Hemodynamics and Phosphodiesterase-5 Inhibitor Treatment Associated with Survival in ILD-PH: A PVRI GoDeep Meta-Registry Analysis.

Background: Pulmonary hypertension (PH) in interstitial lung disease (ILD) lacks approved therapies. The PVRI GoDeep meta-registry collects real-world data of PH patients from international PH referral centers.

Methods: ILD-PH patients and relevant subgroups (IIP, IPF) were stratified by pulmonary vascular resistance (PVR).

Clustering Patients with Pulmonary Hypertension Using the Plasma Proteome.

Patients with pulmonary hypertension are classified according to clinical criteria to inform treatment decisions. Knowledge of the molecular drivers of pulmonary hypertension might better inform treatment choice. To investigate plasma protein clusters in patients with a diagnosis of pulmonary hypertension.

Drugs targeting novel pathways in pulmonary arterial hypertension.

Over the past three decades, several drugs have been developed to target three major dysfunctional pathways in pulmonary arterial hypertension (PAH), including the prostacyclin, endothelin and nitric oxide pathways. Despite these advances, PAH remains incurable, necessitating further drug discovery efforts. New therapies focus on previously untargeted pathways, especially the bone morphogenetic protein (BMP)/transforming growth factor (TGF)-β signalling pathway.

Diagnostic MicroRNA Signatures to Support Classification of Pulmonary Hypertension.

Background: Patients with pulmonary hypertension (PH) are classified based on disease pathogenesis and hemodynamic drivers. Classification informs treatment. The heart failure biomarker NT-proBNP (N-terminal pro-B-type natriuretic peptide) is used to help inform risk but is not specific to PH or sub-classification groups.

Positioning Imatinib for Pulmonary Arterial Hypertension: A Dose-Finding Phase 2 Study.

Imatinib, 400 mg daily, reduces pulmonary vascular resistance and improves exercise capacity in patients with pulmonary arterial hypertension. Concerns about safety and tolerability limit its use. We sought to identify a safe and tolerated dose of oral imatinib between 100 mg and 400 mg daily and evaluate its efficacy.

Association of pulmonary hypertension-targeted therapy and survival in precapillary pulmonary hypertension with mean pulmonary arterial pressure between 21 and 24 mmHg.

Introduction: The definition of pulmonary hypertension (PH) was recently changed and led to a new subset of PH patients with mildly impaired pulmonary haemodynamics, characterised by a mean pulmonary artery pressure (mPAP) of 21-24 mmHg and with a pulmonary vascular resistance (PVR) >2 WU. We evaluated the association of PH-targeted therapy and outcome in mild precapillary PH using the PVRI GoDeep meta-registry.

Methods: All patients with mild precapillary PH (mPAP 21-24 mmHg, pulmonary arterial wedge pressure ≤15 mmHg and PVR >2 WU) diagnosed with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) were enrolled.

Engineered pulmonary artery tissues for measuring contractility, drug testing and disease modelling.

Background And Purpose: Vasoreactivity of pulmonary arteries regulates blood flow through the lungs. Excessive constriction of these vessels contributes to pulmonary arterial hypertension (PAH), a progressive and incurable condition, resulting in right heart failure. The search for new and improved drug treatments is hampered by laboratory models that do not reproduce the vasoactive behaviour of healthy and diseased human arteries.

StratosPHere 2: study protocol for a response-adaptive randomised placebo-controlled phase II trial to evaluate hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2.

Background: Pulmonary arterial hypertension is a life-threatening progressive disorder characterised by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery). Although treatable, there is no known cure for this rare disorder, and its exact cause is unknown. Mutations in the bone morphogenetic protein receptor type-2 (BMPR2) are the most common genetic cause of familial pulmonary arterial hypertension.

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.

Clinical trial design, end-points, and emerging therapies in pulmonary arterial hypertension.

Clinical trials in pulmonary arterial hypertension (PAH) have led to the approval of several effective treatments that improve symptoms, exercise capacity and clinical outcomes. In phase 3 clinical trials, primary end-points must reflect how a patient "feels, functions or survives". In a rare disease like PAH, with an ever-growing number of treatment options and numerous candidate therapies being studied, future clinical trials are now faced with challenges related to sample size requirements, efficiency and demonstration of incremental benefit on traditional end-points in patients receiving background therapy with multiple drugs.

Association of Phosphodiesterase-5 Inhibitor Treatment With Improved Survival in Pulmonary Hypertension Associated With COPD in the Pulmonary Vascular Research Institute GoDeep Meta-Registry.

Background: Patients with COPD frequently demonstrate pulmonary hypertension (PH). Severe PH in patients with COPD, identified by pulmonary vascular resistance (PVR) of > 5 Wood units (WU), is closely linked to impaired transplant-free survival. The impact of PH-targeting pharmacotherapy in this context remains unclear.

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.

Omada: robust clustering of transcriptomes through multiple testing.

Background: Cohort studies increasingly collect biosamples for molecular profiling and are observing molecular heterogeneity. High-throughput RNA sequencing is providing large datasets capable of reflecting disease mechanisms. Clustering approaches have produced a number of tools to help dissect complex heterogeneous datasets, but selecting the appropriate method and parameters to perform exploratory clustering analysis of transcriptomic data requires deep understanding of machine learning and extensive computational experimentation.

Two prospective, multicenter studies for the identification of biomarker signatures for early detection of pulmonary hypertension (PH): The CIPHER and CIPHER-MRI studies.

A blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study aimed to develop a microRNA-based signature for detecting PH in breathless patients and enrolled adults with a high suspicion of PH who had undergone right heart catheterization (RHC). The CIPHER-MRI study was added to assess the performance of this CIPHER signature in a population with low probability of having PH who underwent cardiac magnetic resonance imaging (cMRI) instead of RHC.

ATP13A3 variants promote pulmonary arterial hypertension by disrupting polyamine transport.

Aims: Potential loss-of-function variants of ATP13A3, the gene encoding a P5B-type transport ATPase of undefined function, were recently identified in patients with pulmonary arterial hypertension (PAH). ATP13A3 is implicated in polyamine transport but its function has not been fully elucidated. In this study, we sought to determine the biological function of ATP13A3 in vascular endothelial cells (ECs) and how PAH-associated variants may contribute to disease pathogenesis.

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.

Multi-biobank summary data Mendelian randomisation does not support a causal effect of IL-6 signalling on risk of pulmonary arterial hypertension.

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