Diagnosis and Treatment of Pulmonary Arterial Hypertension

JAMA, Год журнала: 2022, Номер 327(14), С. 1379 - 1379

Опубликована: Апрель 12, 2022

Importance

Pulmonary arterial hypertension (PAH) is a subtype of pulmonary (PH), characterized by remodeling. The prevalence PAH approximately 10.6 cases per 1 million adults in the US. Untreated, progresses to right heart failure and death.

Observations

defined mean artery pressure greater than 20 mm Hg classified into 5 clinical groups based on etiology, pathophysiology, treatment. PH hemodynamically catheterization demonstrating Hg, wedge 15 or lower, vascular resistance 3 Wood units greater. further divided subgroups underlying consisting idiopathic PAH, heritable drug- toxin-associated veno-occlusive disease, long-term responders calcium channel blockers, persistent newborn, as well associated with other medical conditions including connective tissue HIV, congenital disease. Early presenting symptoms are nonspecific typically consist dyspnea exertion fatigue. Currently approved therapy for consists drugs that enhance nitric oxide–cyclic guanosine monophosphate biological pathway (sildenafil, tadalafil, riociguat), prostacyclin agonists (epoprostenol treprostinil), endothelin antagonists (bosentan ambrisentan). With these PAH-specific therapies, 5-year survival has improved from 34% 1991 more 60% 2015. Current treatment combination drug targets pathway, such pathways (eg, ambrisentan tadalafil), shown demonstrable improvement morbidity mortality compared previous conventional single-pathway targeted monotherapy.

Conclusions Relevance

affects an estimated US and, without treatment, First-line combinations target multiple survival.

Язык: Английский

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Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure and Preserved or Reduced Ejection Fraction

Circulation, Год журнала: 2017, Номер 137(17), С. 1796 - 1810

Опубликована: Дек. 15, 2017

Background: We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of veins and the severity is associated with (PH) HF. Methods: Patients HF (n=108; 53 preserved 55 reduced ejection fraction) PH (HF-PH; artery systolic pressure [PASP] ≥40 mm Hg) were compared normal controls (n=12) patients primary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed all analyzable arteries (n=4949), (n=7630), small indeterminate vessels (IV; n=2168) define percent medial thickness (arteries) intimal (%IT) (arteries, veins, IV) relative external diameter. Results: The average arterial 6.9; 11.0; PVOD, 15.0), %IT 4.9; 14.9; 31.1), 14.0; 24.9; 43.9), IV 10.6; 25.8; 50.0) HF-PH higher than ( P <0.0001 for all) but lower PVOD ≤0.005 all). PASP (mm (median, 59 [interquartile range, 50–70]) 91 82–103]). correlated r =0.41) =0.35) more strongly =0.49) =0.55) Associations between remained significant after adjusting did not vary by type. right catheterization (30 14 similar associations transpulmonary gradient vascular existed, numerically stronger %IT. Although slightly ventricular dysfunction, severe. Pulmonary reductions diffusing capacity lungs. Conclusions: HF, global remodeling, correlates most thickening, pattern observed PVOD. These findings expand our understanding pathobiology

Язык: Английский

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Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension

AJP Heart and Circulatory Physiology, Год журнала: 2018, Номер 315(5), С. H1322 - H1331

Опубликована: Авг. 24, 2018

Pulmonary arterial hypertension (PAH) is characterized by remodeling of the extracellular matrix (ECM) pulmonary arteries with increased collagen deposition, cross-linkage collagen, and breakdown elastic laminae. Extracellular occurs due to an imbalance in proteolytic enzymes, such as metalloproteinases, elastases, lysyl oxidases, tissue inhibitor which, turn, results from endothelial cell dysfunction, endothelial-to-mesenchymal transition, inflammation. ECM vascular stiffness occur early disease process, before onset increase intimal medial thickness artery pressure, suggesting that a cause rather than consequence distal remodeling. promote proliferation cells (endothelial cells, smooth muscle adventitial fibroblasts) through mechanoactivation various signaling pathways, including transcriptional cofactors YAP/TAZ, transforming growth factor-β, transient receptor potential channels, Toll-like receptor, NF-κB. Inhibition mechanotransduction prevents reverses experimental hypertension. These data support central role for pathogenesis PAH, making it attractive novel therapeutic target.

Язык: Английский

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The impact of microbiota-derived short-chain fatty acids on macrophage activities in disease: Mechanisms and therapeutic potentials

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 165, С. 115276 - 115276

Опубликована: Авг. 4, 2023

Short-chain fatty acids (SCFAs) derived from the fermentation of carbohydrates by gut microbiota play a crucial role in regulating host physiology. Among them, acetate, propionate, and butyrate are key players various biological processes. Recent research has revealed their significant functions immune inflammatory responses. For instance, reduces development interferon-gamma (IFN-γ) generating cells while promoting regulatory T (Treg) cells. Propionate inhibits initiation Th2 response dendritic (DCs). Notably, SCFAs have an inhibitory impact on polarization M2 macrophages, emphasizing immunomodulatory properties potential for therapeutics. In animal models asthma, both propionate suppress pathway, thus reducing allergic airway inflammation. Moreover, dysbiosis leading to altered SCFA production been implicated prostate cancer progression. trigger autophagy promote accelerating tumor advancement. Manipulating microbiota- producing holds promise treatment. Additionally, enhance expression hypoxia-inducible factor 1 (HIF-1) blocking histone deacetylase, resulting increased antibacterial effectors improved macrophage-mediated elimination microorganisms. This highlights antimicrobial defense mechanisms. comprehensive review provides in-depth analysis latest functional aspects underlying mechanisms relation macrophage activities wide range diseases, including infectious diseases cancers. By elucidating intricate interplay between functions, this aims contribute understanding therapeutic pave way future interventions targeting disease management.

Язык: Английский

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Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension

Antioxidants and Redox Signaling, Год журнала: 2020, Номер 34(12), С. 891 - 914

Опубликована: Авг. 4, 2020

Endothelial-to-mesenchymal transition (EndMT) is a process that encompasses extensive transcriptional reprogramming of activated endothelial cells leading to shift toward mesenchymal cellular phenotypes and functional responses. Initially observed in the context embryonic development, last few decades EndMT increasingly recognized as contributes variety pathologies adult organism. Within settings cardiovascular biology, plays role various diseases, including atherosclerosis, heart valvular disease, cardiac fibrosis, myocardial infarction. also being progressively implicated development progression pulmonary hypertension (PH) arterial (PAH). This review covers current knowledge about PH PAH, provides comprehensive overview seminal discoveries. Topics covered include evidence linking factors associated with PAH hypoxia responses, inflammation, dysregulation bone-morphogenetic protein receptor 2 (BMPR2), redox signaling. amalgamates these discoveries into potential insights for identification underlying mechanisms driving discusses future directions EndMT-based therapeutic strategies disease management.

Язык: Английский

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Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway

Cellular Physiology and Biochemistry, Год журнала: 2017, Номер 42(6), С. 2569 - 2581

Опубликована: Янв. 1, 2017

Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes, and many which are likely to have functional roles vascular remodeling. However, their functions pulmonary arterial hypertension (PAH) remain largely unknown. Pulmonary remodeling is an important pathological feature PAH, leading increased resistance reduced compliance. artery smooth muscle cells (PASMCs) dysfunction involved Long noncoding potential regulators PASMCs function. Herein, we determined whether RNA-maternally expressed gene 3 (MEG3) was PAH-related remodeling.The wall thickness examined by hematoxylin eosin (H&E) staining distal arteries (PAs) isolated from lungs healthy volunteers PAH patients. The expression level MEG3 analyzed qPCR. effects on human were assessed cell counting Kit-8 assay, BrdU incorporation flow cytometry, scratch-wound immunofluorescence, western blotting PASMCs.We revealed that the significantly downregulated lung PAs patients with PAH. knockdown affected proliferation migration vitro. Moreover, inhibition regulated cycle progression made more G0/G1 phase G2/M+S process could stimulate PCNA, Cyclin A E. In addition, found p53 pathway MEG3-induced proliferation.This study identified as critical regulator therapy drug development for treating

Язык: Английский

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BMPR2 acts as a gatekeeper to protect endothelial cells from increased TGFβ responses and altered cell mechanics

PLoS Biology, Год журнала: 2019, Номер 17(12), С. e3000557 - e3000557

Опубликована: Дек. 11, 2019

Balanced transforming growth factor-beta (TGFβ)/bone morphogenetic protein (BMP)-signaling is essential for tissue formation and homeostasis. While gain in TGFβ signaling often found diseases, the underlying cellular mechanisms remain poorly defined. Here we show that receptor BMP type 2 (BMPR2) serves as a central gatekeeper of this balance, highlighted by its deregulation diseases such pulmonary arterial hypertension (PAH). We BMPR2 deficiency endothelial cells (ECs) does not abolish pan-BMP-SMAD1/5 responses but instead favors mixed-heteromeric complexes comprising BMPR1/TGFβR1/TGFβR2 enable enhanced toward TGFβ. These include canonical TGFβ-SMAD2/3 lateral TGFβ-SMAD1/5 well mixed SMAD complexes. Moreover, BMPR2-deficient express genes indicative altered biophysical properties, including up-regulation extracellular matrix (ECM) proteins fibrillin-1 (FBN1) integrins. As such, identified accumulation ectopic FBN1 fibers remodeled with fibronectin (FN) junctions ECs. Ectopic deposits were also proximity to contractile intimal artery lesions heritable PAH (HPAH) patients. In cells, accompanied active β1-integrin highly abundant integrin-linked kinase (ILK) mechano-complexes at cell junctions. Increased integrin-dependent adhesion, spreading, actomyosin-dependent contractility facilitates retrieval from latent fibrillin-bound depots. propose loss endothelial-to-mesenchymal transition (EndMT) allowing myo-fibroblastic character create vicious feed-forward process leading hyperactivated signaling. summary, our findings highlight crucial role homeostasis protecting increased integrin-mediated mechano-transduction.

Язык: Английский

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Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease

Pharmaceuticals, Год журнала: 2021, Номер 14(10), С. 979 - 979

Опубликована: Сен. 26, 2021

Chronic obstructive pulmonary disease (COPD) is one of the leading global causes morbidity and mortality. A hallmark COPD progressive airflow obstruction primarily caused by cigarette smoke (CS). CS exposure an imbalance favoring pro- over antioxidants (oxidative stress), to transcription factor activation increased expression inflammatory mediators proteases. Different cell types, including macrophages, epithelial cells, neutrophils, T lymphocytes, contribute pathophysiology. Alteration in functions results generation oxidative microenvironment, which contributes progression. Current treatments include inhaled corticosteroids bronchodilator therapy. However, these therapies do not effectively halt Due complexity its pathophysiology, risk exacerbating symptoms with existing therapies, other specific effective treatment options are required. Therapies directly or indirectly targeting may be promising alternatives. This review briefly discusses provides update on development clinical testing novel treatments.

Язык: Английский

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The mechanism of the imbalance between proliferation and ferroptosis in pulmonary artery smooth muscle cells based on the activation of SLC7A11

European Journal of Pharmacology, Год журнала: 2022, Номер 928, С. 175093 - 175093

Опубликована: Июнь 11, 2022

Язык: Английский

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The role of p53 in the alternation of vascular functions

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Сен. 6, 2022

Ageing is a risk factor for many degenerative diseases. Cardiovascular diseases (CVDs) are usually big burdens elderly, caregivers and the health system. During aging process, normal functions of vascular cells tissue progressively lost eventually develop Endothelial dysfunction, reduced bioavailability endothelium-derived nitric oxide usual phenomena observed in patients with cardiovascular Myriad studies have been done to investigate delay dysfunction or improve function prolong process. Tumor suppressor gene p53, also transcription factor, act as gatekeeper regulate number genes maintain cell including but not limited proliferation, apoptosis. p53 crosstalk other key factors like hypoxia-inducible 1 alpha that contribute progression Therefore, recent three decades, has drawn scientists’ attention on its effects function. Though role tumor still clear function, it found play regulatory roles may involve remodeling, atherosclerosis pulmonary hypertension. divergent endothelial muscle those conditions. In this review, we describe different physiology. Further cell-specific deficiency atherosclerotic plaque formation common animal models required before therapeutic potential can be realized.

Язык: Английский

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