Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension.

Purpose Of Review: Pulmonary veno-occlusive disease (PVOD) is a rare and life-threatening form of precapillary pulmonary hypertension. This review aims to outline its genetic and environmental risk factors, highlight key diagnostic challenges, and discuss current treatment options.

Recent Findings: PVOD can occur sporadically or as a hereditary autosomal recessive condition with biallelic eukaryotic translation initiation factor 2 alpha kinase 4 ( EIF2AK4) mutations, leading to nearly complete disease penetrance.

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.

Ca Cycling Alteration in a Porcine Model of Right Ventricular Dysfunction.

Background: Pulmonary hypertension is a severe disease with high mortality rates due to right ventricular (RV) failure. The molecular and cellular processes involved in RV remodeling, including Ca handling, remain elusive due to the lack of relevant animal models. In this study, we aim to understand better the pathophysiological mechanisms involved in RV failure.

Pulmonary arterial hypertension and cancer: exploring their resemblance as channelopathies.

Pulmonary arterial hypertension (PAH) and cancer may appear to be unrelated at first, but there is increasing evidence that they share many characteristics and complexities. Pulmonary vascular cells in PAH resemble cancer cells in that they display abnormal growth patterns, resistance to cell death, metabolic changes, and channelopathies. These similarities open new possibilities for researchers and clinicians to apply cancer treatment strategies to PAH and possibly reverse the condition.

Association of Pulmonary Hypertension With Trastuzumab Emtansine: An Analysis of French Pulmonary Hypertension Registry and WHO Pharmacovigilance Database.

Background: Trastuzumab emtansine has been recently suspected to be associated with the development of pulmonary arterial hypertension (PAH).

Research Question: Is there an association between trastuzumab, trastuzumab emtansine, or trastuzumab deruxtecan and the development of PAH?

Study Design And Methods: Characteristics of incident PAH cases treated with trastuzumab, trastuzumab emtansine, or trastuzumab deruxtecan were analyzed from the French Pulmonary Hypertension Registry, the VIGIAPATH program, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization pharmacovigilance database using a broad definition of pulmonary hypertension (PH) and a narrow definition of PAH. A signal of disproportionate reporting was deemed significant if the lower boundary of the 95% credibility interval of the information component (IC) was superior to 0.

Transcriptome analyses reveal common immune system dysregulation in PAH patients and -deficient rats.

Pulmonary arterial hypertension (PAH) is a severe disease caused by progressive distal pulmonary artery obstruction. One cause of PAH are loss-of-function mutations in the potassium channel subfamily K member 3 (KCNK3). KCNK3 encodes a two-pore domain potassium channel, which is crucial for pulmonary circulation homeostasis.

Unraveling the Impact of miR-146a in Pulmonary Arterial Hypertension Pathophysiology and Right Ventricular Function.

Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models.

Orai1/STIMs modulators in pulmonary vascular diseases.

Calcium (Ca) is a secondary messenger that regulates various cellular processes. However, Ca mishandling could lead to pathological conditions. Orai1 is a Cachannel contributing to the store-operated calcium entry (SOCE) and plays a critical role in Ca homeostasis in several cell types.

A correlated light and electron microscopy approach to study the subcellular localization of phosphorylated vimentin in human lung tissue.

Correlative microscopy is an important approach for bridging the resolution gap between fluorescence light and electron microscopy. Here, we describe a fast and simple method for correlative immunofluorescence and immunogold labeling on the same section to elucidate the localization of phosphorylated vimentin (P-Vim), a robust feature of pulmonary vascular remodeling in cells of human lung small arteries. The lung is a complex, soft and difficult tissue to prepare for transmission electron microscopy (TEM).

Characteristics and outcomes of patients developing pulmonary hypertension associated with proteasome inhibitors.

Background: Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH.

Methods: Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials.

Role of KCNK3 Dysfunction in Dasatinib-associated Pulmonary Arterial Hypertension and Endothelial Cell Dysfunction.

Pulmonary arterial (PA) hypertension (PAH) is a severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions.

STIM2 variants regulate Orai1/TRPC1/TRPC4-mediated store-operated Ca entry and mitochondrial Ca homeostasis in cardiomyocytes.

The stromal interaction molecules (STIMs) are the sarcoplasmic reticulum (SR) Ca sensors that trigger store-operated Ca entry (SOCE) in a variety of cell types. While STIM1 isoform has been the focus of the research in cardiac pathophysiology, the function of the homolog STIM2 remains unknown. Using Ca imaging and patch-clamp techniques, we showed that knockdown (KD) of STIM2 by siRNAs increased SOCE and the I current in neonatal rat ventricular cardiomyocytes (NRVMs).

Pulmonary vascular phenotype identified in patients with () or variants: an international multicentre study.

Background: Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by and , respectively, play a pivotal role in pulmonary vascular regulation. variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of and carriers remains largely unexplored.

Pulmonary hypertension associated with diazoxide: the SUR1 paradox.

The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH).

KCNK3 channel is important for the ventilatory response to hypoxia in rats.

To clarify the contribution of KCNK3/TASK-1 channel chemoreflex in response to hypoxia and hypercapnia, we used a unique Kcnk3-deficient rat. We assessed ventilatory variables using plethysmography in Kcnk3-deficient and wild-type rats at rest in response to hypoxia (10% O) and hypercapnia (4% CO). Immunostaining for C-Fos, a marker of neuronal activity, was performed to identify the regions of the respiratory neuronal network involved in the observed response.

Physiological and pathophysiological roles of the KCNK3 potassium channel in the pulmonary circulation and the heart.

Potassium channel subfamily K member 3 (KCNK3), encoded by the KCNK3 gene, is part of the two-pore domain potassium channel family, constitutively active at resting membrane potentials in excitable cells, including smooth muscle and cardiac cells. Several physiological and pharmacological mediators, such as intracellular signalling pathways, extracellular pH, hypoxia and anaesthetics, regulate KCNK3 channel function. Recent studies show that modulation of KCNK3 channel expression and function strongly influences pulmonary vascular cell and cardiomyocyte function.

Contribution of transient receptor potential canonical channels in human and experimental pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is due to progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated store-operated Ca entry (SOCE) contributes to PAH pathogenesis, mediating human PA smooth muscle cell (hPASMC) abnormalities. The transient receptor potential canonical channels (TRPC family) are Ca-permeable channels contributing to SOCE in different cell types, including PASMCs.

Lipidomic Profile Analysis of Lung Tissues Revealed Lipointoxication in Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast to PAH, PVOD is characterized by a particular remodeling of the pulmonary venous system and the obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation. The pathobiological knowledge of PVOD is poor, explaining the absence of medical therapy for PVOD.

Role of Ion Channels in the Development of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is an uncommon, progressive, and fatal disease [...

The SOCE Machinery: An Unbalanced Knowledge between Left and Right Ventricular Pathophysiology.

Right ventricular failure (RVF) is the most important prognostic factor for morbidity and mortality in pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) caused by left heart diseases. However, right ventricle (RV) remodeling is understudied and not targeted by specific therapies. This can be partly explained by the lack of basic knowledge of RV remodeling.

Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, and arterial contractility. Store-operated Ca entry is involved in Ca homeostasis in PASMCs, but its properties in PAH are unclear.