Precision Medicine for Pulmonary Vascular Disease: The Future Is Now (2023 Grover Conference Series).

Pulmonary vascular disease is not a single condition; rather it can accompany a variety of pathologies that impact the pulmonary vasculature. Applying precision medicine strategies to better phenotype, diagnose, monitor, and treat pulmonary vascular disease is increasingly possible with the growing accessibility of powerful clinical and research tools. Nevertheless, challenges exist in implementing these tools to optimal effect.

Structural and functional determination of peptide versus small molecule ligand binding at the apelin receptor.

We describe a structural and functional study of the G protein-coupled apelin receptor, which binds two endogenous peptide ligands, apelin and Elabela/Toddler (ELA), to regulate cardiovascular development and function. Characterisation of naturally occurring apelin receptor variants from the UK Genomics England 100,000 Genomes Project, and AlphaFold2 modelling, identifies T89 as important in the ELA binding site, and R168 as forming extensive interactions with the C-termini of both peptides. Base editing to introduce an R/H168 variant into human stem cell-derived cardiomyocytes demonstrates that this residue is critical for receptor binding and function.

Adaptation of ACMG/AMP guidelines for clinical classification of variants in Pulmonary Arterial Hypertension resolves variants of unclear pathogenicity in ClinVar.

Purpose: Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by pathogenic variants, most frequently in the bone morphogenetic protein receptor type 2 ( ) gene. We formed a ClinGen variant curation expert panel to devise guidelines for the clinical interpretation of variants identified in PAH patients.

Methods: The general ACMG/AMP variant classification criteria were refined for PAH and adapted to following ClinGen procedures.

Sex-specific Genetic Determinants of Right Ventricular Structure and Function.

Rationale: While sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown.

Objectives: To provide biological insights into sex differences in the structure and function of the right ventricle (RV) using common genetic variation.

Methods: RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank.

Role of Forkhead box F1 in the Pathobiology of Pulmonary Arterial Hypertension.

Rationale: Approximately 80% of patients with non-familial pulmonary arterial hypertension (PAH) lack identifiable pathogenic genetic variants. While most genetic studies of PAH have focused on predicted loss-of-function variants, recent approaches have identified ultra-rare missense variants associated with the disease. encodes a highly conserved transcription factor, essential for angiogenesis and vasculogenesis in human and mouse lungs.

Genetics and precision genomics approaches to pulmonary hypertension.

Considerable progress has been made in the genomics of pulmonary arterial hypertension (PAH) since the 6th World Symposium on Pulmonary Hypertension, with the identification of rare variants in several novel genes, as well as common variants that confer a modest increase in PAH risk. Gene and variant curation by an expert panel now provides a robust framework for knowing which genes to test and how to interpret variants in clinical practice. We recommend that genetic testing be offered to specific subgroups of symptomatic patients with PAH, and to children with certain types of group 3 pulmonary hypertension (PH).

Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving vascular remodeling in PVOD. Here we show that administration of MMC in rats mediates activation of protein kinase R (PKR) and the integrated stress response (ISR), which leads to the release of the endothelial adhesion molecule vascular endothelial (VE) cadherin (VE-Cad) in complex with RAD51 to the circulation, disruption of endothelial barrier and vascular remodeling.

Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension.

Background: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare.

Methods: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics.

Results: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated , coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH.

SEMA3G regulates BMP9 inhibition of VEGF-mediated migration and network formation in pulmonary endothelial cells.

Aims: Bone morphogenetic protein-9 (BMP9) is critical for bone morphogenetic protein receptor type-2 (BMPR2) signalling in pulmonary vascular endothelial cells. Furthermore, human genetics studies support the central role of disrupted BMPR2 mediated BMP9 signalling in vascular endothelial cells in the initiation of pulmonary arterial hypertension (PAH). In addition, loss-of-function mutations in BMP9 have been identified in PAH patients.

Shared and Distinct Genomics of Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Embolism.

Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects.

Biallelic variants in the calpain regulatory subunit cause pulmonary arterial hypertension.

Purpose: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families.

Methods: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis.

Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls.

Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving the vascular remodeling in PVOD. We show that the administration of MMC in rats mediates the activation of protein kinase R (PKR) and the integrated stress response (ISR), which lead to the release of the endothelial adhesion molecule VE-Cadherin in the complex with Rad51 to the circulation, disruption of endothelial barrier, and vascular remodeling.

Defining the clinical validity of genes reported to cause pulmonary arterial hypertension.

Purpose: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality.

Risk Factors for Longer-Term Mortality in Discharged Patients with Dementia and SARS-CoV-2 Infection: A Matched Case-Control Study.

Background: Persisting symptoms and increased mortality after SARS-CoV-2 infection has been described in COVID-19 survivors.

Objective: We examined longer-term mortality in patients with dementia and SARS-CoV-2 infection.

Methods: A retrospective matched case-control study of 165 patients with dementia who survived an acute hospital admission with COVID-19 infection, and 1325 patients with dementia who survived a hospital admission but without SARS-CoV-2 infection.

Reduced circulating BMP9 and pBMP10 in hospitalized COVID-19 patients.

Similar to other causes of acute respiratory distress syndrome, coronavirus disease 2019 (COVID-19) is characterized by the aberrant expression of vascular injury biomarkers. We present the first report that circulating plasma bone morphogenetic proteins (BMPs), BMP9 and pBMP10, involved in vascular protection, are reduced in hospitalized patients with COVID-19.

Genetic counselling and testing in pulmonary arterial hypertension: a consensus statement on behalf of the International Consortium for Genetic Studies in PAH.

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members.

A pilot study to examine association of BMI with functional class and 6 min walk distance in idiopathic and heritable PAH: Possible association with estrogen metabolism.

The hypothesis that a relationship exists between body mass index (BMI), functional class, and 6 min walk distance (6MWD) in Group 1-pulmonary arterial hypertension (PAH) was examined. Analysis of data from the UK National Cohort Study for heritable pulmonary arterial/idiopathic PAH suggests increased BMI is a predictor of worse functional class and shorter 6MWD; increased body-weight in mice and man may be associated with increased estrogen metabolism.