scholarly journals Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

2020 ◽  
Author(s):  
Carrie L. Welch ◽  
Wendy K. Chung
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
De Novo ◽  
Genetic Disorders ◽  
Etiologic Heterogeneity ◽  
Pulmonary Arterial ◽  
Genetic And Environmental Factors ◽  
Gene X Environment Interactions ◽  
Genetic Burden ◽  
Pediatric Onset

Pulmonary arterial hypertension is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors, and likely gene x environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 36% of pediatric-onset idiopathic PAH (IPAH) compared to ~11% of adult-onset IPAH. De novo variants are frequently associated with PAH in children, and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, the increased etiologic heterogeneity, poorer prognosis and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

scholarly journals Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1213
Author(s):  
Carrie L. Welch ◽  
Wendy K. Chung
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
De Novo ◽  
Genetic Disorders ◽  
Gene Environment ◽  
Etiologic Heterogeneity ◽  
Pulmonary Arterial ◽  
Genetic And Environmental Factors ◽  
Genetic Burden ◽  
Pediatric Onset

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

scholarly journals Where the congenital heart disease meets the pulmonary arterial hypertension, FLNA matters: a case report and literature review

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaoxian Deng ◽  
Shanshan Li ◽  
Qiu Qiu ◽  
Bowen Jin ◽  
Menghuan Yan ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Congenital Heart ◽  
Pediatric Patients ◽  
De Novo ◽  
Wide Spectrum ◽  
Heart Defects ◽  
Pulmonary Arterial

Abstract Background Pediatric patients with genetic disorders have a higher incidence of pulmonary arterial hypertension (PAH) regardless of their heart defects. Filamin A (FLNA) mutation is recently recognized to be associated with pediatric pulmonary disorders, however, the clinical courses of PAH related to the mutation were reported in limited cases. Here, we presented a case and pooled data for better understanding of the correlation between FLNA mutation and pediatric PAH. Case presentation The patient was a 8-month-old female with repeated episodes of pneumonia. Physical examination revealed cleft lip, cleft palate and developmental retardation. Imaging examination showed a small atrial septal defect (ASD), central pulmonary artery enlargement, left upper lobe of lung atelectasis, and pulmonary infiltration. Genetic test showed she carried a de novo pathogenic variant of FLNA gene (c.5417-1G > A, p.-). Oral medications didn’t slow the progression of PAH in the patient, and she died two years later. Conclusions FLNA mutation causes rare but progressive PAH in addition to a wide spectrum of congenital heart disease and other comorbidities in pediatric patients. We highly recommend genetic testing for pediatric patients when suspected with PAH. Given the high mortality in this group, lung transplantation may offer a better outcome.

Alemtuzumab and de novo pulmonary arterial hypertension: A potential association?

2017 ◽  
Vol 36 (3) ◽  
pp. 370-371 ◽  
Author(s):  
Laura Beaumier ◽  
Sébastien Chanoine ◽  
Boubou Camara ◽  
Christophe Pison ◽  
Pierrick Bedouch
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
De Novo ◽  
Potential Association ◽  
Pulmonary Arterial

scholarly journals Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicate FBLN2, PDGFD and rare de novo variants in PAH

2020 ◽  
Author(s):  
Na Zhu ◽  
Emilia M. Swietlik ◽  
Carrie L. Welch ◽  
Michael W. Pauciulo ◽  
Jacob J. Hagen ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Candidate Genes ◽  
Rare Variant ◽  
De Novo ◽  
Risk Genes ◽  
International Consortium ◽  
Rare Variant Analysis ◽  
Pulmonary Arterial ◽  
Variant Analysis

AbstractBackgroundGroup 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Recent high-throughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases.MethodsTo identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource – Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 2,789 cases and 18,819 controls (11,101 unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzed de novo variants in 124 pediatric trios.ResultsSeven genes with rare deleterious variants were significantly associated (false discovery rate <0.1) with IPAH, including three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (FBLN2, fibulin 2; PDGFD, platelet-derived growth factor D). The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most of the variants occur in conserved protein domains. Variants in known PAH gene, ACVRL1, showed association with APAH. Predicted deleterious de novo variants in pediatric cases exhibited a significant burden compared to the background mutation rate (2.5x, p=7.0E-6). At least eight novel candidate genes carrying de novo variants have plausible roles in lung/heart development.ConclusionsRare variant analysis of a large international consortium identifies two new candidate genes - FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling but have not been previously implicated in PAH. Trio analysis predicts that ~15% of pediatric IPAH may be explained by de novo variants.

scholarly journals O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension

2019 ◽  
Vol 20 (24) ◽  
pp. 6299 ◽  
Author(s):  
Jarrod W. Barnes ◽  
Liping Tian ◽  
Stefanie Krick ◽  
E. Scott Helton ◽  
Rebecca S. Denson ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
De Novo ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Tube Length ◽  
Vegf Expression ◽  
Plexiform Lesions ◽  
Pulmonary Arterial ◽  
Glcnac Transferase

Idiopathic pulmonary arterial hypertension (IPAH) is considered a vasculopathy characterized by elevated pulmonary vascular resistance due to vasoconstriction and/or lung remodeling such as plexiform lesions, the hallmark of the PAH, as well as cell proliferation and vascular and angiogenic dysfunction. The serine/threonine hydroxyl-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) has been shown to drive pulmonary arterial smooth muscle cell (PASMC) proliferation in IPAH. OGT is a cellular nutrient sensor that is essential in maintaining proper cell function through the regulation of cell signaling, proliferation, and metabolism. The aim of this study was to determine the role of OGT and O-GlcNAc in vascular and angiogenic dysfunction in IPAH. Primary isolated human control and IPAH patient PASMCs and pulmonary arterial endothelial cells (PAECs) were grown in the presence or absence of OGT inhibitors and subjected to biochemical assessments in monolayer cultures and tube formation assays, in vitro vascular sprouting 3D spheroid co-culture models, and de novo vascularization models in NODSCID mice. We showed that knockdown of OGT resulted in reduced vascular endothelial growth factor (VEGF) expression in IPAH primary isolated vascular cells. In addition, specificity protein 1 (SP1), a known stimulator of VEGF expression, was shown to have higher O-GlcNAc levels in IPAH compared to control at physiological (5 mM) and high (25 mM) glucose concentrations, and knockdown resulted in decreased VEGF protein levels. Furthermore, human IPAH PAECs demonstrated a significantly higher degree of capillary tube-like structures and increased length compared to control PAECs. Addition of an OGT inhibitor, OSMI-1, significantly reduced the number of tube-like structures and tube length similar to control levels. Assessment of vascular sprouting from an in vitro 3D spheroid co-culture model using IPAH and control PAEC/PASMCs and an in vivo vascularization model using control and PAEC-embedded collagen implants demonstrated higher vascularization in IPAH compared to control. Blocking OGT activity in these experiments, however, altered the vascular sprouting and de novo vascularization in IPAH similar to control levels when compared to controls. Our findings in this report are the first to describe a role for the OGT/O-GlcNAc axis in modulating VEGF expression and vascularization in IPAH. These findings provide greater insight into the potential role that altered glucose uptake and metabolism may have on the angiogenic process and the development of plexiform lesions. Therefore, we believe that the OGT/O-GlcNAc axis may be a potential therapeutic target for treating the angiogenic dysregulation that is present in IPAH.

scholarly journals De novo synthesize of bile acids in pulmonary arterial hypertension lung

Metabolomics ◽  
2014 ◽  
Vol 10 (6) ◽  
pp. 1169-1175 ◽  
Author(s):  
Yidan D. Zhao ◽  
Hana Z. H. Yun ◽  
Jenny Peng ◽  
Li Yin ◽  
Lei Chu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Bile Acids ◽  
De Novo ◽  
Pulmonary Arterial

scholarly journals Pulmonary arterial hypertension outcomes upon endothelin-1 receptor antagonist switch to macitentan

2019 ◽  
Vol 47 (5) ◽  
pp. 2177-2186 ◽  
Author(s):  
Timothy Tynan ◽  
Kathryn Hird ◽  
Tara Hannon ◽  
Eli Gabbay
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
De Novo ◽  
Cohort Analysis ◽  
Functional Class ◽  
World Health ◽  
Control Group ◽  
6Mwt Distance ◽  
Pulmonary Arterial ◽  
Health Organization

Objectives To assess whether switching patients with suboptimally controlled pulmonary arterial hypertension from bosentan or ambrisentan to macitentan would improve six-minute walk test (6MWT) distance and World Health Organization functional class. Methods This was a retrospective cohort analysis of 37 patients from a single center. Patients were separated into three heterogeneous treatment groups and followed for 18 months: switch group (n = 14): patients switched to macitentan from bosentan/ambrisentan; added group (n = 11): patients who began macitentan as de novo therapy (n = 5) or who added macitentan to an existing sildenafil regimen (n = 6); and control group (n = 12): patients for whom sildenafil and/or bosentan/ambrisentan therapy was unchanged. Results Mortality was observed in two patients (one each, switch and added groups). Patients in the control group had one hospital admission and 100% survival. There was significant improvement in functional class for the switch and added groups. Statistically significant improvement was observed in 6MWT distance in the added group alone. Overall, 92% of patients continued macitentan throughout the study. Conclusion Macitentan was well tolerated. For bosentan/ambrisentan-treated patients with suboptimally controlled pulmonary arterial hypertension, switching to macitentan may facilitate an improvement in functional class.

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