of whom were <1 year of age at initial homograft exposure) in childhood. We also examined homograft explant specimens for endothelial preservation and expression of HLA and A and B blood group antigens. We observed no differences in isohemagglutinins between patients who received ABO-incompatible versus ABO-compatible homografts. Allosensitization to HLA was present in 88% of patients (9 of 9 ABO-incompatible recipients and 5 of 7 ABO-compatible recipients). In 7 homograft explant specimens (median implant duration 10.1 years), the vasa vasorum endothelium was intact with ABO blood group antigen expression on 3 of 5 non-O homografts. These data suggest that tolerance to incompatible A and B blood group antigens does not occur following placement of ABO-incompatible homografts in childhood., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: The contribution of ABO blood group mismatching on the rate of cardiac homograft failure is uncertain. It has been shown that there is lack of expression of A and B blood group antigens on fresh and cryopreserved homograft valves. However, expression of these antigens on the homograft vessel conduit has not been reported., Methods: Unused portions of cryopreserved pulmonary artery homografts (n = 16) were immunohistochemically stained and examined for expression of endothelial cell marker CD31 and A and B blood group antigens. The staining pattern for each antigen was described. Comparison of homograft donor blood group (as determined by immunostaining) to the blood group reported by the homograft supplier was made., Results: Staining of CD31 and A and B blood group antigens was poor on the luminal surface (tunica intima) of the homograft conduit but strong in the vaso vasorum of the tunica media and adventitia. Homograft donor blood group was consistent with the reported donor blood group in 15 of 16 specimens (4 group A, 3 group B, 8 group O). In one specimen (reported as group O), we detected strong expression of CD31 and A antigen on the endothelium of the vaso vasorum., Conclusions: Cryopreserved homografts strongly express A and B blood group antigens on well-preserved endothelial surfaces of the medial and adventitial vaso vasorum. The significance of this finding with regard to the immunologic response to mismatched ABO blood group antigens and homograft longevity is uncertain.