Proteomic analysis of the serum in patients with idiopathic pulmonary arterial hypertension

Idiopathic pulmonary arterial hypertension(IPAH) is a rare disease of unknown etiology.The exact pathogenesis of pulmonary arterial hypertension is still not well known.In the past decades,many protein molecules have been found to be in-volved in the development of IPAH.With proteomic techniques,profiling of human plasma proteome becomes more feasible in searching for disease-related markers.In present study,we showed the protein expression profiles of the serum of IPAH and healthy controls after depleting a few high-abundant proteins in serum.Thirteen spots had changed significantly in IPAH com-pared with healthy controls and were identified by LC-MS/MS.Alpha-1-antitrypsin and vitronectin were down-regulated in IPAH and may be valuable candidates for further explorations of their roles in the development of IPAH.

Novel therapy for idiopathic pulmonary arterial hypertension： Can hepatocyte growth factor be beneficial？

Idiopathic pulmonary arterial hypertension （IPAH） is a progressive, nearly fatal condition that until recently has had very few treatment options. Median survival time for untreated IPAH was 2.8 years without effective drug intervention. IPAH is characterized by deregulated proliferation of pulmonary arterial endothelial and intimal smooth muscle cells resulting in progressive pulmonary vascular remodeling and an increase in pulmonary arterial pressure. In order to alleviate their symptoms, anticoagulants, diuretics, calcium channel blockers and inotropic agents have been used to treat patients with PAH. Moreover, specific targeted therapies using prostacyclins,

Prognostic value of the echocardiographic right/left ventricular end-diastolic diameter ratio in patients with idiopathic pulmonary arterial hypertension

Background Previous studies have shown that an echocardiographic right/left ventricular end-diastolic diameter ratio(RV/LV ratio)≥0.9 is an independent predictor of poor prognosis in patients with acute pulmonary embolism. The prognostic value of the RV/LV ratio in patients with idiopathic pulmonary arterial hypertension(IPAH) is still unknown. Methods We retrospectively enrolled 95 consecutive patients with newly diagnosed IPAH and 16 of them were reevaluated by echocardiography at 3-12 months following targeted therapy.Follow-up data were obtained by telephone interviews and review of the patients’ records.Results The RV/LV ratio was in parallel with the severity of World Health Orgnization(WHO) functional class and mean right atrial pressure.The RV/LV ratio was positively correlated with total pulmonary resistance(P P P 2 saturation(P P = 0.001),weight and absence of targeted therapy were independent predictors of death.No significant changes in the RV/LV ratio before and after targeted therapy were observed. A baseline RV/LV ratio≥0.84 or a further increase in the RV/LV ratio during targeted therapy indicated a poor prognosis. Conclusions The RV/LV ratio helps to assess the severity of IPAH and serves as an independent predictor of prognosis in patients with IPAH.

Screening key target genes for pulmonary arterial hypertension based on bioinformatics

Background:Screening key target genes for pulmonary arterial hypertension(PAH)based on bioinformatics to provide a reference for the clinical development of drugs to cure PAH.Methods:The keyword“pulmonary arterial hypertension”was used to search related genes in the National Center for Biotechnology Information database(NCBI).The obtained genes data was input to the database of Database for Annotation,Visualization and Integrated Discovery(DAVID)(Version 6.8)to collect relevant information about pathways and genes.And the data of genes were enriched in 37 pathways and genes with occurrence frequency≥10 were respectively imported into the String database to construct protein-protein interaction(PPI)network diagrams,and the two network diagrams were compared.Results:VEGFA,MAPK1,MAPK3,IL6,JUN and TNF were among the highest-ranked genes in two network diagrams.Conclusion:The pathogenesis of PAH is associated with multiple pathways such as the TGF-βsignaling pathway,PI3K-Akt signaling pathway,MAPK signaling pathway,HIF-1 signaling pathway and so on.The study of VEGFA,MAPK1,MAPK3,IL6,JUN and TNF are closely related to PAH is necessary for us to study further.Through gene interaction network and pathway analysis of disease-associated genes,which will help us to screen the critical target genes of PAH and provide a reference for clinical development of effective drugs for PAH.

Home-made fenestrated amplatzer occluder for atrial septal defect and pulmonary arterial hypertension

We report the management of a patient with secundum atrial septal defect （ASD） and severe pulmonary hypertension. A 65-year-old male with recently diagnosed atrial septal defect was referred to our centre for decompensated right heart failure with rest and exercise induced dispnea and severe pulmonary hypertension. Right heart catheterization confirmed a mean pulmonary pressure of about 55 mmHg and a Qp/Qs of 2.7. An occlusion test with a compliant large balloon demonstrated partial fall of pulmonary arterial pressure. The implantation of a home-made fenestrated Amplatzer ASD Occluder （ASO） was planned in order to decrease left-to-right shunt and promote further decrease of pulmonary arterial pressure in the long-term. Thus, by means of mechanical intracardiac echocardiography study with a 9F 9 MHz Ultralce catheter （Boston Scientific Corp.）, we selected a 34 mm ASO for implantation. Four millimeter fenestration was made inflating a 4 mm non-compliant coronary balloon throughout the waist of the ASO, which was successfully implanted under intmcardiac echocardiography. After six months, a decrease of pulmonary arterial pressure to 24 mmHg and full compensated right heart failure was observed on transthoracic echocardiography and clinical examination. This case suggests that Wanscatheter closure with home-made fenestrated ASD in elderly patients with severe pulmonary hypertension is feasible.

The clinical features and effects with target therapy for post splenectomy pulmonary hypertension

Objective To analyze the clinical features and effects of target therapy of post splenectomy pulmonary hypertension, and improve the diagnosis and treatment of the disease.Methods Clinical data of 18 patients with post splenectomy pulmonary hypertension admitted to our hospital from October 2006 to March 2017 were systematically reviewed.

Pulmonary arterial hypertension associated with systemic sclerosis: Current diagnostic approach and therapeutic strategies

Pulmonary arterial hypertension(PAH) represents a devastating vascular complication of systemic sclerosis(SSc) and is found in 10%-15% of cases carrying a severe prognosis. PAH has a dramatic impact on the clinical course and overall survival, being the single most common cause of death in patients with this entity. The clinical course and aggressive progression of PAH has led clinicians to perform annual screening for it, since early detection and diagnosis are the cornerstone of a prompt therapeutic intervention. The diagnosis of PAH can be challenging to clinicians, particularly in its early stages, since in the context of SSc, the multiple causes of dyspnea need to be assessed. Doppler echocardiography represents the best initial screening tool, however, right heart catheterization remains the gold standard and definitive diagnostic means. Remarkable advances have been achieved in elucidating the pathogenesis of PAH in the past two decades, leading to the development of disease-specific targeted therapies: prostacyclin analogues, endothelin receptor antagonists and inhibitors of five phosphodiesterase pathways. However, the clinical response to these therapies in SSc-associated PAH has not been as great as the one seen with idiopathic PAH. This review also focuses on the diagnosis and novel therapies that are currently available for PAH, as well as potential future therapeutic developments based on newly acquired knowledge of diverse pathogenic mechanisms.

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension:State of the art

Chronic thromboembolic pulmonary hypertension(CTEPH)is a complex chronic disease in which pulmonary artery stenosis or obstruction caused by organized thrombus can lead to increased pulmonary artery pressure and pulmonary vascular resistance,ultimately triggering progressive right heart failure and death.Currently,its exact mechanism is not fully understood.Pulmonary endarterectomy(PEA)has immediate effects with low perioperative mortality and satisfactory prognosis in experienced expert centers for CTEPH patients with proximal lesions.Nevertheless,37%of patients are deemed unsuitable for PEA surgery due to comorbidities and other factors,and nearly half of the operated patients have residual or recurrent pulmonary hypertension.Riociguat is the only approved drug for CTEPH,although its effect is limited.Balloon pulmonary angioplasty(BPA)is a promising alternative treatment for patients with CTEPH.After more than 30 years of development and refinements,emerging evidence has confirmed its role in patients with inoperable CTEPH or residual/recurrent pulmonary hypertension,with acceptable complications and comparable longterm prognosis to PEA.This review summarizes the pathophysiology of CTEPH,BPA history and development,therapeutic principles,indications and contraindications,interventional procedures,imaging modalities,efficacy and prognosis,complications and management,bridging and hybrid therapies,ongoing clinical trials and future prospects.

Integrated bioinformatics analysis of key candidate genes and therapeutic drugs for idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis is a form of fibrotic and fatal lung disease worldwide with unknownetiology and mechanisms. This manuscript focused on clarifying the core protein-protein interaction network, genesand related pathways correlated with idiopathic pulmonary fibrosis in detail. Methods: Gene chip (GSE24206) wasacquired from the Gene Expression Omnibus database. GEO2R was a R-based online tool to screen differentialexpressed genes. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analysis were utilized toascertain gene function and key signaling pathways. The Search Tool for the Retrieval of Interacting Genes was usedto construct the protein-protein interaction network. Key genes and module analysis were screened out usingCytohubba and MCODE plugin. The candidate therapeutic molecular drugs were searched for IPF using DGIdbdatabase. Results: A cohort of 240 differential expression of genes (113 up-regulated and 127 down-regulated) wereknocked out. Gene Ontology enrichment analysis indicated that some differential expression of genes were involvedin extracellular matrix and neutrophil chemotaxis. The Kyoto Encyclopedia of Genes and Genomes pathways werepredominantly involved in chemokine signaling pathway and ECM-receptor interactions. Two significant modulesand 5 hub genes were strongly implicated in idiopathic pulmonary fibrosis from protein-protein interaction network.The 2 module genes were primarily enriched in the cytokine-cytokine receptor, TNF signaling pathway, toll-likesignaling pathway, and Wnt signaling pathway. Finally, 41 small molecules were identified by DGIdb database as thepotential drugs of idiopathic pulmonary fibrosis. Conclusion: To conclude, in this study, the hub genes, signalingpathways, and small molecules will conduce to better understanding the mechanisms and may provide new methodsto the therapy of idiopathic pulmonary fibrosis.

A Network Meta-analysis of the Efficacy and Safety of Targeted Drug Combinations in the Treatment of Pulmonary Arterial Hypertension

Objective:This network meta-analysis aims to compare the efficacy and safety of different targeted drug combination treatment for pulmonary arterial hypertension(PAH).Methods:Searches were conducted in Cochrane,PubMed,EMBASE,China National Knowledge Infrastructure,China Biomedical Literature Database,Wanfang Database,and ViP Chinese Science and Technology Journal Data to identify both published and unpublished randomized controlled trials from inception until January 1,2022.The risk of bias in the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions.A network metaanalysis was performed using Stata 16.0 software.The efficacy and safety of different targeted drugs combined treatment for PAH were evaluated based on forest plot,funnel plot,and surface under the cumulative ranking.Results:A total of 29 randomized controlled trails with 4,448 patients treated with 10 different types of targeted drug combinations were included in this study.The results of the surface under the cumulative ranking showed that the combination regimen was the best clinical option to improve symptoms and delay progression in patients with pulmonary artery hypertension compared with monotherapy.Sildenafil in combination with ambrisentan significantly improved the 6-minute walk distance and reduced N-terminal pro-brain natriuretic peptide levels.Bosentan in combination with sildenafil significantly reduced mean pulmonary artery pressure,whereas bosentan in combination with epoprostenol was more effective than other combinations in reducing pulmonary vascular resistance.Bosentan in combination with tadalafil significantly improved the Borg dyspnea score,and bosentan in combination with iloprost was the best combination for improving World Health Organization functional class/New York Heart Association functional class.In terms of safety,there was no significant reduction in the incidence of adverse events,hospitalizations,or allcause mortality for combination therapy compared with monotherapy.Bosentan combined with sildenafil significantly reduced the risk of serious adverse events,but the risk of discontinuation due to an adverse event was higher than monotherapy.Sildenafil combined with epoprostenol reduced the risk of clinical worsening in patients with PAH.Conclusion:Compared with monotherapy,targeted drug combinations for PAH significantly improves exercise tolerance,pulmonary hemodynamic parameters,and reduces the risk of serious adverse events and clinical worsening in patients.Bosentan in combination with sildenafil and bosentan in combination with iloprost are combinations of targeted agents with significant efficacy and better safety profile than monotherapy for the treatment of PAH.Sildenafil in combination with epoprostenol has a low risk of clinical worsening in PAH.

Potential impact of specific therapy on pregnant women with pulmonary arterial hypertension without cardiac shunt:a descriptive study in northern China

Background:Pregnancy in women with pulmonary arterial hypertension(PAH)is a fatal condition,despite the effectiveness of PAH-specific therapies.The coverage status and effect of specific therapies in pregnant patients with PAH without cardiac shunts in China remain unclear.To investigate this issue,we conducted a multicenter retrospective study in northern China.Methods:The study included 85 patients who were admitted to 4 clinical centers in Shandong Province between October 2010 and August 2020.Maternal endpoint events included(1)maternal death and/or(2)major adverse cardiac events,both occurring during pregnancy or within 6 weeks postpartum.Results:Although the overall mortality rate was encouraging(11.8%),the number of patients receiving PAH-specific therapies was extremely low(28.2%).Moreover,only 15.3%of patients received adequate duration of PAH-specific therapy(≥4 weeks)before delivery,and this subgroup showed the lowest major adverse cardiac events rate(7.7%)compared with that in the untreated(19.7%)and short-time treated groups(<4 weeks;54.5%).Conclusion:Pregnant patients with PAH without cardiac shunts face significantly increased mortality risks.Short-term PAH-specific therapy does not guarantee favorable maternal outcomes.Prepregnancy screening,early identification,and timely intervention are expected to improve maternal outcomes in pregnant women with PAH.

Rhodiola crenulata extract decreases fatty acid oxidation and autophagy to ameliorate pulmonary arterial hypertension by targeting inhibiton of acylcarnitine in rats

Pulmonary arterial hypertension(PAH)is a devastating pulmonary circulation disease lacking high-efficiency therapeutics.The present study aims to decipher the therapeutic mechanism of Rhodiola crenulata,a well-known traditional chinese medicine with cardiopulmonary protection capacity,on PAH by exploiting functional lipidomics.The rat model with PAH was successfully established for first,following Rhodiola crenulata water extract(RCE)treatment,then analysis of chemical constituents of RCE was performed,additional morphologic,hemodynamic,echocardiographic measurements were examined,further targeted lipidomics assay was performed to identify differential lipidomes,at last accordingly mechanism assay was done by combining qRT-PCR,Western blot and ELISA.Differential lipidomes were identified and characterized to differentiate the rats with PAH from healthy controls,mostly assigned to acylcarnitines,phosphatidylcholines,sphingomyelin associated with the PAH development.Excitingly,RCE administration reversed high level of decadienyl-L-carnitine by the modulation of metabolic enzyme CPT1A in mRNA and protein level in serum and lung in the rats with PAH.Furthermore,RCE was observed to reduce autophagy,confirmed by significantly inhibited PPARγ,LC3B,ATG7 and upregulated p62,and inactivated LKB1-AMPK signal pathway.Notably,we accurately identified the constituents in RCE,and delineated the therapeutic mechansim that RCE ameliorated PAH through inhibition of fatty acid oxidation and autophagy.Altogether,RCE might be a potential therapeutic medicine with multi-targets characteristics to prevent the progression of PAH.This novel findings pave a critical foundation for the use of RCE in the treatment of PAH.

Targeted treatment strategy for patients with severe pulmonary hypertension secondary to connective tissue diseases

Background:Pulmonary arterial hypertension(PAH)associated with connective tissue diseases(CTD)(CTD-PAH)remains a difficult challenge in clinical practice.We aimed to evaluate the effects of targeted vasodilators in patients with severe CTD-PAH.Methods:The data of 53 patients with severe CTD-PAH hospitalized at the Department of Rheumatology and Immunology,The Affiliated Drum Tower Hospital of Nanjing University Medical School,were retrospectively reviewed.Patients were followed up for an average of 2 years to track their outcomes.The efficacy of treatment and the survival rate of patients with severe CTD-PAH were determined.Results:Among the causes of severe CTD-PAH,systemic lupus erythematosus(SLE)was the most common(39.6%),and the age at onset in patients with SLE-PAH was younger than that of patients with other CTD.Bosentan was more effective than sildenafil in reducing pulmonary artery pressure,improving cardiac function,and increasing survival time.Combination therapy with targeted vasodilators significantly improved the prognosis of patients with severe CTD-PAH compared with monotherapy.Conclusions:Patients with severe CTD-PAH should be treated early with targeted vasodilators.In this study,bosentan was superior to sildenafil.Combined treatment might be an option for severe CTD-PAH.

Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis(IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure.Recently, phosphatidylinositol 3-kinase(PI3 K)/protein kinase B(PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3 K/AKT in fibrotic processes is increasingly prominent, with PI3 K/AKT inhibitors currently under clinical evaluation in IPF. Therefore,PI3 K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3 K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3 K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.

特发性肺纤维化合并肺动脉高压的发病机制和治疗进展

特发性肺纤维化的晚期常合并肺动脉高压,病理表现为肺血管重塑、增殖和炎症,肺动脉高压的出现加重原有肺部疾病症状,导致右心衰竭,死亡风险增加、预后差、社会及家庭负担重。特发性肺纤维化合并肺动脉高压目前病因尚不明确、治疗棘手。本文对特发性肺纤维化合并肺动脉高压的发病机制及治疗进展进行综述,以期为特发性肺纤维化合并肺动脉高压的研究和治疗方案的制定提供新的思路。

经胸实时三维超声心动图评估特发性肺动脉高压患者三尖瓣几何构型的价值

目的:研究经胸实时三维超声心动图在评估特发性肺动脉高压(IPAH)患者的三尖瓣几何构型中的应用价值。方法:前瞻性入选2017年9月至2018年12月在中国医学科学院阜外医院就诊的IPAH患者30例(为IPAH组),健康志愿者15例为对照组。所有研究对象均行经胸二维及三维超声心动图检查,并使用四维自动三尖瓣定量(4D Auto-TVQ)在聚焦右心室切面分析三尖瓣结构。肺动脉高压患者均在超声心动图检查后48 h内采用右心导管检查确诊。结果:IPAH组的三尖瓣形态学参数瓣环面积、瓣环周长、四腔心直径、瓣叶结合点高度、幕状区最大高度和幕状区容积均显著大于对照组(P均<0.05)。与对照组相比,IPAH组瓣环收缩期位移明显更小(P<0.05)。两组的瓣环面积变化率和两腔心直径差异均无统计学意义(P均>0.05)。IPAH患者的三尖瓣幕状区最大高度和瓣叶接合点高度均与右心室舒张末期容积具有良好相关性(r=0.710、0.515,P均<0.05);瓣环周长、四腔心直径和瓣环面积均与右心房收缩末期容积具有良好相关性(r=0.712、0.558、0.545,P均<0.05)。结论:IPAH患者三尖瓣幕状区最大高度、瓣叶接合点高度和幕状区容积明显增大,三尖瓣环扩张主要体现在四腔心切面直径。三尖瓣幕状区高度与右心室容积相关,而三尖瓣环尺寸与右心房容积相关。

ECMO在肺纤维化合并肺气肿受者肺移植术中的临床应用效果

目的探讨肺移植术中不同体外膜肺氧合(ECMO)转流方式对肺纤维化合并肺气肿(CPFE)患者预后的影响。方法回顾性分析44例接受肺移植的CPFE患者,并将其分为静脉-静脉ECMO(VV-ECMO)组(30例)和静脉-动脉ECMO(VA-ECMO)组(14例)。比较两组患者术前、术中、术后及随访相关指标。结果与VV-ECMO组比较,VA-ECMO组患者年龄较小,术前肺动脉压力较高,后外侧切口类型较少,手术时间较长,术后支气管胸膜瘘发生率较高(均为P<0.05)。两组术后肺动脉压力均下降,且VA-ECMO组下降幅度较大(P<0.05)。两组术后生存率差异无统计学意义(P>0.05)。结论VA-ECMO和VV-ECMO应用于CPFE患者肺移植术中均安全有效,转流方式对患者的短中期预后无显著影响,其中VA-ECMO更适用于术前肺动脉压较高的患者。

靶向异常通路的动脉性肺动脉高压新型药物研发

动脉性肺动脉高压(pulmonary arterial hypertension,PAH)是以肺血管阻力和肺动脉压力升高为主要表现的肺血管疾病,肺小血管重塑是其重要病理改变,如不及时治疗可导致右心室衰竭,威胁生命。目前针对PAH的治疗选择有限,已上市药物的主要作用是扩张肺血管,虽能缓解症状,但对预后的改善效果不佳。近年来,对PAH发病机制的研究取得了多项突破,多种信号通路的异常对PAH的作用已被逐渐阐明,以这些通路中的关键成员为靶点,已有多种新型药物正在研发和开展临床试验。本综述将这些疾病相关的信号通路归纳为5类,讨论针对这些异常通路的药物研发最新进展,重点关注已进入Ⅱ期临床试验阶段的新药物,探讨其作用机制及疗效,以期为今后PAH的新药研发提供参考。

代谢重编程在特发性肺纤维化发病中的作用

肺纤维化是由肺泡上皮反复受损,导致异常的上皮-成纤维细胞转化和肌成纤维细胞产生,进而导致细胞外基质大量积累和间质重塑引起的。与大多数肿瘤细胞类似,肺纤维化过程中也发生了代谢重编程,包括糖、脂、氨基酸代谢等改变,具体表现为糖酵解的上调、脂肪酸氧化减弱而合成增强、谷氨酰胺分解增加。糖酵解为纤维化形成过程中巨噬细胞、成纤维细胞等的大量增殖提供快速和高效的能量供应,满足其能量需求。活化后的成纤维细胞氨基酸代谢重编程不仅促进了胶原的合成,也在羟脯氨酸合成过程中通过形成ROS加剧了肌成纤维细胞活化进程。

动脉型肺动脉高压治疗研究进展

动脉型肺动脉高压(PAH)是一种慢性进展性心肺疾病,其主要病理改变是血管收缩和肺动脉增生性重构以及右心室肥厚引起肺动脉压力持续升高。深入探究PAH发病机制可以发现,其相关途径有血管增生、血管壁重构、氧化应激、炎症反应与基因调控等。虽然近年来PAH在治疗方面取得很大进展,但其死亡率仍然很高,当前临床治疗方法并未有效改善预后,该病对患者身体、社会、工作和情感等方面产生了很大影响。本文将对PAH治疗方面最新研究进行综述,以期为PAH临床治疗提供新的线索。