Role of ROS/Kv/HIF Axis in the Development of Hypoxia-Induced Pulmonary Hypertension

Hypoxic pulmonary hypertension (HPH) is a common complication in patients with chronic obstructive pulmonary disease (COPD), sleep-disordered breathing, or dwellers in high altitude. The exact mechanisms underlying the development of HPH still remain unclear. Reactive oxygen species (ROS),hypoxia inducible factors (HIF), and potassium channels (KV) are believed as the main factors during the development of HPH. We propose that the “ROS/Kv/HIF axis” may play an important initiating role in the development of HPH. Being formed under a hypoxic condition, ROS affects the expression and function of HIFs or KV, and consequently triggers multiple downstream signaling pathways and genes expression that participate in promoting pulmonary vasoconstriction and arterial remodeling. Thus, further study determining the initiating role of “ROS/Kv/HIF axis” in the development of HPH could provide theoretic evidences to better understand the underlying mechanisms of HPH, and help identify new potential targets in the treatment of HPH.

Expressions of G2A and OGR1 in peripheral blood cells of patients with hypoxia-induced pulmonary hypertension

Objective: To detect the expression changes of proton-sensing receptor G protein-coupled receptor 2A (G2A) and ovarian cancer G protein-coupled receptors 1 (OGR1) in human peripheral blood cells of patients with hypoxia-induced pulmonary hypertension (HPH). Methods: Thirty-one patients with HPH were enrolled for IPH group, 16 males and 15 females, aged (65.19 ± 5.86) years;and 30 healthy people were enrolled for control group (NC group), 15 males and 15 females, aged (63.47 ± 6.16) years. The peripheral blood samples were collected and the mRNA expressions of G2A and OGR1 were determined by using real-time fluorescent quantitative PCR. The pulmonary arterial pressure (PAP) of HPH group was detected with echocardiography for the analysis of blood gas and pulmonary function testing. Human peripheral blood was collected to detect the mRNA levels of G2A, OGR1 and the serum levels of tumor necrosis factor-α (TNF-α). Results: PaCO2 was increased significantly in HPH group than that in NC group (p < .05). The percentage of forced expiratory volume in 1 s in predicted value (FEV1 pro%) and the ratio of FEV1/forced vital capacity (FVC) in HPH group were significant lower than those in NC group (p < .05). The expressions of peripheral blood G2A mRNA and TNF-α in HPH group were increased dramatically than those in NC group (p < .05). The expressions of OGR1 mRNA in peripheral blood had no difference between HPH group and NC group. The expressions of G2A mRNA and TNF-α in HPH group were positively related to pulmonary artery pressure significantly. Conclusions: The expression of proton-sensing receptor G2A and the level of TNF-α were increased in peripheral blood cells of patients with pulmonary hypertension. The expressions of TNF-α and G2A had positive correlations with pulmonary artery pressure.

Pulmonary artery stent thrombosis and symptomatic pulmonary hypertension following COVID-19 infection in Alagille patient:A case report

BACKGROUND Alagille syndrome is a multisystem disease that results in various vascular anomalies,commonly involving the cardiac and pulmonary systems.To the best of our knowledge,there is no literature regarding the cardiovascular outcomes of these patients in association with coronavirus disease 2019(COVID-19).CASE SUMMARY A 34-year-old woman with a history of Alagille syndrome who underwent successful atrial septal defect with partial anomalous pulmonary veins and patent ductus arteriosus repair,as well as left pulmonary artery catheterization and stenting in childhood due to pulmonary stenosis.The patient was without any respiratory symptoms and was a dancer prior to contracting COVID-19.Several weeks after her COVID-19 infection,she developed left pulmonary artery stent thrombosis and subsequent symptomatic pulmonary hypertension.A treatment strategy of anticoagulation alongside pharmacological agents for pulmonary hypertension for 3 months followed by balloon pulmonary artery angioplasty to reopen the stenosis was unsuccessful.CONCLUSION In the era of COVID-19,patients with pulmonary vascular malformations and endovascular stents are at an increased risk for chronic thromboembolic disease.Patients may benefit from prophylactic antiplatelet or anticoagulation therapy.Stent thrombosis is a devastating phenomenon and should be treated urgently and aggressively with balloon pulmonary angioplasty,and/or a thrombolytic agent.

Hypoxia-inducible factor-1 alpha regulates the role of vascular endothelial growth factor on pulmonary arteries of rats with hypoxia-induced pulmonary hypertension

Background Hypoxia-inducible factor-1α (HIF-1α) is one of the pivotal mediators in the response of lungs to decreased oxygen availability, and increasingly has been implicated in the pathogenesis of pulmonary hypertension. Vascular endothelial growth factor (VEGF), a downstream target gene of HIF-1α, plays an important role in the pathogenesis of hypoxic pulmonary hypertension and hypoxic pulmonary artery remodelling. In this study, we investigated the dynamic expression of HIF-1α and VEGF in pulmonary artery of rats with hypoxia-induced pulmonary hypertension. Methods Forty male Wistar rats were exposed to hypoxia for 0, 3, 7, 14 or 21 days. Mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricle hypertrophy index (RVHI) were estimated. Lungs were inflated and fixed for in situ hybridisation and immunohistochemistry. Results mPAP values were significantly higher than the control values after 7days of hypoxia [(18.4±0.4) mmHg, P<0.05]. RVHI developed significantly after 14 days of hypoxia. Expression of HIF-1α protein increased in pulmonary arterial tunica intima of all hypoxic rats. In pulmonary arterial tunica media, HIF-1α protein was markedly increased by day 3 (0.20±0.02, P<0.05), reached the peak by day 7, then declined after day 14 of hypoxia. HIF-1α mRNA increased significantly after day 14 of hypoxia (0.20±0.02, P<0.05). VEGF protein began to increase markedly after day 7 of hypoxia, reaching its peak around day 14 of hypoxia (0.15±0.02, P<0.05). VEGF mRNA began to increase after day 7 of hypoxia, then remained more or less stable from day 7 onwards. VEGF mRNA is located mainly in tunica intima and tunica media, whereas VEGF protein is located predominantly in tunica intima. Linear analysis showed that HIF-1α mRNA, VEGF and mPAP were correlated with hypoxic pulmonary artery remodelling. HIF-1α mRNA was positively correlated with VEGF mRNA and protein (P<0.01). Conclusion HIF-1α and VEGF are both involved in the pathogenesis of hypoxia-induced pulmonary hypertension in rats.

NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15

Background:Pulmonary hypertension(PH)represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling.However,the mechanism underlying hypoxia-induced vascular remodeling is not fully elucidated.Methods and Results:By using quantitative polymerase chain reactions,western blotting,and immunohistochemistry,we demon-strate that the expression of N-myc downstream regulated gene-1(NDRG1)is markedly increased in hypoxia-stimulated endothelial cells in a time-dependent manner as well as in human and rat endothelium lesions.To determine the role of NDRG1 in endothelial dysfunction,we performed loss-of-function studies using NDRG1 short hairpin RNAs and NDRG1 over-expression plasmids.In vitro,silencing NDRG1 attenuated proliferation,migration,and tube formation of human pulmonary artery endothelial cells(HPAECs)un-der hypoxia,while NDRG1 over-expression promoted these behaviors of HPAECs.Mechanistically,NDRG1 can directly interact with TATA-box binding protein associated factor 15(TAF15)and promote its nuclear localization.Knockdown of TAF15 abrogated the effect of NDRG1 on the proliferation,migration and tube formation capacity of HPAECs.Bioinformatics studies found that TAF15 was involved in regulating PI3K-Akt,p53,and hypoxia-inducible factor 1(HIF-1)signaling pathways,which have been proved to be PH-related pathways.In addition,vascular remodeling and right ventricular hypertrophy induced by hypoxia were markedly alleviated in NDRG1 knock-down rats compared with their wild-type littermates.Conclusions:Taken together,our results indicate that hypoxia-induced upregulation of NDRG1 contributes to endothelial dysfunction through targeting TAF15,which ultimately contributes to the development of hypoxia-induced PH.

Risk Stratification and Prognosis of Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

Background:Current guidelines for managing pulmonary arterial hypertension(PAH)recommend a risk strati-fication approach.However,the applicability and accuracy of these strategies for PAH associated with congenital heart disease(PAH-CHD)require further validation.This study aims to validate the reliability and predictive accuracy of a simplified stratification strategy for PAH-CHD patients over a three-year follow-up.Additionally,new prognostic variables are identified and novel risk stratification methods are developed for assessing and managing PAH-CHD patients.Methods:This retrospective study included 126 PAH-CHD patients.Clinical and biochemical variables across risk groups were assessed using Kruskal-Wallis and Fisher’s exact tests.Indepen-dent risk factors were identified using ordered logistic regression,while Kaplan-Meier and Cox proportional hazards regression analyses evaluated their impact on all-cause mortality.A new stratification model for the PAH-CHD population was constructed based on these analyses.Results:Significant survival differences across stratified risk groups were observed(p<0.001),validating the effectiveness of the simplified risk stratification method in PAH-CHD patients.Prothrombin activity was a strong independent predictor of adverse outcomes of PAH-CHD patients(Hazard ratio 0.95,p<0.001,C-index 0.70).A model combining N-terminal pro-brain natriuretic peptide,prothrombin activity,albumin,and right atrial area achieved an area under the curve of 0.89 and a C-index of 0.85.Conclusions:The simplified risk stratification method is applicable to PAH-CHD patients.Prothrombin activity is a strong independent predictor of adverse outcomes.A comprehensive risk stratification approach,incorporating both established and novel biomarkers,enhances accessibility and offers predictive efficacy during follow-up for PAH-CHD patients,comparable to established models.

Treatment and Clinical Management of Chronic Thromboembolic Pulmonary Hypertension:An Update of Literature Review

Chronic thromboembolic pulmonary hypertension(CTEPH)is a chronic,progressive,debilitating,and life-threa-tening complication of pulmonary embolism(PE).Recent technological advances have permitted various treat-ment options for the treatment of CTEPH,including surgery,angioplasty,and medical treatment,depending on the location and characteristics of lesions.Pulmonary endarterectomy(PEA)is the treatment of choice for CTEPH,as it offers excellent long-term outcomes and a high probability of recovery.Moreover,various medical and interventional therapies are currently being developed for patients with inoperable CTEPH.This review mainly summarizes the current treatment approaches of CTEPH,offering more options for specialist physicians to,thus,better manage chronic thromboembolic syndromes.

Development of pulmonary hypertension remains a major hurdle to corrective surgery in Down syndrome

Down syndrome is the most common chromosomal abnormality encountered in clinical practice with 50%of them having associated congenital heart disease(CHD).Shunt lesions account for around 75%of all CHDs in Down syndrome.Down syndrome patients,especially with large shunts are particularly predisposed to early development of severe pulmonary hypertension(PH)compared with shunt lesions in general population.This necessitates timely surgical correction which remains the only viable option to prevent long term morbidity and mortality.However,despite clear recommendations,there is wide gap between actual practice and fear of underlying PH which often leads to surgical refusals in Down syndrome even when the shunt is reversible.Another peculiarity is that Down syndrome patients can develop PH even after successful correction of shunt.It is not uncommon to come across Down syndrome patients with uncorrected shunts in adulthood with irreversible PH at which stage intracardiac repair is contraindicated and the only option available is a combined heartlung transplant.However,despite the guidelines laid by authorities,the rates of cardiac transplant in adult Down syndrome remain dismal largely attributable to the high prevalence of intellectual disability in them.The index case presents a real-world scenario highlighting the impact of severe PH on treatment strategies and discrimination driven by the fear of worse outcomes in these patients.

The Potential of Circular RNAs as Biomarkers in Pulmonary Arterial Hypertension Related to Congenital Heart Disease

A particular type of endogenous noncoding RNAs known as circular RNAs(circRNAs)has now become possible biomarkers for several diseases because of their stability and tissue-specific expression patterns.CircRNAs might play a role in various of biological processes.The identification of particular circRNAs dysregulated in pulmonary arterial hypertension(PAH)raises the possibility of these molecules serving as biomarkers for the disease’s early diagnosis and treatment.This review mainly summarizes the role and potential of circRNA as a future biomarker in PAH related to congenital heart disease.This study presented several potential circRNA targets as diagnostic biomarkers for PAH,discussed their biological functions,and addressed the challenges that need to be considered for their application in clinical settings.

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.

Intervention control of aerobic exercise in maintaining quality of life and pulmonary hypertension in hemodialysis patients

BACKGROUND Pulmonary hypertension is a serious complication in the treatment of maintenance hemodialysis patients,which seriously affects the quality of life of patients and threatens their life safety.Prevention,treatment and improvement of pulmonary hypertension are of great significance to improve the quality of life of patients.AIM To investigate the intervention and control of pedal-powered bicycle in maintaining quality of life and pulmonary hypertension in hemodialysis patients.METHODS 73 patients with maintenance hemadialysis combined with pulmonary arterial hypertension at a hemodialysis center in a certain hospital from May 2021 to May 2022 are selected.Patients are divided into two groups,37 cases in the control group(group C)and 36 cases in the intervention group(group I).Patients are divided into two groups,group C is treated with oral administration of betaglandin sodium combined with routine nursing care.Based on group C,group I conducts power cycling exercises.RESULTS After treatment,group I patients had higher muscle strength,36-Item Short Form Health Survey scores,and Kidney Disease Targets Areas scores;The 6-minute walk distance test index level was higher and the Borg score was lower;The group I had lower systolic blood pressure,greater vital capacity,higher positive emotion,lower systolic pulmonary artery pressure index level,higher arterial partial oxygen pressure level,lower pulmonary vascular resistance index level,and higher blood oxygen saturation level[158.91±11.89 vs 152.56±12.81,1795.01±603.18 vs 1907.20±574.15,24.00(22.00,29.00)vs 24.00(22.00,28.00),P<0.001].CONCLUSION Aerobic exercise combined with Western medicine treatment can effectively improve patients'pulmonary hypertension,alleviate their negative emotions,and enable them to achieve a higher level of quality of life.

Independent prognostic value of lipocalin-2 in congenital heart disease-associated pulmonary artery hypertension

BACKGROUND Timely and accurate evaluation of the patient's pulmonary arterial pressure(PAP)is of great significance for the treatment of congenital heart disease.Currently,there is no non-invasive gold standard method for evaluating PAP.AIM To assess the prognostic value of lipocalin-2(LCN2)in relation to PAP in patients with congenital heart disease associated with pulmonary artery hypertension.METHODS We conducted a retrospective analysis of 69 pediatric patients diagnosed with ventricular septal defects.The patients’clinical and laboratory data were collected.The serum LCN2 concentrations were compared between the pulmonary arterial hypertension(PAH)group and the nonPAH group.The correlation of LCN2 concentration with PAH classification was evaluated using binary logistic regression analysis.The receiver operating characteristic(ROC)curve was used to evaluate the diagnostic potential of LCN2 for PAH.RESULTS Serum LCN2 concentration significantly correlated with patients’mean PAP(r=0.544,P<0.001),but not correlated with creatinine(P=0.446)or blood urea nitrogen(P=0.747).LCN2 levels were significantly correlated with PAH in both univariate[odds ratio(OR)1.107,95%CI:1.033-1.185,P=0.004)]and multivariate regression analysis(OR 1.150,95%CI:1.027-1.288,P=0.015).ROC curve analysis revealed an area under the curve of 0.783 for LCN2.At the cutoff value of 19.42 ng/mL,the sensitivity and specificity of LCN2 for diagnosing PAH is 90.19%and 55.56%,respectively.LCN2 concentration also significantly correlated with the post-repair mean PAP in patients with congenital heart disease(r=0.532,P=0.009).CONCLUSION LCN2 is emerging as a candidate biomarker for assessing PAP in patients with congenital heart disease.Its high sensitivity in diagnosing PAH makes it a valuable tool in patient management.

Pulmonary hypertension post-liver transplant:A case report

BACKGROUND Liver transplantation(LTx)is vital in patients with end-stage liver disease,with metabolic dysfunction-associated steatotic liver disease being the most common indication.Primary sclerosing cholangitis(PSC)is an important indication.Portopulmonary hypertension,associated with portal hypertension,poses a significant perioperative risk,making pretransplant screening essential.CASE SUMMARY We report the case of a 41-year-old woman with PSC who developed severe pul-monary hypertension years after a successful LTx.She presented with worsening dyspnea on exertion and presyncope.Diagnostic evaluation confirmed severe precapillary pulmonary hypertension without evidence of recurrent portal hy-pertension.Initial management with Sildenafil and Macitentan led to a significant improvement in her symptoms,exercise capacity,and biomarkers.This case highlights the rare development of de novo pulmonary hypertension in a liver transplant recipient without recurrent portal hypertension,possibly linked to autoimmune processes or primary liver disease itself.The patient’s positive re-sponse to the combination therapy underscores the importance of prompt diag-nosis and aggressive management.CONCLUSION In conclusion,pulmonary arterial hypertension post-LTx is a rare but serious complication with a poor prognosis,necessitating further research to better understand its mechanisms and to develop effective strategies for prevention and treatment.

Impact of diabetes mellitus on mortality in pulmonary hypertension:A systematic review and meta-analysis

BACKGROUND Pulmonary hypertension(PH)is a progressive disease characterized by endothelial dysfunction and vascular remodeling and is a leading cause of mortality worldwide.Although it is independently associated with multiple comorbidities,the impact of diabetes mellitus(DM)on mortality in patients with PH remains uncertain.To address this issue,we conducted a systematic review and meta-analysis to investigate the effect of DM on survival in patients with pulmonary hypertension.AIM To investigate the impact of diabetes mellitus on mortality in pulmonary hypertension patients.METHODS We conducted a comprehensive search of four major electronic bibliographic databases like PubMed,Google Scholar,Scopus,and Embase,and identified 106 relevant studies,out of 1561 articles,published since the year 2000 for full-text review.Fourteen retrospective and prospective cohort studies that compared survival between patients with DM and those without DM in the context of PH were deemed eligible for inclusion in our meta-analysis.The study was registered on PROSPERO with the identifier CRD42023390232.RESULTS A total of 116455 patients with PH were included in the meta-analysis,of whom 41228 suffered from DM and 75227 did not.The results of our meta-analysis indicate an elevated mortality rate among PH patients with diabetes mellitus in comparison to those without DM[odds ratio(OR)=1.40,95%CI:1.15–1.70,P=0.0006].The metaregression analysis unveiled a statistically significant negative association between mean age and effect size(coefficient=-0.036,P value=0.018).Conversely,a statistically significant positive association was detected between female proportion and effect size(coefficient=0.000,P value<0.001).CONCLUSION Our meta-analysis,which included approximately 116500 PH patients,revealed that the presence of diabetes mellitus was associated with increased odds of mortality when compared to non-diabetic patients.The metaregression analysis indicates that studies with older participants and lower proportions of females tend to exhibit smaller effect sizes.Clinically,these findings underscore the importance of incorporating diabetes status into the risk stratification of patients with PH with more aggressive monitoring and early intervention to improve prognosis potentially.

Effects of combined aerobic,resistance and inspiratory training in patients with pulmonary hypertension:A systematic review

BACKGROUND Pulmonary hypertension(PH)is a serious progressive disorder of the modern world,characterized by endothelial dysfunction and impaired vasoreactivity.Patients with PH usually present exercise intolerance from the very early stages and reduced exercise capacity.Exercise training has been shown to have beneficial effects in patients with cardiovascular comorbidities.However,data regarding the effects of combined exercise training programs in patients with PH still remains limited.AIM To investigate the effects of combined exercise training programs on exercise capacity and quality of life in patients with PH.METHODS Our search included all available randomized controlled trials(RCTs)regarding combined aerobic,resistance and inspiratory training programs in patients with PH in 4 databases(Pubmed,PEDro,Embase,CINAHL)from 2012 to 2022.Five RCTs were included in the final analysis.Functional capacity,assessed by peak VO_(2)or 6-min walking test(6MWT),as well as quality of life,assessed by the SF-36 questionnaire,were set as the primary outcomes in our study.RESULTS Peak VO_(2)was measured in 4 out of the 5 RCTs while 6MWT was measured in all RCTs.Both indices of functional capacity were significantly increased in patients with PH who underwent combined exercise training compared to the controls in all of the included RCTs(P<0.05).Quality of life was measured in 4 out of 5 RCTs.Although patients improved their quality of life in each group,however,only 2 RCTs demonstrated further improvement in patients performing combined training compared to controls.CONCLUSION By this systematic review,we have demonstrated that combined aerobic,resistance and inspiratory exercise training is safe and has beneficial effects on aerobic capacity and quality of life in patients with PH.Such exercise training regimen may be part of the therapeutic strategy of the syndrome.

Novel Role of Calcium-Sensitive Receptors in Chronic Hypoxia-Induced Proliferation of Pulmonary Vein Smooth Muscle Cells

Objective:Vascular remodeling due to chronic hypoxia(CH)occurs not only in the pulmonary arteries but also in the pulmonary veins.Pulmonary vascular remodeling arises from the proliferation of pulmonary vascular myocytes.However,the mechanism by which CH induces the proliferation of pulmonary vein smooth muscle cells(PVSMCs)is unknown.This study aimed to investigate the mechanism by which CH affects the proliferation of PVSMCs.Methods:PVSMCs were isolated from rat distal pulmonary veins and exposed to CH(4%O2,60h),and the expression of the calcium-sensitive receptor(CaSR)was detected by Western blotting and immunofluorescence.MTT assay was used to detect the proliferation viability of the cells,and the changes in the intracellular calcium concentration were detected by laser confocal scanning technique.Results:CaSR expression was present in rat distal PVSMCs,and CaSR protein expression was upregulated under hypoxia.The positive regulator spermine not only enhanced CH-induced CaSR upregulation but also enhanced CH-induced increase in cell viability and calcium ion concentration.The negative CaSR regulator NPS2143 not only attenuated CH-induced CaSR upregulation but also inhibited CH-induced cell viability and calcium ion concentration.Conclusion:CaSR-mediated hyperproliferation is a novel pathogenic mechanism for the development of proliferation in distal PVSMCs under CH conditions.

Inhibition of Expression of Hypoxia-inducible Factor-1α mRNA by Nitric Oxide in Hypoxic Pulmonary Hypertension Rats

In order to study the effect of nitric oxide (NO) on the expression of hypoxia inducible factor 1 alpha (HIF 1α) mRNA in hypoxic pulmonary hypertension (HPH) rats, 30 healthy male Wistar rats were randomly divided into normoxic control group, chronic hypoxic group and hypoxia plus L argine (L Arg) group. The animal model of HPH was developed. The mean pulmonary arterial pressure (mPAP) was measured by inserting a microcatheter into the pulmonary artery. The HIF 1α mRNA expression levels were detected by in situ hybridization (ISH) and semiquantitative RT PCR. It was found that after 14 days hypoxia, the mPAP in normoxic control group (17.6±2 7 mmHg,1 mmHg=0 133 kPa) was significantly lower than that in chronic hypoxic group(35.8±6.1 mmHg, t =0.2918, P <0.05) and mPAP in chronic hypoxic group was higher than that in hypoxia plus L argine group(24.4±3.8 mmHg, t =0.2563, P <0.05). ISH showed that the expression of HIF 1α mRNA in the intraacinar pulmonary arteriolae (IAPA) in normoxic control group (0.1076±0.0205) was markedly weaker than that in chronic hypoxic group (0.3317±0.0683, t =3.125, P <0.05) and that in chronic hypoxic group was stronger than that in hypoxia plus L argine group (0.1928±0.0381, t =2.844, P <0.05). RT PCR showed that the content of HIF 1α mRNA in chronic hypoxic group (2.5395±0.6449) was 2.16 times and 1.75 times higher than that in normoxic control group (1.1781±0.3628) and hypoxia plus L argine group (1.4511±0.3981), respectively. It is concluded that NO can reduce the mPAP by the inhibition of the expression of HIF 1α mRNA, which may be one of the mechanisms through which NO affects the pathogenesis of HPH.

Contribution of oxidative stress to pulmonary arterial hypertension

Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI 2 (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure.

Pulmonary hypertension in hereditary haemorrhagic telangiectasia

Hereditary haemorrhagic telangiectasia(HHT) is an autosomal dominant inherited disorder characterised by vascular malformations in predominantly the brain,liverand lungs.Pulmonary hypertension(PH) is increasingly recognised as a severe complication of HHT.PH may be categorised into two distinct types in patients with HHT.Post-capillary PH most often results from a high pulmonary blood flow that accompanies the high cardiac output state associated with liver arteriovenous malformations.Less frequently,the HHT-related gene mutations in ENG or ACVRL1 appear to predispose patients with HHT to develop pre-capillary pulmonary arterial hypertension.Differentiation between both forms of PH by right heart catheterisation is essential,since both entities are associated with severe morbidity and mortality with different treatment options.Therefore all HHT patients should be referred to an HHT centre.

Hemodynamic assessment of pulmonary hypertension

There has been significant progress in our understanding of the pathobiology, epidemiology and prognosis of pulmonary vascular disease and, over the past few years, there has been an explosion of clinical therapeutic trials for pulmonary arterial hypertension (PAH). The increasing number of different conditions now associated with PAH and the appearance of new diagnostic techniques have led to a need for a systematic diagnostic approaches and a new disease classification, which has resulted in notable improvements in the quality and efficacy of clinical care. We appreciate traditional resting right heart catheterization techniques (which still remain the gold standard for diagnosing PAH and managing patients on therapy) and look forward to novel invasive techniques (e.g. intravascular ultrasound) that add greatly to our understanding of right ventricle and pulmonary circulation, and for the interpretation of data from clinical trials as well.