scholarly journals Genetics and genomics of pulmonary arterial hypertension

2019 ◽  
Vol 53 (1) ◽  
pp. 1801899 ◽  
Author(s):  
Nicholas W. Morrell ◽  
Micheala A. Aldred ◽  
Wendy K. Chung ◽  
C. Gregory Elliott ◽  
William C. Nichols ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Diagnosis ◽  
Molecular Classification ◽  
Incomplete Penetrance ◽  
Therapeutic Approaches ◽  
Genomic Studies ◽  
Pulmonary Arterial ◽  
The Impact

Since 2000 there have been major advances in our understanding of the genetic and genomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based on existing knowledge, around 25–30% of patients diagnosed with idiopathic PAH have an underlying Mendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, we summarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches. In addition, factors determining the incomplete penetrance observed in HPAH are discussed. The currently available approaches to genetic testing and counselling, and the impact of a genetic diagnosis on clinical management of the patient with PAH, are presented. Advances in DNA sequencing technology are rapidly expanding our ability to undertake genomic studies at scale in large cohorts. In the future, such studies will provide a more complete picture of the genetic contribution to PAH and, potentially, a molecular classification of this disease.

scholarly journals Heritable pulmonary hypertension: from bench to bedside

2017 ◽  
Vol 26 (145) ◽  
pp. 170037 ◽  
Author(s):  
Barbara Girerd ◽  
Jason Weatherald ◽  
David Montani ◽  
Marc Humbert
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Diagnosis ◽  
Predictive Testing ◽  
Incomplete Penetrance ◽  
European Respiratory Society ◽  
Dominant Disease ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension

Mutations in the BMPR2 gene, and more rarely in ACVRL1, endoglin, caveolin-1, KCNK3 and TBX4 genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance. Bi-allelic mutations in the EIF2AK4 gene predispose to heritable pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis, an autosomal recessive disease with an unknown penetrance.In France, the national pulmonary hypertension referral centre offers genetic counselling and testing to adults and children. Predictive testing is also proposed to adult relatives at risk of carrying a predisposing mutation. In that context, we offer all asymptomatic BMPR2 mutation carriers a programme to detect pulmonary arterial hypertension at an early phase, as recommended by the 2015 European Society Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Finally, pre-implantation genetic diagnosis has been conducted on five embryos from two couples in which the fathers were carriers of a pathogenic BMPR2 mutation.

scholarly journals Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3178
Author(s):  
Natalia Gallego ◽  
Alejandro Cruz-Utrilla ◽  
Inmaculada Guillén ◽  
Amparo Moya Bonora ◽  
Nuria Ochoa ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Incomplete Penetrance ◽  
Presumptive Diagnosis ◽  
Pathogenic Variants ◽  
Pulmonary Arterial ◽  
Next Generation Sequencing Ngs

Pulmonary arterial hypertension (PAH) sometimes co-exists with hereditary hemorrhagic telangiectasia (HHT). Despite being clinically diagnosable according to Curaçao criteria, HHT can be difficult to diagnose due to its clinically heterogenicity and highly overlapping with PAH. Genetic analysis of the associated genes ACVRL1, ENG, SMAD4 and GDF2 can help to confirm or discard the presumptive diagnosis. As part of the clinical routine and to establish a genetic diagnosis, we have analyzed a cohort of patients with PAH and overlapping HHT features through a customized Next Generation Sequencing (NGS) panel of 21 genes, designed and validated in-house. We detected a homozygous missense variant in GDF2 in a pediatric patient diagnosed with PAH associated with HHT and a missense variant along with a heterozygous deletion in another idiopathic PAH patient (compound heterozygous inheritance). In order to establish variant segregation, we analyzed all available family members. In both cases, parents were carriers for the variants, but neither was affected. Our results expand the clinical spectrum and the inheritance pattern associated with GDF2 pathogenic variants suggesting incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance.

scholarly journals Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 779
Author(s):  
Daria S. Kostyunina ◽  
Paul McLoughlin
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Sex Chromosomes ◽  
Bone Morphogenetic Protein 2 ◽  
Sex Dimorphism ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary hypertension (PH) is a condition characterised by an abnormal elevation of pulmonary artery pressure caused by an increased pulmonary vascular resistance, frequently leading to right ventricular failure and reduced survival. Marked sexual dimorphism is observed in patients with pulmonary arterial hypertension, a form of pulmonary hypertension with a particularly severe clinical course. The incidence in females is 2–4 times greater than in males, although the disease is less severe in females. We review the contribution of the sex chromosomes to this sex dimorphism highlighting the impact of proteins, microRNAs and long non-coding RNAs encoded on the X and Y chromosomes. These genes are centrally involved in the cellular pathways that cause increased pulmonary vascular resistance including the production of reactive oxygen species, altered metabolism, apoptosis, inflammation, vasoconstriction and vascular remodelling. The interaction with genetic mutations on autosomal genes that cause heritable pulmonary arterial hypertension such as bone morphogenetic protein 2 (BMPR2) are examined. The mechanisms that can lead to differences in the expression of genes located on the X chromosomes between females and males are also reviewed. A better understanding of the mechanisms of sex dimorphism in this disease will contribute to the development of more effective therapies for both women and men.

scholarly journals Symptoms, impacts, and suitability of the Pulmonary Arterial Hypertension – Symptoms and Impact (PAH-SYMPACT™) questionnaire in patients with chronic thromboembolic pulmonary hypertension (CTEPH): a qualitative interview study

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Brooke Currie ◽  
Evan Davies ◽  
Amélie Beaudet ◽  
Larissa Stassek ◽  
Leah Kleinman
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Shortness Of Breath ◽  
Response Options ◽  
Qualitative Interview Study ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
The Impact

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare form of pulmonary hypertension caused by blood clots and scar tissue in the blood vessels of the lungs. Health-related quality of life is often significantly impaired in patients with CTEPH. However, a better understanding of how CTEPH symptoms affect patients’ lives is needed to optimally assess the impact of the disease and treatment. Objectives This qualitative study aimed to better understand the symptoms of CTEPH and how they affect patients’ lives, as well as to determine the appropriateness of the Pulmonary Arterial Hypertension – Symptoms and Impact (PAH-SYMPACT™) questionnaire for use in this patient population. Methods Adults diagnosed with CTEPH, recruited from two clinical sites in the US, participated in one-to-one qualitative telephone interviews. They described their experience of CTEPH symptoms and the impact these symptoms have on their lives. They also provided feedback on the comprehensibility and relevance of the PAH-SYMPACT™‘s instructions, items, and response options. Results Participants (N = 12) had a mean age of 62.5 years. Two thirds were female and most (83%) had undergone pulmonary endarterectomy and/or balloon pulmonary angioplasty. The most frequently endorsed symptoms were shortness of breath (endorsed by all 12 participants), fatigue (11 participants), and lightheadedness (10 participants). All participants identified shortness of breath as an “extremely important” symptom, and seven participants rated fatigue as “extremely important.” The most frequent impacts of CTEPH were on ability to walk quickly (endorsed by all 12 participants), ability to walk up inclines or stairs (11 participants), and ability to carry things (11 participants). The PAH-SYMPACT™ items were relevant to most participants and reflected their experience of CTEPH. All participants indicated that no important CTEPH symptoms were missing from the PAH-SYMPACT™. Overall, the instructions, items, and response options of the PAH-SYMPACT™ were clear and easy to understand. Conclusions The symptoms and impacts experienced by patients with CTEPH align with items included in the PAH-SYMPACT™. The PAH-SYMPACT™ appears to be fit for purpose for assessing disease status in patients with CTEPH.

scholarly journals EXPRESS: Genetic basis of pulmonary arterial hypertension: A prospective study from a highly inbred population

2021 ◽  
pp. 204589402110320
Author(s):  
Abdullah Aldalaan ◽  
Khushnooda Ramzan ◽  
Sarfraz Saleemi ◽  
Ihab Weheba ◽  
Laila Alquait ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Basis ◽  
Genetic Diagnosis ◽  
Saudi Arabian ◽  
High Rate ◽  
Risk Genes ◽  
Entire Cohort ◽  
Pulmonary Arterial ◽  
A Prospective Study

Pulmonary arterial hypertension (PAH), whether idiopathic PAH (IPAH), heritable PAH, or associated with other conditions, is a rare and potentially lethal disease characterized by progressive vascular changes. To date, there is limited data on the genetic basis of PAH in the Arab region, and none from Saudi Arabian patients. This study aims to identify genetic variations and to evaluate the frequency of risk genes associated to PAH, in Saudi Arabian patients. Adult PAH patients, diagnosed with IPAH and pulmonary veno-occlusive disease (PVOD), of Saudi Arabian origin, were enrolled in this study. Forty-eight patients were subjected to whole exome sequencing (WES), with screening of 26 genes suggested to be associated with the disease. The median age at diagnosis was 29.5 years of age, with females accounting for 89.5% of our cohort population. Overall, we identified variations in 9 genes previously associated with PAH, in 16 patients. Fourteen of these variants have not been described before. Plausible deleterious variants in risk genes were identified in 33.3% (n=16/48) of our entire cohort and 25% of these cases carried variants in BMPR2 (n=4/16). Our results highlight the genetic etiology of PAH in Saudi Arabia patients and provides new insights for the genetic diagnosis of familial and IPAH, as well as for the identification of the biological pathways of the disease. This will enable the development of new target therapeutic strategies, for a disease with a high rate of morbidity and mortality.

scholarly journals The striated muscles in pulmonary arterial hypertension: adaptations beyond the right ventricle

2015 ◽  
Vol 46 (3) ◽  
pp. 832-842 ◽  
Author(s):  
Emmy Manders ◽  
Silvia Rain ◽  
Harm-Jan Bogaard ◽  
M. Louis Handoko ◽  
Ger J.M. Stienen ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Exercise Intolerance ◽  
Muscle Dysfunction ◽  
Striated Muscles ◽  
Pulmonary Arterial ◽  
The Right ◽  
The Impact

Pulmonary arterial hypertension (PAH) is a fatal lung disease characterised by progressive remodelling of the small pulmonary vessels. The daily-life activities of patients with PAH are severely limited by exertional fatigue and dyspnoea. Typically, these symptoms have been explained by right heart failure. However, an increasing number of studies reveal that the impact of the PAH reaches further than the pulmonary circulation. Striated muscles other than the right ventricle are affected in PAH, such as the left ventricle, the diaphragm and peripheral skeletal muscles. Alterations in these striated muscles are associated with exercise intolerance and reduced quality of life. In this Back to Basics article on striated muscle function in PAH, we provide insight into the pathophysiological mechanisms causing muscle dysfunction in PAH and discuss potential new therapeutic strategies to restore muscle dysfunction.

Pulmonary hypertension genes as major diagnostic tools

ESC CardioMed ◽  
2018 ◽  
pp. 2490-2493
Author(s):  
Mélanie Eyries ◽  
Barbara Girerd ◽  
David Montani ◽  
David-Alexandre Tregouët ◽  
Marc Humbert ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Gene Mutations ◽  
Diagnostic Tools ◽  
Genetic Mutations ◽  
Incomplete Penetrance ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Sporadic Cases ◽  
Pulmonary Arterial

A few genes have been shown to be major predisposing factors for pulmonary hypertension and are responsible for heritable forms of the disease. However, for nearly all genes described, not all mutation carriers develop the disease (autosomal transmission with incomplete penetrance) explaining the presence of genetic mutations in apparently sporadic cases. Beside mutations in major genes (BMPR2 for pulmonary arterial hypertension and EIF2AK4 for recessive heritable pulmonary veno-occlusive disease), other genes have been involved in a very limited number of cases (KCNK3, CAV1, and Smad8). Gene mutations are also been found as part of syndromic diseases (ACVRL1 mutations in hereditary haemorrhagic telangiectasia and TBX4 in small patella syndrome).

scholarly journals Novel Therapeutic Approaches of Pulmonary Arterial Hypertension

2019 ◽  
Vol 28 (02) ◽  
pp. 112-117
Author(s):  
Sanjay Tyagi ◽  
Vishal Batra
Keyword(s):  
Nitric Oxide ◽  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Endothelin Receptors ◽  
Pulmonary Vasculature ◽  
Therapeutic Approaches ◽  
Uncommon Disease ◽  
Pulmonary Arterial ◽  
Novel Therapeutic

AbstractPulmonary arterial hypertension (PAH) is an uncommon disease characterized progressive remodeling of pulmonary vasculature. Although treatment for PAH have improved in last two decades but the outcome remains fatal. Currently, the therapies for PAH target three well-established pathways the nitric oxide (NO) pathway, endothelin receptors, and prostanoids. There are multiple potential targets for development of newer drugs in PAH which requires meticulous research and clinical trials.

scholarly journals Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension

2020 ◽  
pp. 1902061
Author(s):  
David Macias ◽  
Stephen Moore ◽  
Alexi Crosby ◽  
Mark Southwood ◽  
Xinlin Du ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Target Genes ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyper-proliferative phenotype and over-active arginase activity in blood outgrowth endothelial cells from IPAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

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