Pulmonary Vascular Resistance in Pulmonary Arterial Hypertension: La Piece de Resistance?
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ABSTRACT:
SUBMITTER: Weatherald J
PROVIDER: S-EPMC7885847 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
Pulmonary Vascular Resistance in Pulmonary Arterial Hypertension: La Pièce de Résistance?
Weatherald Jason J Boucly Athénaïs A Savale Laurent L Jaïs Xavier X Montani David D Humbert Marc M Sitbon Olivier O
American journal of respiratory and critical care medicine 20210201 4
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Project description: Not available
| S-EPMC7885839 | biostudies-literature
Project description:Pathogens must be able to overcome both host defenses and antimicrobial treatment in order to successfully infect and maintain colonization of the host. One way fungi accomplish this feat and overcome intercellular toxin accumulation is efflux pumps, in particular ATP-binding cassette transporters and transporters of the major facilitator superfamily. Members of these two superfamilies remove many toxic compounds by coupling transport with ATP hydrolysis or a proton gradient, respectively. Fungal genomes encode a plethora of members of these families of transporters compared to other organisms. In this review we discuss the role these two fungal superfamilies of transporters play in virulence and resistance to antifungal agents. These efflux transporters are responsible not only for export of compounds involved in pathogenesis such as secondary metabolites, but also export of host-derived antimicrobial compounds. In addition, we examine the current knowledge of these transporters in resistance of pathogens to clinically relevant antifungal agents.
| S-EPMC2695561 | biostudies-other
Project description:BackgroundPulmonary arterial compliance (PAC) was previously shown to be an important prognostic factor in pulmonary arterial hypertension (PAH), in addition to the conventional pulmonary vascular resistance (PVR). The product of PAC and PVR, the arterial time (RC) constant, expresses the logarithmic relationship between the hemodynamic parameters. The objective of the study was to test RC constant stability in PAH patients followed beyond 12 months after diagnosis, and to report possible RC variations in different etiologies.MethodsFourteen PAH patients followed between 2008 and 2019 were included. Type 1 PAH was defined as a mean pulmonary artery pressure (PAP) ≥25 mmHg at rest and PVR ≥3 Wood units (WU). All patients who fulfilled WHO group I PAH criteria and had undergone two right heart catheterizations at least 1 year apart were included. The recorded hemodynamic data for each patient were used to compute PVR and PAC.ResultsPAH etiologies included scleroderma (n=2), liver cirrhosis (n=1), hereditary hemorrhagic telangiectasia (HHT) (n=1), mixed connective tissue disease (MCTD) (n=3), and idiopathic (n=7). The RC constant remained stable for all 14 patients over a follow-up period of 3.9±2 years. Patients with MCTD displayed more favorable hemodynamics, evidenced by higher RC (12.54 vs. 10.01, P<0.01) and PAC values (2.59 vs. 1.62, P=0.02), when compared with non-MCTD PAH patients. For the entire cohort the mean PAP measured 51±14 mmHg at baseline, and 46±13 mmHg at follow-up, respectively.ConclusionsThe relationship between PAC and PVR remains stable in follow-up periods averaging 4 years, making compliance an important disease marker past the early stages. Patients with MCTD displayed more advantageous hemodynamic profiles when compared with patients with other PAH etiologies.
| S-EPMC7330329 | biostudies-literature
Project description:In idiopathic pulmonary arterial hypertension (PAH), increased pulmonary vascular resistance is associated with structural narrowing of small (resistance) vessels and increased vascular tone. Current information on pulmonary vascular remodeling is mostly limited to averaged increases in wall thickness, but information on number of vessels affected and internal diameter decreases for vessels of different sizes is limited. Our aim was to quantify numbers of affected vessels and their internal diameter decrease for differently sized vessels in PAH in comparison with non-PAH patients. Internal and external diameters of transversally cut vessels were measured in five control subjects and six PAH patients. Resistance vessels were classified in Strahler orders, internal diameters 13 μm (order 1) to 500 μm (order 8). The number fraction, that is, percentage of affected vessels, and the internal diameter fraction, that is, percentage diameter of normal diameter, were calculated. In PAH, not all resistance vessels are affected. The number fraction is about 30%, that is, 70% of vessels have diameters not different from vessels of control subjects. Within each order, the decrease in diameter of affected vessels is variable with an averaged diameter fraction of 50-70%. Narrowing of resistance vessels is heterogeneous: not all vessels are narrowed, and the decrease in internal diameters, even within a single order, vary largely. This heterogeneous narrowing alone cannot explain the large resistance increase in PAH We suggest that rarefaction could be an important contributor to the hemodynamic changes.
| S-EPMC5371554 | biostudies-literature
Project description:AimsAs pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality, particularly among patients with right ventricular (RV) dysfunction, we aimed to determine the impact of therapy to reduce pulmonary vascular resistance (PVR) on RV and LV deformation in PAH.Methods and resultsRight ventricular free wall longitudinal strain (FWLS) and LV global circumferential strain (CS) were measured at baseline, 12 weeks, and 24 weeks in 68 patients with advanced PAH randomized to imatinib or placebo in the Imatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study (IMPRES) trial, and compared with 30 healthy controls. Compared with controls, PAH was associated with impaired RV FWLS (-15.9 ± 5.4 vs. -30.8 ± 4.3, respectively; P < 0.0001) and LV septal CS (-24.2 ± 8.2 vs. -31.4 ± 5.3, respectively, P < 0.0001), but not LV global CS. Improvement in PVR and mean pulmonary artery pressure (MPAP) over a 24-week period was significantly associated with improvement in RV FWLS (r = 0.39, P = 0.02; 0.33, P = 0.04 respectively), LV global CS (r = 0.61, P = 0.0001; r = 0.60, P = 0.0001, respectively), and LV septal CS (r = 0.50, P = 0.005; r = 0.56, P = 0.002, respectively). These associations were most robust with LV global and septal CS. Imatinib therapy was associated with improvement in RV FWLS compared with placebo.ConclusionsPAH is associated with impaired biventricular deformation. Reduction in PVR is associated with improvements in both RV and LV deformation, coupled to improvements in MPAP and stroke volume index, with LV global and septal CS the strongest correlates of these changes. RV FWLS is sensitive to treatment effect, demonstrating greater improvement with imatinib compared with placebo.Trial registrationNCT00902174.
| S-EPMC5551563 | biostudies-literature
Project description:Although obesity, dyslipidemia and insulin resistance (IR) are well known risk factors for systemic cardiovascular disease, their impact on pulmonary arterial hypertension (PAH) is unknown. The present authors' previous studies indicate that IR may be a risk factor for PAH. The current study has investigated the prevalence of IR in PAH and explored its relationship with disease severity. Clinical data and fasting blood samples were evaluated in 81 nondiabetic PAH females. In total, 967 National Health and Nutrition Examination Surveys (NHANES) females served as controls. The fasting triglyceride to high-density lipoprotein cholesterol ratio was used as a surrogate of insulin sensitivity. While body mass index was similar in NHANES versus PAH females (28.6 versus 28.7 kg.m(-2)), PAH females were more likely to have IR (45.7 versus 21.5%) and less likely to be insulin sensitive (IS; 43.2 versus 57.8%). PAH females mostly (82.7%) had New York Heart Association (NYHA) class II and III symptoms. Aetiology, NYHA class, 6-min walk-distance and haemodynamics did not differ between IR and IS PAH groups. However, the presence of IR and a higher NYHA class was associated with poorer 6-months event-free survival (58 versus 79%). Insulin resistance appears to be more common in pulmonary arterial hypertension females than in the general population, and may be a novel risk factor or disease modifier that might impact on survival.
| S-EPMC2785883 | biostudies-literature
Project description:Oral treprostinil has been shown to improve exercise capacity and delay disease progression in patients with pulmonary arterial hypertension (PAH), but its effects on hemodynamics are not well-characterized. The FREEDOM-EV trial was a Phase III, international, placebo-controlled, double-blind, event-driven study in 690 participants with PAH who were taking a single oral PAH therapy. FREEDOM-EV demonstrated a significantly reduced risk for clinical worsening with oral treprostinil taken three times daily and did not uncover new safety signals in PAH patients. Sixty-one participants in the FREEDOM-EV trial volunteered for a hemodynamics sub-study. Pulmonary artery compliance (PAC), a ratio of stroke volume to pulmonary pulse pressure, significantly increased from Baseline to Week 24 in the oral treprostinil group compared with the placebo group (geometric mean 26.4% active vs. -6.0% placebo; ANCOVA p=0.007). There was a significant increase in cardiac output in the oral treprostinil group compared to the placebo group (geometric mean 11.3% active vs. -6.4% placebo; ANCOVA p=0.005) and a corresponding significant reduction in pulmonary vascular resistance (PVR) (geometric mean -21.5 active vs. -1.8% placebo; ANCOVA p=0.02) from Baseline to Week 24. These data suggest that increased compliance contributes to the physiological mechanism by which oral treprostinil improves exercise capacity and delays clinical worsening for patients with PAH.
| S-EPMC10024312 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype.
| S-EPMC4881582 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of EIF2AK4 gene (encoding general control nonderepressible 2 kinase, GCN2) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely in patients with PAH. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here, we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and patients with idiopathic PAH. Unexpectedly, loss of GCN2 kinase activity in Eif2ak4-/- mice with genetic disruption of the kinase domain induced neither PVOD nor pulmonary hypertension (PH) but inhibited hypoxia-induced PH. RNA-sequencing analysis suggested endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2α. Restored Edn1 expression in ECs of Eif2ak4-/- mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss-of-function mutations.
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Project description:Notch signalling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1-4) regulating diverse cellular processes have been identified. Of these, Notch3 is expressed almost exclusively in vascular smooth muscle cells (VSMCs), where it is critically involved in vascular development and differentiation. Under pathological conditions, Notch3 regulates VSMC switching between the contractile and synthetic phenotypes. Abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because of the importance of Notch3 in VSMC (de)differentiation, Notch3 has been implicated in the pathophysiology of pulmonary vascular remodelling in PAH. Here we review the current literature on the role of Notch in VSMC function with a focus on Notch3 signalling in pulmonary artery VSMCs, and discuss potential implications in pulmonary artery remodelling in PAH.
| S-EPMC6928565 | biostudies-literature