RESUMO
It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximize long-term outcomes. To better define the nature of PH in the setting of developmental lung disorders (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities, and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasized to create an interdisciplinary consensus.
RESUMO
Tbx4 protein, expressed in mesenchyme of the developing lung, contributes to airway branching and distal lung growth. An association between pediatric onset of pulmonary arterial hypertension (PAH) and genetic variations coding for the T-box transcription factor 4 gene (TBX4) has been increasingly recognized. Tbx4-related PAH onset has a bimodal age distribution, including severe to lethal PAH in newborns and later onset PAH. We present an autopsy study of a 24-year-old male with a heterozygous TBX4 variant, who developed pulmonary arterial hypertension at age 12 years. This unique case highlights the complex pulmonary histopathology leading to lethal cardiopulmonary failure in the setting of TBX4 mutation.
Assuntos
Mutação em Linhagem Germinativa , Hipertensão Arterial Pulmonar , Masculino , Criança , Humanos , Recém-Nascido , Adulto Jovem , Adulto , Hipertensão Arterial Pulmonar/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Pulmão , Mutação , Fenótipo , Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar Primária Familiar/metabolismo , Fatores de Transcrição/genéticaRESUMO
Over the past decade, recognition of the profound impact of the TBX4 (T-box 4) gene, which encodes a member of the evolutionarily conserved family of T-box-containing transcription factors, on respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research directions to fill the gaps in our understanding of TBX4 function and of how TBX4 disruption affects development.
Assuntos
Proteínas com Domínio T , Fatores de Transcrição , Animais , Humanos , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , FenótipoRESUMO
The purpose of this study was to evaluate intrapulmonary arteriovenous shunts in patients with and without sudden unexplained infant death. We identified open intrapulmonary bronchopulmonary anastomoses as potential pathways for right-to-left shunt in a subset of infants with sudden unexplained infant death.
Assuntos
Pulmão , Morte Súbita do Lactente , Humanos , Morte Súbita do Lactente/etiologia , Morte do Lactente , Pulmão/diagnóstico por imagem , Cardiopatias Congênitas , Malformações Arteriovenosas , Masculino , Feminino , LactenteRESUMO
BACKGROUND: Germline mutation in bone morphogenetic protein type II (BMPR2) is the most common cause of idiopathic/heritable pulmonary hypertension in pediatric patients. Despite the discovery of this gene there are no known descriptions of the CT or CT angiography findings in these children. OBJECTIVE: To correlate the clinical presentation, pathology and chest CT findings in pediatric patients with pulmonary hypertension caused by mutations in the BMPR2 gene. MATERIALS AND METHODS: We performed a search to identify pediatric patients with a BMPR2 mutation and CT or CT angiography with the clinical history of pulmonary hypertension. Three pediatric radiologists reviewed the children's CT imaging findings and ranked the dominant findings in order of prevalence via consensus. RESULTS: We identified three children with pulmonary hypertension and confirmed germline BMPR2 mutations, two of whom had undergone lung biopsy. We then correlated the imaging findings with histopathology and clinical course. CONCLUSION: All of our patients with BMPR2 mutations demonstrated a distinct CT pattern of ground-glass nodules with a prominent central enhancing vessel/nodule. These findings correlated well with the pathological findings of plexogenic arteriopathy.
Assuntos
Hipertensão Pulmonar , Humanos , Criança , Hipertensão Pulmonar/genética , Mutação , Hipertensão Pulmonar Primária Familiar , Tomografia Computadorizada por Raios X , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genéticaRESUMO
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.
Assuntos
Hipertensão Pulmonar Primária Familiar/diagnóstico , Microscopia de Contraste de Fase/métodos , Artéria Pulmonar/patologia , Síncrotrons/instrumentação , Microtomografia por Raio-X/métodos , Adulto , Estudos de Casos e Controles , Hipertensão Pulmonar Primária Familiar/classificação , Hipertensão Pulmonar Primária Familiar/diagnóstico por imagem , Feminino , Hemodinâmica , Humanos , Masculino , Remodelação VascularRESUMO
Cardiac angiosarcoma (AS) is an extremely rare, malignant vascular tumor with <10 cases reported in the pediatric literature. Prognosis is dismal with overall survival often <1 year from initial diagnosis. In this report, we present the case of a 10-year-old boy with metastatic cardiac AS who is currently alive and is the longest pediatric survivor of metastatic cardiac AS reported in the literature. This is the only published pediatric case to successfully use a combination of surgical resection, conventional chemotherapy, radiation and targeted therapies including bevacizumab and pazopanib for metastatic cardiac AS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Neoplasias Cardíacas/terapia , Hemangiossarcoma/terapia , Segunda Neoplasia Primária/terapia , Procedimentos Cirúrgicos Operatórios/métodos , Bevacizumab/administração & dosagem , Criança , Terapia Combinada , Neoplasias Cardíacas/patologia , Hemangiossarcoma/secundário , Humanos , Indazóis , Masculino , Segunda Neoplasia Primária/patologia , Prognóstico , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagemRESUMO
This study aimed to explore the value of synchrotron-based phase-contrast microcomputed tomography (micro-CT) in pulmonary vascular pathobiology. The microanatomy of the lung is complex with intricate branching patterns. Tissue sections are therefore difficult to interpret. Recruited intrapulmonary bronchopulmonary anastomoses (IBAs) have been described in several forms of pulmonary hypertension, including alveolar capillary dysplasia with misaligned pulmonary veins (ACD/MPV). Here, we examine paraffin-embedded tissue using this nondestructive method for high-resolution three-dimensional imaging. Blocks of healthy and ACD/MPV lung tissue were used. Pulmonary and bronchial arteries in the ACD/MPV block had been preinjected with dye. One section per block was stained, and areas of interest were marked to allow precise beam-alignment during image acquisition at the X02DA TOMCAT beamline (Swiss Light Source). A ×4 magnifying objective coupled to a 20-µm thick scintillating material and a sCMOS detector yielded the best trade-off between spatial resolution and field-of-view. A phase retrieval algorithm was applied and virtual tomographic slices and video clips of the imaged volumes were produced. Dye injections generated a distinct attenuation difference between vessels and surrounding tissue, facilitating segmentation and three-dimensional rendering. Histology and immunohistochemistry post-imaging offered complementary information. IBAs were confirmed in ACD/MPV, and the MPVs were positioned like bronchial veins/venules. We demonstrate the advantages of using synchrotron-based phase-contrast micro-CT for three-dimensional characterization of pulmonary microvascular anatomy in paraffin-embedded tissue. Vascular dye injections add additional value. We confirm intrapulmonary shunting in ACD/MPV and provide support for the hypothesis that MPVs are dilated bronchial veins/venules.
Assuntos
Pulmão/patologia , Síndrome da Persistência do Padrão de Circulação Fetal/patologia , Alvéolos Pulmonares/anormalidades , Veias Pulmonares/patologia , Brônquios/patologia , Humanos , Hipertensão Pulmonar/patologia , Imageamento Tridimensional/métodos , Recém-Nascido , Microscopia de Contraste de Fase/métodos , Alvéolos Pulmonares/patologia , Síncrotrons , Microtomografia por Raio-X/métodosRESUMO
Pulmonary hypertension (pHTN) is a severe, life-threatening disease, which can be idiopathic or associated with an underlying syndrome or genetic diagnosis. Here we discuss a patient who presented with severe pHTN and was later found to be compound heterozygous for pathogenic variants in the NFU1 gene causing multiple mitochondrial dysfunctions syndrome 1 (MMDS1). Review of autopsy slides from an older sibling revealed the same diagnosis along with pulmonary findings consistent with a developmental lung disorder. In particular, these postmortem, autopsy findings have not been described previously in humans with this mitochondrial syndrome and suggest a possible developmental basis for the severe pHTN seen in this disease. Given the rarity of patients reported with MMDS1, we review the current state of knowledge of this disease and our novel management strategies for pHTN and MMDS1-associated complications in this population.
Assuntos
Proteínas de Transporte/genética , Deficiências do Desenvolvimento/etiologia , Hipertensão Pulmonar/etiologia , Doenças Mitocondriais/complicações , Mutação , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Hipertensão Pulmonar/patologia , Recém-Nascido , Masculino , Doenças Mitocondriais/genética , PrognósticoRESUMO
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.
Assuntos
Aorta/fisiopatologia , Hemodinâmica , Artéria Pulmonar/fisiopatologia , Doença Cardiopulmonar/fisiopatologia , Remodelação Vascular , Animais , Aorta/metabolismo , Aorta/patologia , Pressão Arterial/fisiologia , Proliferação de Células , Oclusão Coronária/genética , Oclusão Coronária/metabolismo , Oclusão Coronária/fisiopatologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Feto , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Óxido Nítrico/metabolismo , Gravidez , Cultura Primária de Células , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Circulação Pulmonar/fisiologia , Doença Cardiopulmonar/congênito , Doença Cardiopulmonar/metabolismo , Doença Cardiopulmonar/patologia , OvinosRESUMO
Rare variants in the T-box transcription factor 4 gene (TBX4) have recently been recognised as an emerging cause of paediatric pulmonary hypertension (PH). Their pathophysiology and contribution to persistent pulmonary hypertension in neonates (PPHN) are unknown. We sought to define the spectrum of clinical manifestations and histopathology associated with TBX4 variants in neonates and children with PH.We assessed clinical data and lung tissue in 19 children with PH, including PPHN, carrying TBX4 rare variants identified by next-generation sequencing and copy number variation arrays.Variants included six 17q23 deletions encompassing the entire TBX4 locus and neighbouring genes, and 12 likely damaging mutations. 10 infants presented with neonatal hypoxic respiratory failure and PPHN, and were subsequently discharged home. PH was diagnosed later in infancy or childhood. Three children died and two required lung transplantation. Associated anomalies included patent ductus arteriosus, septal defects, foot anomalies and developmental disability, the latter with a higher prevalence in deletion carriers. Histology in seven infants showed abnormal distal lung development and pulmonary hypertensive remodelling.TBX4 mutations and 17q23 deletions underlie a new form of developmental lung disease manifesting with severe, often biphasic PH at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies.
Assuntos
Deleção de Genes , Hipertensão Pulmonar/genética , Proteínas com Domínio T/genética , Adolescente , Adulto , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Variação Genética , Heterozigoto , Humanos , Lactente , Recém-Nascido , Pulmão/crescimento & desenvolvimento , Transplante de Pulmão , Masculino , Mutação , Fenótipo , Resistência Vascular , Adulto JovemRESUMO
Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia, or normoxia as a control in custom, gas-permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10 h/day CIH (AHI = 12/h), static hypoxia, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and static hypoxia slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67 vs. 12%, P = 0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival (P = 0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared with the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer.
Assuntos
Proliferação de Células , Hipóxia/complicações , Mieloma Múltiplo/patologia , Animais , Linhagem Celular Tumoral , Doença Crônica , Progressão da Doença , Feminino , Hipóxia/metabolismo , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/complicações , Mieloma Múltiplo/metabolismo , Fatores de Tempo , Carga Tumoral , Hipóxia Tumoral , Microambiente TumoralRESUMO
BACKGROUND: The expression of the NKX2-1 gene and its encoded protein, thyroid transcription factor 1 (TTF-1), plays a role in pulmonary surfactant homeostasis and lung development. NKX2-1 mutations have been associated with neonatal respiratory distress, hypotonia, choreoathetosis and congenital hypothyroidism. These clinical findings have been coined brain-lung-thyroid syndrome, although not all three organs are always involved. While many of these children develop interstitial lung disease, no systematic review of chest high-resolution CT (HRCT) findings has been reported. OBJECTIVE: To summarize the clinical presentations, pathology and HRCT imaging findings of children with NKX2-1 mutations. MATERIALS AND METHODS: We identified six children with NKX2-1 mutations, deletions or duplications confirmed via genetic testing at our institution. Three pediatric radiologists reviewed the children's HRCT imaging findings and ranked the dominant findings in order of prevalence via consensus. We then correlated the imaging findings with histopathology and clinical course. RESULTS: All children in the study were heterozygous for NKX2-1 mutations, deletions or duplications. Ground-glass opacities were the most common imaging feature, present in all but one child. Consolidation was also a prevalent finding in 4/6 of the children. Architectural distortion was less common. CONCLUSION: HRCT findings of TTF-1 deficiency are heterogeneous and evolve over time. There is significant overlap between the HRCT findings of TTF-1 deficiency, other surfactant dysfunction mutations, and pulmonary interstitial glycogenosis. TTF-1 deficiency should be considered in term infants presenting with interstitial lung disease, especially if hypotonia or hypothyroidism is present.
Assuntos
Atetose/diagnóstico por imagem , Atetose/genética , Coreia/diagnóstico por imagem , Coreia/genética , Hipotireoidismo Congênito/diagnóstico por imagem , Hipotireoidismo Congênito/genética , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico por imagem , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Fator Nuclear 1 de Tireoide/genética , Tomografia Computadorizada por Raios X/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fator Nuclear 1 de Tireoide/deficiênciaRESUMO
While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (nâ¯=â¯61). Additional prospective echocardiograms were obtained when possible (nâ¯=â¯22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney pâ¯<â¯.001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney pâ¯<â¯.0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.
Assuntos
Doenças Autoimunes do Sistema Nervoso/complicações , Exodesoxirribonucleases/genética , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Helicase IFIH1 Induzida por Interferon/genética , Mutação , Malformações do Sistema Nervoso/complicações , Fosfoproteínas/genética , Adolescente , Criança , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
OBJECTIVES: To determine the incidence, characteristics of, and risk factors contributing to the development of pulmonary hypertension in children with Down syndrome. STUDY DESIGN: This retrospective, review of a large cohort (n = 1242) of children with Down syndrome receiving care at a specialized referral center evaluated clinical data and serial echocardiograms from a clinic database and electronic medical records. Pulmonary hypertension characteristics and comorbidities were reviewed. Pulmonary hypertension was considered transient if echocardiographic evidence of pulmonary hypertension resolved without recurrence, persistent if no resolution, and recurrent if evidence of pulmonary hypertension returned after a period of resolution. RESULTS: The incidence of pulmonary hypertension in children with Down syndrome was 28% (n = 346). Median age at initial diagnosis was 5 days (range: 0-7067 days). Pulmonary hypertension was differentiated into transient (70%), persistent (15%), and recurrent (15%) disease. Median duration of transient pulmonary hypertension was 8 months (range: 0.1-130.2 months). Median age at recurrence was 2.5 years (range 0.2-11.5 years). Initial pulmonary hypertension diagnosis was classified as World Health Organization group I disease in 82%, with 45% associated with congenital heart disease (CHD), and 38% persistent pulmonary hypertension of the newborn (PPHN). The pulmonary hypertension recurrence rate was significant and similar for both those with initial PPHN (12%) and non-PPHN (16%). A majority (87%) of patients with recurrent pulmonary hypertension were classified as World Health Organization group III. Frequently identified comorbid conditions included CHD, obstructive sleep apnea, intermittent hypoxia, and recurrent pneumonia. CONCLUSIONS: Pulmonary hypertension is common in children with Down syndrome, is typically transient, and related to CHD or PPHN but can recur in the setting of respiratory disease such as obstructive sleep apnea, intermittent hypoxia, and recurrent pneumonia.
Assuntos
Síndrome de Down/diagnóstico , Síndrome de Down/epidemiologia , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Distribuição por Idade , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Bases de Dados Factuais , Síndrome de Down/terapia , Ecocardiografia Doppler/métodos , Feminino , Humanos , Hipertensão Pulmonar/terapia , Lactente , Recém-Nascido , Masculino , Monitorização Fisiológica , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Estados UnidosRESUMO
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.