Mufangji tang ameliorates pulmonary arterial hypertension through improving vascular remodeling,inhibiting inflammatory response and oxidative stress,and inducing apoptosis

Background:Mufangji tang(MFJT)is composed of Ramulus Cinnamomi,Radix Ginseng,Cocculus orbiculatus(Linn.)DC.,and Gypsum.In clinical settings,MFJT has been effectively employed in addressing a range of respiratory disorders,notably including pulmonary arterial hypertension(PAH).However,the mechanism of action of MFJT on PAH remains unknown.Methods:In this study,a monocrotaline-induced PAH rat model was established and treated with MFJT.The therapeutic effects of MFJT on PAH rat model were evaluated.Network pharmacology was conducted to screen the possible targets for MFJT on PAH,and the molecular docking between the main active components and the core targets was carried out.The key targets identified from network pharmacology were tested.Results:Results showed significant therapeutic effects of MFJT on PAH rat model.Analysis of network pharmacology revealed several potential targets related to apoptosis,inflammation,oxidative stress,and vascular remodeling.Molecular docking showed that the key components were well docked with the core targets.Further experimental validation results that MFJT treatment induced apoptosis(downregulated Bcl-2 levels and upregulated Bax levels in lung tissue),inhibited inflammatory response and oxdative stress(decreased the levels of IL-1β,TNF-α,inducible NOS,and malondialdehyde,and increased the levels of endothelial nitric oxide synthase,nitric oxide,glutathione and superoxide dismutase),reduced the proliferation of pulmonary arterial smooth muscle cells(downregulated ET-1 andβ-catenin levels and ERK1/2 phosphorylation,increased GSK3βlevels).Conclusion:Our study revealed MFJT treatment could alleviate PAH in rats via induction of apoptosis,inhibition of inflammation and oxidative stress,and the prevention of vascular remodeling.

“Treat-Repair-Treat”:Management of Left Main Coronary Compression by a Pulmonary Artery Aneurysm in a Patient with Atrial Septal Defect and Significant Pulmonary Hypertension

Left main coronary compression syndrome(LMCS)may complicate pulmonary artery aneurysms(PAA),usually developed in the context of pulmonary arterial hypertension(PAH).We report the case of a 51-year-old female patient with an atrial septal defect(unsuitable for device closure)complicated by a PAA generating a 90%left main stenosis.The significant PAH held us back from immediate surgery.After specific dual PAH-targeted therapy(sildenafil and bosentan),the atrial septal defect could be closed with a unidirectional valved patch;the PAAinduced LMCS was treated by reductive arterioplasty.The postoperative course was uneventful.Follow-up showed clinical improvement,but PAH treatment was still needed.After three months,coronary angiography showed only an insignificant residual left main stenosis,proving that reductive pulmonary arterioplasty was effective in treating LMCS.Any PAA requires further evaluation for LMCS,a dangerous but treatable complication.The“treat-repair-treat”strategy and shunt-closure with a unidirectional valved patch can both improve surgical prospects of LMCS with shunt-related PAH.

Endogenous sulfur dioxide attenuates hypoxia-induced pulmonary artery hypertension via promoting the eNOS/cGMP/PKG cascade and downregulating the RhoA/ROCK pathway

Endogenous sulfur dioxide(SO_(2) )is a novel gasotransmitter involved in the pathophysiologic process of pulmonary artery hypertension(PAH).However,the molecular pathways on which endogenous SO_(2) impact remains unclarified.Methods In the present study,the regulatory role of endogenous SO_(2) in the pathogenesis of PAH and its associated molecular mechanisms were investigated.A Wistar rat model of PAH induced by hypoxic exposure was established.Endogenous SO_(2) content in rat plasma and rat lungs,mean PAH,ratio of right ventricular/(left ventricular+septum)[RV/(LV+SP)]and body weight of Wistar rats were examined.Protein expression of aspartate aminotransferase 1(AAT1),endothelial nitric oxide synthase(e NOS)and Rho-associated coiled kinase(ROCK)in rat lung tissues were determined by western blot.Activation of AAT1 and Ras homolog gene family member A(Rho A)in rat lungs were detected by assay kits according to manufacturers’instructions.The concentration of nitric oxide(NO),level of cyclic guanosine monophosphate(c GMP)and activity of protein kinase G(PKG)in rat lung tissues after exposure to hypoxic conditions or treatment with SO_(2) donor were also examined using commercial kits.Results Our data showed that the endogenous SO_(2) /AAT1 pathway was markedly downregulated in rats with PAH induced by hypoxic exposure.However,SO_(2) donor upregulated the endogenous SO_(2) pathway and attenuated PAH.Further investigation revealed that in the PAH model,the e NOS/c GMP/PKG cascade was downregulated and the Rho A/ROCK pathway was upregulated,which could be reversed by SO_(2) donor.Conclusions In conclusion,the endogenous SO_(2) /AAT1 pathway might protect against the development of hypoxic exposure induced PAH by promoting the e NOS/c GMP/PKG cascade and downregulating Rho A/ROCK pathway.

Comparative analysis of early and middle outcomes of the arterial switch operation in children with complete transposition of the great arteries with ventricular septal defect and severe pulmonary artery hypertension

Background The best age for the arterial switch operation （ASO） in complete transposition of great arteries with ventricular septal defect is usually considered to be within six months. This is because of severe pulmonary arterial hypertension and pulmonary arterial obstructive pathological changes. There are few reports on ASO surgery in children older than three years old. Methods We studied 41 children, including 24 males and 17 females, from January 2010 to December 2011. They were divided into three groups by operation age; 15 patients were 〈1 year old, 13 were 1-3 years old, and 13 were 〉3 years old. Associated cardiac abnormalities included patent ductus arteriosus in six cases, atrial septal defect in five cases, and mitral regurgitation in two cases. All the patients had echocardiography before the operation. Seventeen patients underwent a coronary computed tomography examination and five patients underwent right heart catheterization. All ASO surgeries were performed under inhalation anesthesia and hypothermic cardiopulmonary bypass. Results Three operative deaths occurred. Two were in the 〈1 year old group, who died from severe postoperative low cardiac output. The other was two years old and died of postoperative multiple organ failure. There was no significant difference in postoperative mortality and the recent mid-term survival rate among the three groups. Thirty-eight cases were followed up for an average of 11.2 months, ranging 6-20 months. One seven years old patient died of acute diarrhea and electrolyte disturbance arrhythmia caused by food poisoning. Three patients more than three years old still had residual pulmonary arterial hypertension. Conclusion Children older than three years old can still undergo the ASO procedure, but residual pulmonary hypertension is present.

NR4A1 enhances glycolysis in hypoxia-exposed pulmonary artery smooth muscle cells by upregulating HIF-1αexpression

Background:Pulmonary arterial hypertension(PAH)is a chronic and progressive disease that is strongly associated with dysregulation of glucose metabolism.Alterations in nuclear receptor subfamily 4 group A member 1(NR4A1)activity alter the outcome of PAH.This study aimed to investigate the effects of NR4A1 on glycolysis in PAH and its underlying mechanisms.Methods:This study included twenty healthy volunteers and twenty-three PAH patients,and plasma samples were collected from the participants.To mimic the conditions of PAH in vitro,a hypoxia-induced model of pulmonary artery smooth muscle cell(PASMC)model was established.The proliferation of PASMCs was assessed using CCK8 assays.Results:Levels of NR4A1,hypoxia-inducible factor-1α(HIF-1α),and various glycolysis-related enzymes were measured.In addition,extracellular glucose and lactate production were assessed.The interaction between NR4A1 and HIF-1αwas evaluated by co-immunoprecipitation assays.Levels of NR4A1 and HIF-1αwas increased in PAH patients,and exposure to hypoxia resulted in increased levels of NR4A1 and HIF-1αin PASMCs.NR4A1 interacted with HIF-1α.NR4A1 overexpression enhanced hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,decreased glucose levels,increased lactate levels and promoted hypoxic PASMC viability.Conversely,silencing NR4A1 decreased hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,promoted glucose production,reduced lactate levels and inhibited hypoxic PASMC viability.Furthermore,overexpression of HIF-1αreversed the regulation of glycolysis caused by NR4A1 knockdown.Conclusion:NR4A1 enhances glycolysis in hypoxia-induced PASMCs by upregulating HIF-1α.Our findings indicate that the management of NR4A1 activity may be a promising strategy for PAH therapy.

Rutaecarpine attenuates monocrotaline-induced pulmonary arterial hypertension in a Sprague-Dawley rat model

Background:Pulmonary arterial hypertension presents with obliterative remodeling of the pulmonary arteries and progressive elevation of pulmonary vascular resistance,which increase the risk of right ventricular failure and death.It has been reported in previous studies that rutaecarpine plays a crucial role in anti-inflammatory and antioxidant activities,which may help regulate cell apoptosis and cell proliferation.The purpose of this study was to determine the effects of rutaecarpine in the rat model of monocrotaline-induced pulmonary hypertension.Methods:We induced pulmonary arterial hypertension in adult Sprague-Dawley rats by injecting monocrotaline(60 mg/kg)and then treated with rutaecarpine(40 mg/kg·d)or sildenafil(30 mg/kg·d)(positive control).Subsequently,pulmonary function,inflammation,cytokines and pulmonary vascular remodeling or proliferation were assessed.Results:Rutaecarpine was found to improve monocrotaline-induced mean pulmonary artery pressure,cardiac index,right heart index,right ventricular hypertrophy index,pulmonary artery remodeling and pulmonary function.reverse transcription-quantitative polymerase chain reaction demonstrated a decrease in tumor necrosis factor-α,interleukin-6 and interleukin-1β,whereas western blots a significantly decrease in the expression of nuclear factor kappa-B,endothelin-1,extracellular signal-regulated kinases 1/2,B cell lymphoma-2,Beclin1 and microtubule-associated protein1 light chain 3-II protein,and increase in the expression of Bax,caspase-3 and p62 protein.Conclusion:Rutaecarpine attenuated pulmonary arterial hypertension by inhibiting inflammation,oxidative stress,cell proliferation and autophagy,while promoting apoptosis.

Bosentan Is Associated with a Reduction in Right Ventricular Systolic Pressure N-Terminal Pro-Hormone B-Type Natriuretic Peptide Levels in Young Patients with Pulmonary Hypertension

Pulmonary hypertension is a rare and potentially fatal disease in children if left untreated. Emerging therapies, including Bosentan, a dual endothelin receptor antagonist, have shown significant benefits in the adult pulmonary hypertension population;however, few studies have assessed the efficacy and safety of endothelin receptor antagonists in infants and young children. Our study was a single-center retrospective analysis of patients less than two years of age with a confirmed diagnosis of pulmonary hypertension and initiated on Bosentan therapy between 2017 and 2020. Twelve cases met eligibility criteria. Demographic data, laboratory data, echocardiographic, and cardiac catheterization data were analyzed. With treatment, there was a statistically significant decrease in mean right ventricular systolic pressure estimated by the tricuspid regurgitation jet (79 ± 23 mmHg reduced to 52 ± 25 mmHg;p < 0.001) N-terminal pro-hormone B-type natriuretic peptide levels (21,071 reduced to 2,037;p < 0.001). Additionally, improvement and eventual normalization of right ventricular function and septal geometry was seen within the first four months of therapy. Patients who underwent cardiac catheterization after therapy initiation (n = 4) demonstrated hemodynamic improvements;however, only the decrease in diastolic pulmonary artery pressure was statistically significant (p = 0.018). No significant differences in hemoglobin, platelet count, or liver function tests were observed between groups. In conclusion, these data suggest that Bosentan may be an effective and relatively safe treatment option for children less than two years of age with pulmonary hypertension. Further long-term randomized control studies are necessary to validate the potential clinical benefit of utilizing this drug therapy in young children.

Pulmonary arterial hypertension confirmed by right heart catheterization following COVID-19 pneumonia: A case report and review of literature

BACKGROUND Pulmonary arterial hypertension(PAH)is a disease of the arterioles resulting in an increased resistance in pulmonary circulation with associated high pressures in the pulmonary arteries,causing irreversible remodeling of the pulmonary arterial walls.Coronavirus disease 2019(COVID-19)has been associated with development of new onset PAH in the literature leading to symptoms of dyspnea,cough and fatigue that persist in spite of resolution of acute COVID-19 infection.However,the majority of these cases of COVID related PAH were diagnosed using echocardiographic data or via right heart catheterization in mechanically ventilated patients.CASE SUMMARY Our case is the first reported case of COVID related PAH diagnosed by right heart catheterization in a non-mechanically ventilated patient.Right heart catheterization has been the gold standard for diagnosis of pulmonary hypertension.Our patient had right heart catheterization four months after her initial COVID-19 infection due to persistent dyspnea.CONCLUSION This revealed new onset PAH that developed following her infection with COVID-19,an emerging sequela of the infection.

Choriocarcinoma-associated pulmonary thromboembolism and pulmonary hypertension： a case report

Cases of pulmonary embolism and pulmonary artery hypertension caused by choriocarcinoma represent a rare clinical emergency. We report a case of a 25-year-old woman who presented with pulmonary embolism and hyper- tension and died soon after complete pulmonary embolectomy. A related literature review revealed that almost all of these patients had previously experienced a spontaneous abortion （average, 6 months） and were not pregnant.

Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether salvianolic acid A(SAA)extracted from the traditional Chinese medicine′Dan Shen′attenuated vascular remodeling in a PAH rat model,and elucidated the underlying mechanisms.METHODS PAH was induced in rats by injecting a single dose of monocrotaline(MCT 60 mg·kg-1,sc).The rats were orally treated with either SAA(0.3,1,3 mg·kg-1·d-1)or a positive control bosentan(30 mg·kg-1·d-1)for 4 weeks.Echocardiography and hemodynamic measurements were performed on d 28.Then the hearts and lungs were harvested,the organ indices and pulmonary artery wall thickness were calculated,and biochemical and histochemical analysis were conducted.The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting.RESULTS Treatment with SAA or bosentan effectively ameliorated MCTinduced pulmonary artery remodeling,pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure(RVSP).Furthermore,the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium,parenchymal injury and collagen deposition in the lungs.Moreover,the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs.The treatments partially restored MCT-induced reductions of bone morphogenetic protein typeⅡreceptor(BMPRⅡ)and phosphorylated Smad1/5 in the lungs.CONCLUSION SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRⅡ-Smad pathway and inhibiting apoptosis.Thus,SAA may have therapeutic potential for the patients at high risk of PAH.

Quercetin attenuates the progression of monocrotaline-induced pulmonary hypertension in rats

Pulmonary arterial hypertension （PAH） is a progressive disease associated with increased constriction and remodeling of the pulmonary vasculature. Quercetin is a natural fiavonoid and has a variety of pharmacological effects including improvement of endothelial cell function. However, its pharmacological effects on pulmonary hypertension have been rarely reported. We sought to observe the protective effect of quercetin in rats with monocrotaline induced PAH. We divided 30 male Sprague-Dawley rats randomly into three groups with ten rats in each group： the monocrotaline group, the quercetin group and the control group. We found that, compared with the controls, the mean pulmonary artery pressure （mPAP） and the right ventricular hypertrophy index in the monocrotaline group were significantly higher （P 〈 0.01）. Quercetin caused a significant reduction both in the mPAP and fight ventricular hypertrophy index compared with the monocrotaline group （P 〈 0.01） while no difference was found between the quercefin group and the control group （P 〉 0.05）. Monocrotaline induced a marked increase in the wall thickness （WT） in small and mid-sized pulmonary arteries compared with the controls （P 〈 0.01）. Monocrotaline also induced a marked increase in the wall area （WA） in small [（56.38 ±6.65）% in monocrotaline vs. （19.80±4.63）% in control] and mid-sized [（43.71± 5.38）% in monocrotaline vs. （14.24± 3.66）% in control] pulmonary arteries （P 〈 0.01）. Quercefin treatment markedly reduced monocrotaline induced increase in both WT and WA （P 〈 0.01）, which, however, still remained significantly elevated compared with those of the controls （P 〈 0.01）. Furthermore, compared with controls, proliferating cell nuclear antigen （PCNA） expression in the pulmonary artery tissues was markedly increased by monocrotaline [（45.59± 1.27） in monocrotaline vs. （9.64± 0.69） in controls], which was significantly attenuated by quercetin. Our animal experiment indicated that quercetin could have protective effects on monocrotaline-induced PAH.

Selexipag as Add-on Therapy for Patients with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease:A Single-Center Retrospective Study

Purpose:This study examined the efficacy and safety of selexipag in treating pulmonary arterial hypertension(PAH)associated with congenital heart disease(CHD).Materials and Methods:We conducted a retrospective study of patients with CHD-associated PAH,treated with selexipag since December 2017.Thirteen adult patients(mean age,45.4 years;women,77%)were treated with selexipag as add-on therapy.Baseline characteristics,World Health Organization functional class,6-minute walking distance(6MWD)test results,N-terminal pro-B-type natriuretic peptide levels,echocardiographic data,and incidence of side effects were assessed.Results:The majority of patients(12/13,92.3%)experienced more than one treatment-associated complication;one patient dropped out of the study due to intolerable myalgia.The results of 6MWD test(from 299.2±56.2 m to 363.8±86.5 m,p=0.039)and tricuspid regurgitation(TR)pressure gradient(from 84.7±20.5 mmHg to 61.6±24.0 mmHg,p=0.018)improved and remained improved after selexipag treatment in 12 patients.Based on the results of a non-invasive risk assessment,8(66.7%)patients showed improvement,3(25.0%)showed no interval change,and the status of one patient(8.3%)deteriorated.Moreover,compared to patients treated with a low dosage,patients treated with a medium-to-high dosage showed a greater increase in 6MWD results(88.3±26.4 m vs.55.3±27.6 m,p=0.043)and a greater reduction in the TR pressure gradient(-33.7±10.9 mmHg vs.-12.5±12.0 mmHg,p=0.015).Conclusion:Selexipag is an efficient pulmonary vasodilator as add-on therapy in treating CHD-associated PAH.

Perioperative Nursing for Adult Congenital Heart Disease with Severe Pulmonary Arterial Hypertension

Objectives: To explore the main points of perioperative nursing for adult congenital heart disease with severe pulmonary arterial hypertension. Methods: A retrospective study of 13 patients with congenital heart disease and severe pulmonary arterial hypertension who admitted to the perioperative period of care from January 2018 to December 2019. To prevent perioperative complications of the patients, the focus is on respiratory and circulatory system care, followed by blood coagulation monitoring, digestive system protection and psychological care. Results: All 13 patients passed the perioperative period and were discharged from ICU. Conclusion: Adult congenital heart disease with severe pulmonary arterial hypertension has high perioperative risk, respiratory and circulatory system care is the key.

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.

Osthole attenuates pulmonary arterial hypertension by modulation of phospholipid metabolism

OBJECTIVE Pulmonary arterial hypertension(PAH)is a malignant pulmonary vascular disease lacking efficacy therapeutics.Therefore,it urgently needs to develop safe and effective drugs for PAH treatment.Osthole derived from Cnidium monnieri(L.)Cusson(Shechuangzi)or Angelica pubescens Maxim(Duhuo)has the capacity to alleviate PAH by decreasing pulmonary arterial pressure and alleviating pulmonary vascular remodeling in rats,which is a candidate drug for the prevention of PAH,but the underlying modulatory mechanism is still unclear.Our study aims at investigating the metabolic modulatory mechanism of osthole against PAH employing functional metabolomics strategy.METHODS PAH model rats were successfully established with MCT,following osthole administration,then functional metabolomics based on untargeted metabolomics assay,targeted lipidomics analysis,qRT-PCR,Western blotting and ELISA were performed to investigate the modulatory mechanism of osthole against pulmonary arterial pressure and pulmonary vascular remodeling in PAH.RESULTS Untargeted metabolomics results found that sphingosine 1-phosphate(S1P)was the differential metabolites characterized PAH and reversed by osthole treatment.S1P is a crucial sphingolipid metabolite catalyzed by sphingosine kinases1(Sphk1)and functions as promoting PASMCs proliferation contributing to pulmonary vascular remodeling and pulmonary arterial pressure increase.We revealed that osthole reversed high level of S1P by modulating metabolic enzyme Sphk1 via inactivating microRNA-21-PI3K/Akt/mTOR signal pathway to decrease pulmonary arterial pressure in rats with PAH.Then,targeted phospholipid metabolomics results uncovered that decadienyl-L-carnitine(C10:2)was the differential metabolite characterized PAH and corrected by osthole treatment in rat with PAH.C10:2 is the intermediate metabolite of fatty acid oxidation(FAO),and C10:2 accumulation indicated mitochondrial dysfunction and FAO increase.CONCLUSION Osthole could block lipid metabolic reprogramming through functional modulating the expression of fatty acid translocase,fatty acid synthase,phospholipase A2,carnitine palmitoyltransferase 1A to inhibit C10:2,thus to improve mitochondrial dysfunction and inhibit utilizing lipid to biosynthesize necessary essence for pulmonary artery smooth muscle cells(PASMCs)proliferation.Moreover,we delineated that C10:2 and metabolic reprogramming enzymes were modulated by miRNA-22-3p which was involved in PASMCs proliferation and pulmonary vascular remodeling.Therefore,osthole inhibited miRNA-22-3p mediated lipid metabolic reprogramming to ameliorate pulmonary vascular remodeling.

Pulmonary hypertension secondary to seronegative rheumatoid arthritis overlapping antisynthetase syndrome:A case report

BACKGROUND Polyarthritis is the most frequent clinical manifestation in antisynthetase syndrome(ASS)forms of idiopathic inflammatory myositis and may be misdiagnosed as rheumatoid arthritis(RA),particularly in patients with seronegative RA(SNRA).It is unclear whether there is an overlap between ASS and RA,or if ASS sometimes mimics RA.Pulmonary hypertension(PAH)is common in connective tissue diseases(CTDs).However,published reports on CTD-PAH do not include overlapping CTDs,and its incidence and impact on patient prognosis are unclear.CASE SUMMARY We report the case of a 63-year-old woman who presented with a 3-mo history of symptom aggravation of recurrent symmetrical joint swelling and pain that had persisted for over 10 years.The patient was diagnosed with RA and interstitial lung disease.The patient repeatedly presented to the hospital’s respiratory and rhe-umatology departments with arthralgia,plus shortness of breath after activity.Relevant tests indicated that anti-CCP and RF remained negative,while anti-J0-1 and anti-Ro-52 were strongly positive.It was not until recently that we recognized that this could be an unusual case of SNRA with concurrent ASS.Joint pain was relieved after regular anti-rheumatic treatment.Chest computed tomography scans showed that pulmonary interstitial changes did not progress significantly over several years;however,they showed gradual widening of the pulmonary artery,and cardiac ultrasound indicated elevated pulmonary artery systolic pressure.The prescribed treatment of PAH was not effective in improving shortness of breath.CONCLUSION Overlap of RA and ASS may be missed.Further research is necessary to facilitate early diagnosis,effective evaluation,and prognosis.

NOTCH3 Mutations and CADASIL Phenotype in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

Background:The etiology of pulmonary arterial hypertension associated with congenital heart disease(PAHCHD)is complicated and the phenotype is heterogeneous.Genetic defects of NOTCH3 were associated withcerebral disease and pulmonary hypertension.However,the relationship between NOTCH3 mutations and theclinical phenotype has not been reported in CHD-PAH.Methods:We eventually enrolled 142 PAH-CHD patientsfrom Fuwai Hospital.Whole exome sequencing(WES)was performed to screen the rare deleterious variants ofNOTCH3 gene.Results:This PAH-CHD cohort included 43(30.3%)men and 99(69.7%)women with the meanage 29.8±10.9 years old.The pathogenic or likely pathogenic mutations of NOTCH3 were identified in five cases.Patients 2,5,8 and 11 carried the same NOTCH3 mutation c.1630C>T(pArg544Cys),which is the hot-spotmutation for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL).Patient 3 carried the NOTCH3 mutation p.Arg75Gln that has also been reported to be associatedwith the CADASIL.Patients 2,5,8,11 took the examination of the cerebral magnetic resonance imaging(MRI)and confirmed the phenotype of CADASIL.Conclusions:We first reported the NOTCH3 rare mutationsand CADASIL phenotypes in CHD-PAH patients.The NOTCH3 rare variants were with a relatively high positiverate and CADASIL phenotypes were likely enriched in PAH-CHD patients.The preoperative neurological examinationmight be recommended for PAH-CHD patients to determine the surgical contraindications and reduceintraoperative neurological complications.

Discharge planning for children with ventricular septal defect and pulmonary arterial hypertension in China

Objective:To evaluate the effectiveness of discharge planning on maternal caring knowledge,maternal caring behavior,maternal discharge readiness and the rehospitalization of children with ventricular septal defect and pulmonary arterial hypertension(VSD-PAH).Background:Children with congenital heart disease(CHD)with pulmonary arterial hypertension(PAH)have more complications after surgery than those without PAH.Discharge planning is an effective strategy to help children leave the hospital safely,and receive appropriate care after discharge.Methods:A quasi-experimental design was used.Sixty children and their mothers were recruited and divided into two groups:the control group received conventional care,the intervention group received both conventional care and additional discharge planning care.Results:(1)After admission,maternal caring knowledge between the two groups was similar.(2)At discharge,maternal discharge readiness,maternal caring knowledge and maternal caring behavior in the intervention group was significantly higher compared to the control group(t=3.35,p=0.001;F=84.74,p<0.001;F=23.82,p<0.001).This difference persisted after discharge,and was evident at one month and three months after discharge.(3)However,no significant difference in the readmission rate of children after discharge was evident between the two groups.Conclusions:Discharge planning improves the maternal discharge readiness,maternal caring knowledge and maternal caring behaviors.However,this planning did not reduce the readmission rate of children with CHD-PAH.

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.

Treatment with neurohormonal inhibitors and prognostic outcome in pulmonary arterial hypertension with risk factors for left heart disease

BACKGROUND Despite major advances in pharmacologic treatment,patients with pulmonary arterial hypertension(PAH)still have a considerably reduced life expectancy.In this context,chronic hyperactivity of the neurohormonal axis has been shown to be detrimental in PAH,thus providing novel insights on the role of neurohormonal blockade as a potential therapeutic target.AIM To evaluate the application and prognostic effect of neurohormonal inhibitors(NEUi)in a single-center sample of patients with idiopathic PAH and risk factors for left heart disease.METHODS We analyzed data retrospectively collected from our register of right heart catheterizations performed consecutively from January 1,2005 to October 31,2018.Patients on beta-blocker,angiotensin-converting enzyme inhibitor,angiotensin receptor blocker or mineralocorticoid receptor antagonist at the time of right heart catheterization were classified as NEUi users and compared to NEUi nonrecipients.RESULTS Complete data were available for 57 PAH subjects:27 of those(47.4%)were taking at least one NEUi at the time of right heart catheterization and were compared with the remaining 36 NEUi non-recipients.NEUi users were older and had a higher cardiovascular risk profile compared to non-recipients.Additionally,NEUi non-users had a higher probability of dying during the course of follow-up than NEUi recipients(56.7%vs 25.9%,log-rank P=0.020).CONCLUSION The above data highlighted a subgroup of patients with PAH and comorbidities for left heart disease in which NEUi use has shown to be associated with improved survival.Future prospective studies are needed to identify the most appropriate therapeutic strategies in this subset population.