Reliability of Echocardiographic Pulmonary Vascular Resistance to Screen for the New Definition of Precapillary Pulmonary Hypertension in Uncorrected Secundum Atrial Septal Defect

Background and Objective:The most feared complication of uncorrected secundum Atrial Septal Defect(ASD)is pulmonary arterial hypertension(PAH).Pulmonary vascular resistance(PVR)is crucial in detecting precapil-lary pulmonary hypertension(PH)to guide the need for PAH-specific therapy.There is a change in the cut-off value of PVR according to the recently updated PH guideline.How echocardiographic PVR(PVRecho)correlates to PVR by right heart catheterization(RHC)(PVRcath)according to the new guidelines has not been known.The aim of this study is to determine the reliability of PVRecho in detecting PAH in Uncorrected Ostium Secundum ASD based on the current updated guideline and to help screen the high PVR group.Methods:429 ostium secun-dum ASD in the COngenital HeARt Disease in Adult and Pulmonary Hypertension(COHARD-PH)registry was divided into three groups according to the PVR.PVRecho was calculated using Abbas’Formula and compared the its gold standard,the PVRcath.The correlation between the two methods was analyzed.The Bland-Altman plot was used to analyze the agreement between the two methods.Receiver operating characteristics(ROC)analysis was used to determine the PVRecho cut-off value for high PVR.Results:The majority of the population(63.5%)had high PVR.Female gender dominated the study population(84%).PVR_(echo) was significantly correlated with PVRcath(r=0.6225,p<0.0001).Bland-Altman plot among all groups and in subgroups analysis showed a wide range of agreement.PVRecho underestimated PVRcath 5.124 WU.In subgroup analysis,PVRecho overestimated PVRcath 0.35 WU in those with PVR<2 WU.In the second and third groups,PVR_(echo) underestimated PVRcath 0.52 and 10.77 WU,respectively.Conclusion:PVRecho is reliable in predicting high PVR in uncorrected secun-dum ASD.However,there is a wide range of agreement.PVR_(echo) cut-off value of>1.62 WU showed good dis-criminatory power in determining high PVR.

Hypoxia promotes pulmonary vascular remodeling via HIF-1α to regulate mitochondrial dynamics

Background Increasing research suggests that mitochondrial defect plays a major role in pulmonary hypertension(PH) pathogenesis. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation and apoptosis balance. However, the molecular mechanism underlying of this balance is still unknown. Methods To clarify the biological effects of hypoxic air exposure and hypoxia-inducible factor-1α(HIF-1α) on pulmonary arterial smooth muscle cell(PASMC) and pulmonary arterial hypertension rats, the cells were cultured in a hypoxic chamber under oxygen concentrations. Cell viability, reactive oxygen species level, cell death, mitochondrial morphology, mitochondrial membrane potential, mitochondrial function and mitochondrial biosynthesis, as well as fission-and fusion-related proteins, were measured under hypoxic conditions. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure, right ventricular hypertrophy index and right ventricular weight/body weight ratio were examined and recorded. Further, we assessed the role of HIF-1α in the development and progression of PH using HIF-1α gene knockdown using small interfering RNA transfection. Mdivi-1 treatment was performed before hypoxia to inhibit dynamin-related protein 1(Drp1). Results We found that HIF-1α expression was increased during hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and hypoxia-stimulated PASMCs proliferation and apoptosis. We also found that targeting mitochondrial fission Drp1 by mitochondrial division inhibitor Mdivi-1 was effective in PH model rats. The results showed that mitochondrial dynamics were involved in the pulmonary vascular remodeling under hypoxia in vivo and in vitro. Furthermore, HIF-1α also modulated mitochondrial dynamics in pulmonary vascular remodeling under hypoxia through directly regulating the expression of Drp1. Conclusions In conclusion, our data suggests that abnormal mitochondrial dynamics could be a marker for the early diagnosis of PH and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in PH.

Effects of low ambient temperatures and dietary vitamin C supplementation on pulmonary vascular remodeling and hypoxic gene expression of 21-d-old broilers

The objective of this study was to evaluate the effects of low ambient temperature （LAT） and dietary vitamin C （VC） sup- plementation on pulmonary vascular remodeling （PVR） and the relative expression of hypoxia inducible factor-la （HIF-la）, vascular endothelial growth factor （VEGF） and its receptor 2 （VEGFR-2） mRNA of lungs in 21-d-old broilers. 400 1-d-old male Cobb broilers were assigned randomly to 4 treatments as follows for 21 d： 1 ） LAT and a basal diet; 2） LAT and a basal diet supplemented with 1 000 mg kg-1 VC （LAT＋VC）; 3） normal ambient temperature （NAT） and a basal diet; 4） NAT and a basal diet supplemented with 1 000 mg kg-1 VC （NAT＋VC）. Each treatment was composed of 10 replicates of 10 birds per replicate. Samples of lung were collected after the broilers were killed at d 21. LAT increased the ratio of vessel wall area to vessel total area （WA/TA, %） and mean media thickness in pulmonary arterioles （mMTPA, %） （P〈0.05）. Dietary VC supplementation decreased mMTPA （P〈0.05）, but had no effect on the WA/TA. LAT increased （P〈0.05） the relative mRNA expression of HIF-la, VEGF and VEGFR-2, while adding VC to the diet could decrease （P〈0.05） their relative mRNA expression. A significant positive correlation existed between the level of VEGF mRNA expression and the value of WA/WT （P〈0.05） or mMTPA （P〈0.05）. These results suggested LAT resulted in pulmonary vascular remodeling, and the increase of HIF-la, VEGF and VEGFR-2 mRNA expression, and dietary VC supplementation can alleviate pulmonary vascular remodeling in broiler by affecting these gene expression.

Increasing angiotensin-converting enzyme(ACE)2/ACE axes ratio alleviates early pulmonary vascular remodeling in a porcine model of acute pulmonary embolism with cardiac arrest

BACKGROUND:Acute pulmonary embolism(APE)with cardiac arrest(CA)is characterized by high mortality in emergency due to pulmonary arterial hypertension(PAH).This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme(ACE)2-angiotensin(Ang)(1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor(AT1)axis(ACE2/ACE axes)ratio on pulmonary artery lesion after return of spontaneous circulation(ROSC).METHODS:To establish a porcine massive APE with CA model,autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg(1 mmHg=0.133 kPa).Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation.Pigs were divided into four groups of five pigs each:control group,APE-CA group,ROSC-saline group,and ROSC-captopril group,to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril.RESULTS:Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells.Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor(VEGF)in the APE-CA group compared with the control group.Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC.Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2(Bcl-2)/Bcl-2-associated X(Bax)ratio and decreasing cleaved caspase-3 expression.CONCLUSION:Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE.

Effect of prenatal tetrandrine therapy on pulmonary vascular structural remodeling in the nitrofen-induced CDH rat model

To examine the effects of prenatal tetrandrine (Tet) therapy on pulmonary arterial structural remodeling in nitrofen-induced congenital diaphragmatic hernia (CDH) Methods CDH was induced in fetal rats by maternal administration of 100*!mg nitrofen by gavage on day 9 5 of gestation (term, day 22) Control animals received olive oil (OO) Tet (24*!mg/kg per day) or normal saline (NS) was given by gavage every day from 16 to 20 days of gestation, and fetuses were delivered by caesarean section on day 21 5 Lung sections from 3 fetuses in each group were studied The number of vessels were calculated, the external diameter (ED), medial wall thickness (MT), percent of medial wall thickness, and wall structure were evaluated by image analysis software Results In the pre-acinar arteries, CDH-NS pups had a significantly increased %MT compared with the OO-NS group ( P <0 05), while CDH-Tet animals had a reduced %MT compared with the CDH-NS rats ( P <0 05) Similar results were seen in the intra-acinar level Significant differences were observed between CDH-NS animals and OO-NS controls in the percentage of muscularized intra-acinar blood vessels ( P <0 001) Tet-treated CDH pups had a reduced percentage of muscularized intra-acinar arteries compared with CDH-NS animals Conclusions Medial hypertrophy is present in both the pre-acinar and intra-acinar arteries in the nitrofen-induced CDH rat model Tet treatment inhibits medial hypertrophy and reduces the percentage of muscularized intra-acinar vessels Prenatal Tet therapy may be efficacious in reducing the risk of PH in human newborns with CDH

Protective effect of baicalin on experimental pulmonary arterial hypertension through inhibition of pulmonary vascular remodeling

Previous studies have shown that baicalin can attenuate pulmonary arterial hypertension and right ventricular hypertrophy.However,the potential mechanism remains unexplored.Nuclear factor-κB(NF-κB)and bone morphogenetic protein(BMP)signaling pathway play an important role in monocrotaline(MCT)induced pulmonary arterial hypertension(PAH).Therefore,we aimed to observe the regulation of baicalin on the NF-κB-BMP axis and the subsequent anti-proliferation in pulmonary vascular.Our results showed that baicalin could significantly decrease right ventricular systolic pressure(RVSP)and the RV/left ventricle plus septum ratio(P<0.05),and attenuate vascular remodeling.Furthermore,the result of westen blot showed that the protein expression level of BMP receptor 2(BMPR2)was significantly increased,while NF-κB p65,p-NF-κB p65,inhibitor of NF-κB(I-κBα)and the BMP antagonist,gremlin 1 were significantly down-regulated in the baicalin group(P<0.05).On the other hand,the result of immunohistochemical staining in lung showed that the capillary density of pulmonary arterioles significantly increased in the baicalin group compared with the MCT group(P<0.05).We concluded that baicalin exerted the protective effects against the lung and heart damage through inhibiting NF-κB-BMP signaling pathway,providing new mechanistic information about PAH and right ventricular hypertrophy.

The Role of Endogenous Carbon Monoxide in the Hypoxic Vascular Remodeling of Rat Model of Hypoxic Pulmonary Hypertension

We investigated the expression of heme oxygenase 1 (HO 1) gene and production of endogenous carbon monoxide (CO) in the rat lung tissue at different time points of chronic hypoxic pulmonary hypertension and the effect of hemin on the expression of HO 1 gene and pulmonary hypertension. A rat model of hypoxic pulmonary hypertension was recreated by exposure to intermittent normobaric hypoxic environment (10 % O 2). Reverse transcriptase polymerase chain reaction (RT PCR) was performed to determine the level of HO 1 mRNA in the rat lung tissue and double wave length spectrophotometry was used to evaluate the quantity of COHb in arterial blood. Cardiac catheterization was employed to measure the right ventricular systolic pressure (RVSP) and HE staining was performed in dissected lung tissue to observe the pathological changes of the intra acinar pulmonary arteries (IAPA). It was found that (1) There was a low level of HO 1 mRNA in normal rat lung tissue, but the level of HO 1 mRNA increased by 2-4 times in the lung tissue of hypoxic rats ( P <0.01). The quantity of COHb was 2-3 times those of control group ( P <0.01 or P <0.05). These were accompanied by the increased of RVSP and the thickened IAPA; (2) Hemin could keep the HO 1 mRNA and COHb in the hypoxic rat lung tissue at a high level, and partially suppressed the increase of rat RVSP, thereby ameliorating the pathological changes of IAPA. In conclusion, the upregulation of the expression of HO 1 gene and production of CO in the rat lung of hypoxic pulmonary hypertension plays a role of inhibition in the development of hypoxic pulmonary hypertension. Hemin has a therapeutic effect on hypoxic pulmonary hypertension.

Seabuckthorn Berries Extract Attenuates Pulmonary Vascular Hyperpermeability in Lipopolysaccharide-Induced Acute Lung Injury in Mice

Objective:To investigate the effect of seabuckthorn berries extract(SBE)on pulmonary vascular hyperpermeability in the mice model of acute lung injury(ALI)induced by lipopolysaccharide(LPS).Methods:Sixty Kunming mice were allocated into 6 groups by a random number table,including control,LPS,dexamethasone(Dex,1 mg/kg),and 120,240 and 480 mg/kg SBE groups,10 mice in each group.Except the control group,mice were pre-treated with Dex and SBE,respectively,for 7 days before LPS was intraperitoneally injected to induce ALl.Pulmonary vascular hyperpermeabilitywas evaluated by histopathologic observation and transvascular leakagedetermination.Tumor necrosis factor alpha(TNF-α)and interleukin-6(IL-6)levels in serum were measured using enzyme-linked immunosorbent assay.The expression of nuclear factor-kappa B(NF-k B)p65 in lung cells was determined by immunofluorescence analysis.The contents of cytoplasmic inhibitorof nuclear factor-kBkinase(IKK)and nuclearp65,as wellasdownstreamproteins of E-selectin(CD62E)and intercellular adhesion molecule-1(ICAM-1),were determined using Western blot analysis.Results:Histopathological observation confirmed SBEtreatment alleviatedmorphological lesion induced by LPS.Compared with the LPS group,480 mg/kg SBE significantly decreased the water content of lung,Evans blue accumulation in lung tissue,and protein concentration and neutrophils count in bronchoalveolar lavage fluid(P<o.01);moreover,480 mg/kg SBE significantly suppressed release of TNF-αand IL-6,and down-regulated expressions of IKK,nuclear p65,ICAM-1 and CD62E(P<0.01).Conclusion:SBE maintained alveolar-capillary barrier integrity under endotoxin challenge in mice by suppressing the key factors in the pathogenesis of ALl.

The substitution of SERCA2 redox cysteine 674 promotes pulmonary vascular remodeling by activating IRE1α/XBP1s pathway

Pulmonary hypertension(PH) is a life-threatening disease characterized by pulmonary vascular remodeling, in which hyperproliferation of pulmonary artery smooth muscle cells(PASMCs)plays an important role. The cysteine 674(C674) in the sarcoplasmic/endoplasmic reticulum Ca^(2+)ATPase 2(SERCA2) is the critical redox regulatory cysteine to regulate SERCA2 activity. Heterozygous SERCA2 C674 S knock-in mice(SKI), where one copy of C674 was substituted by serine to represent partial C674 oxidative inactivation, developed significant pulmonary vascular remodeling resembling human PH, and their right ventricular systolic pressure modestly increased with age. In PASMCs, substitution of C674 activated inositol requiring enzyme 1 alpha(IRE1 a) and spliced X-box binding protein 1(XBP1 s) pathway, accelerated cell cycle and cell proliferation, which reversed by IRE1 a/XBP1 s pathway inhibitor 4μ8 C. In addition, suppressing the IRE1 a/XBP1 s pathway prevented pulmonary vascular remodeling caused by substitution of C674. Similar to SERCA2 a, SERCA2 b is also important to restrict the proliferation of PASMCs. Our study articulates the causal effect of C674 oxidative inactivation on the development of pulmonary vascular remodeling and PH, emphasizing the importance of C674 in restricting PASMC proliferation to maintain pulmonary vascular homeostasis. Moreover, the IRE1 a/XBP1 s pathway and SERCA2 might be potential targets for PH therapy.

VASOACTIVE INTESTINAL POLYPEPTIDE PREVENTS INJURY OF PULMONARY VASCULAR PERMEABILITY DUE TO XANTHINE WITH XANTHINE OXIDASE

Hyperpermeability is a crux of pathogenesis of sudden lung edema in many pulmonary disorders. especially in acute lung injury and adult respiratory distress syndrome(ARDS). Using our modified method for assessment of pulmonary vascular permeability. we observed the effects of xanthine with xanthine oxidase(X-XO) perfused in rat pulmonary artery and the protection of vasoactive intestinal polypeptide(VIP) against the injury of pulmonary vascular permeabilrty. After addition of xanthine oxidase in the perfusate reservoir containing xanthine￣(125) I-albumin leak index (￣(125)IALI)was remarkably increased while peak airway pressure(Paw) was not significantly increased, and perfusion pressure of pulmonary artery(Ppa)and lung wet/dry weight ratio(W/D) were only slightly increased. Xanthine plus xanthine oxidase also increased thromboxane B_2(TX B_2) and 6-keto-prostaglandin F_(1α)(6-keto -PGF_(1α)) in the perfusate. Treatment with VIP obviously reduced or totally prevented all signs of injury. Simultaneously, VIP also diminished or abolished the associated generation of arachidonate products. The results indicated that VIP has potent protective activity against injury of pulmonary vascular permeability and may be a physiological modulator of inflammatory damage to vascular endothelium associated with toxic oxygen metacolites.

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.

Sustained low diffusing capacity in hepatopulmonary syndrome after liver transplantation

AIM： To study the presence of sustained low diffusing capacity （DLco） after liver transplantation （LT） in patients with hepatopulmonary syndrome （HPS）. METHODS： Six patients with mild-to-severe HPS and 24 without HPS who underwent LT were prospectively followed before and after LT at mid-term （median, 15 mo）. HPS patients were also assessed at Iong-tem （median, 86 mo）. RESULTS： Before LT, HPS patients showed lower PaO2 （71 ± 8 mmHg）, higher AaPO2 （43 ± 10 mmHg） and lower DLco （54% ± 9% predicted）, due to a combination of moderate-to-severe ventilation-perfusion （VA/Q） imbalance, mild shunt and diffusion limitation, than non- HPS patients （94 ± 4 mmHg and 19 ± 3 mmHg, and 85% ± 3% predicted, respectively） （P 〈 0.05 each）. Seven non-HPS patients had also reduced DLco （70% ± 4% predicted）. At mid- and long-term after LT, compared to pre- LT, HPS patients normalized PaO2 （91 ± 3 mmHg and 87 ± 5 mmHg）, AaPO2 （14 ± 3 mmHg and 23 ± 5 mmHg） and all VA/Q descriptors （P 〈 0.05 each） without changes in DLco （53% ± 8% and 56% ± 7% predicted, respectively）. Post-LT DLco in non-HPS patients with pre- LT low DLco was unchanged （75% ± 6% predicted）. CONCLUSION： While complete VA/Q resolution in HPS indicates a reversible functional disturbance, sustained low DLco after LT also present in some non-HPS patients, points to persistence of sub-clinical liver-induced pulmonary vascular changes.

Animal models of pulmonary hypertension due to left heart disease

Pulmonary hypertension due to left heart disease(PH-LHD) is regarded as the most prevalent form of pulmonary hypertension(PH). Indeed, PH is an independent risk factor and predicts adverse prognosis for patients with left heart disease(LHD). Clinically, there are no drugs or treatments that directly address PH-LHD, and treatment of LHD alone will not also ameliorate PH. To target the underlying physiopathological alterations of PH-LHD and to develop novel therapeutic approaches for this population, animal models that simulate the pathophysiology of PH-LHD are required. There are several available models for PH-LHD that have been successfully employed in rodents or large animals by artificially provoking an elevated pressure load on the left heart, which by transduction elicits an escalated pressure in pulmonary artery. In addition, metabolic derangement combined with aortic banding or vascular endothelial growth factor receptor antagonist is also currently applied to reproduce the phenotype of PH-LHD. As of today, none of the animal models exactly recapitulates the condition of patients with PH-LHD. Nevertheless, the selection of an appropriate animal model is essential in basic and translational studies of PH-LHD. Therefore, this review will summarize the characteristics of each PH-LHD animal model and discuss the advantages and limitations of the different models.

Role of cardiovascular intervention as a bridge to liver transplantation

End stage liver disease(ESLD) is associated with many specific derangements in cardiovascular physiology, which influence perioperative outcomes and may pro-foundly influence diagnostic and management strate-gies in the preoperative period. This review focuses on evidence-based diagnosis and management of coro-nary, hemodynamic and pulmonary vascular disease in this population with an emphasis on specific strategies that may provide a bridge to transplantation. Specifi-cally, we address the underlying prevalence of cardio-vascular disease states in the ESLD population, and relevant diagnostic criteria thereof. We highlight tradi-tional and non-traditional predictors of cardiovascular outcomes following liver transplant, as well as data to guide risk-factor based diagnostic strategies. We go on to discuss the alterations in cardiovascular physiology which influence positive- and negative-predictive values of standard noninvasive testing modalities in the ESLD population, and review the data regarding the safetyand efficacy of invasive testing in the face of ESLD and its co-morbidities. Finally, based upon the totality of available data, we outline an evidence-based ap-proach for the management of ischemia, heart failure and pulmonary vascular disease in this population. It is our hope that such evidence-driven strategies can be employed to more safely bridge appropriate candidates to liver transplant, and to improve their cardiovascular health and outcomes in the peri-operative period.

Dead Space Breathing in Patients with Malignancies: Determination by Cardiopulmonary Exercise Testing

Rationale: Patients with cancer commonly experience dyspnea originating from ventilatory, circulatory and musculoskeletal sources, and dyspnea is best determined by cardiopulmonary exercise testing (CPET). Objectives: In this retrospective pilot study, we evaluated patients with hematologic and solid malignancies by CPET to determine the primary source of their dyspnea. Methods: Subjects were exercised on a cycle ergometer with increasing workloads. Minute ventilation, heart rate, breathing reserve, oxygen uptake (V’O2), O2-pulse, ventilatory equivalents for carbon dioxide and oxygen (V’E/V’CO2 and V’E/V’O2, respectively) were measured at baseline and peak exercise. The slope and intercept for V’E/V’CO2 was computed for all subjects. Peak V’O2 4% predicted indicated a circulatory or ventilatory limitation. Results: Complete clinical and physiological data were available for 36 patients (M/F 20/16);32 (89%) exhibited ventilatory or circulatory limitation as shown by a reduced peak V’O2 and 10 subjects with normal physiologic data. The largest cohort comprised the pulmonary vascular group (n = 18) whose mean ± SD peak V’O2 was 61% ± 17% predicted. There were close associations between V’O2 and spirometric values. Peak V’E/V’O2 and V’E/V’CO2 were highest in the circulatory and ventilatory cohorts, consistent with increase in dead space breathing. The intercept of the V’E-V’CO2 relationship was lowest in patients with cardiovascular impairment. Conclusion: Dyspneic patients with malignancies exhibit dead space breathing, many exhibiting a circulatory source for exercise limitation with a prominent pulmonary vascular component. Potential factors include effects of chemo- and radiation therapy on cardiac function and pulmonary vascular endothelium.

Efficacy of Bosentan in Patients after Fontan Procedures：a Double-blind, Randomized Controlled Trial

Fontan surgery is a widely used palliative procedure that significantly improves the survival period of patients with complex congenital heart disease（CHD）. However, it does not decrease postoperative complication rate. Previous studies suggested that elevated mean pulmonary artery pressure（m PAP） and vascular resistance lead to decreased exercise tolerance and myocardial dysfunction. Therapy with endothelial receptor antagonists（Bosentan） has been demonstrated to improve the patients＇ prognosis. A double-blind, randomized controlled trial was performed to explore the efficacy of Bosentan in treating patients who underwent the Fontan procedure. Eligible participants were randomly divided into Bosentan group and control group. Liver function was tested at a local hospital and the results were reported to the phone inspector every month. If the results suggested abnormal liver function, treatment would be adjusted or terminated. All the participants finished the follow-up study, with no patients lost to follow-up. Unblinding after 2-year follow-up, no mortality was observed in either group. However, secondary end-points were found to be significantly different in the comparable groups. The cardiac function and 6-min walking distance in the Bosentan group were significantly superior to those in the control group（P=0.018 and P=0.027）. Bosentan could improve New York Heart Association（NYHA） functional status and improve the results of the 6-min walking test（6MWT） in Fontan patients post-surgery, and no other benefits were observed. Furthermore, a primary meta-analysis study systematically reviewed all the similar clinical trails worldwide and concluded an overall NYHA class improvement in Fontan patients who received Bosentan treatments.

Phospholipase A_2 and Its Relationship with Acute Lung Injury in Acute Pancreatitis in Dogs

Acute fulminant pancreatitis was produced in dogs by injection of autobile into the main pancreatic duct.After injection the phospholipase A_2(PLA_2)activities in serum,lung lymph and bronchoalveolar lavage fluid(BAL)were elevated significantly,lung lymph flow and pulmonary transvascular potein clearance increased progressively,protein content and cell numbers in BAL in the experimental animals were significantly higher than those in the control animals.Furthermore the lung index,wet to dry lung weight ratio,extravascular lung water to bloodless dry lung weight ra- tio,extravascuar lung water to bloodless dry lung weight ratio increased significantly as compared to control animals.Pretreatment with PLA_2 inhibitor,chloroquine,blocked the changes mentioned above.This experiment suggests:1.PLA_2 activity in lung lymph fluid as well as in serum and BAL is elevated in acute hemorrhagic pancreatitis.2.Elevated PLA_2 activity may increase the pulmonary vascular permeability.3.PLA_2 is the major factor leading to pulmonary edema in acute hemorrhagic pancreatitis.4.Phagocytes contribute to the lung injury induced by PLA_2 to some ex- tent.

Roles of NHE-1 in the proliferation and apoptosis of pulmonary artery smooth muscle cells in rats

Objective To evaluate the roles of Na +/H + exchanger-1 (NHE-1)in the proliferation and apoptosis of pulmonary artery smooth muscle cells in rats. Methods Twenty Wistar rats were randomized into control group and 3-week hypoxic group. Intracellular pH (pHi) of the smooth muscle was determined with fluorescence measurement of the pH-sensitive dye BCECF-AM, and the expression of NHE-1 mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR). Primary culture of pulmonary artery smooth muscle cells in vitro was performed. In situ cell death detection kit (TUNEL) was used for studying the effect of specific NHE-1 inhibitor-dimethyl amiloride (DMA) on the apoptosis of muscle cells which had intracellular acidification. Results pHi value and NHE-1 mRNA expression of pulmonary artery smooth muscle cells were significantly higher in the hypoxic group than in the control group (P【0.01, P【0.001). DMA elevated the apoptotic ratio remarkably. The effect was enhanced when DMA concentration increased and the time prolonged.Conclusions With the function of adjusting pHi, NHE-1 may play an important role in the proliferation and apoptosis of pulmonary artery smooth muscle cells.

The effect of rehabilitation exercise on the expression of glutaminase and cardiopulmonary remodeling in pulmonary hypertension

Pulmonary hypertension(PH)is featured by pulmonary vascular and cardiac remodeling.Rehabilitation exercise can improve patients’quality of life.We previously pinpointed a potential glutamine metabolism dysfunction in PH.Hence,we aim to investigate whether rehabilitation exercise could mitigate right ventricular and pulmonary vascular remodeling and its effect on glutaminase(GLS).We collected clinical indicators of PH patients and analyzed their correlation with GLS.Rehabilitation exercise(moderate intensity swimming exercise)was performed in monocrotaline-induced PH(MCT-PH)rats.We found that plasma GLS1 level in patients was lower than healthy subjects,and it was negatively correlated with end-systolic stage eccentricity index,right atrial transverse dimension and right atrial longitudinal dimension.MCT-PH rats displayed pulmonary vascular remodeling and right ventricular hypertrophy.Compared to control rats,higher levels of GLS1 and GLS2 mRNA in lung and lower levels of these two isoforms of GLS in right ventricle(RV)were displayed in MCT-PH rats.After swimming exercise,GLS mRNA levels in the lung and RV were significantly upregulated,and the cross-sectional area of right ventricular cardiomyocytes was significantly decreased although the percentage of pulmonary arteriolar medial wall thickness was not significantly changed.Therefore,we hold the opinion that plasma GLS1 level was decreased in PH.The transcriptional levels of GLS1 and GLS2 were increased in the lung tissues in PH,but were decreased in the RV tissues.Meanwhile,the changes of GLS levels indicated the pulmonary vascular and right ventricular remodeling.Whereas moderate intensity swimming exercise might improve the right ventricular remodeling by regulating the levels of GLS.

Echocardiogram in predicting correctable shunts in ventricular septal defect patients associated with severe pulmonary hypertension

Background Echocardiogram is a simple and useful tool in disease assessment.In ventricular septal defect(VSD)patients with severe pulmonary hypertension(PH),it is difficult to judge whether further intervention is needed.Therefore,this study aimed to investigate the application of echocardiogram in predicting the severity of pulmonary hypertension and guide subsequent management.Methods This study included VSD patients who underwent right heart catheterization(RHC)examination in Guangdong Provincial People's Hospital from January2011 to December 2022.An estimated pulmonary artery systolic pressure(e PASP)higher than 60 mm Hg was defined as severe PH in this study.Logistic regression analysis and receiver operating characteristic curve(ROC)analysis were used.Results A total of 186 VSD patients with severe PH(e PASP more than 60 mm Hg)were included in this study,with 158 cases in the non-correctable group and 28 cases in the collectable group.In univariable logistic regression,left atrium dimension(LA),left ventricular end-diastolic dimension(LVDd),left ventricular end-systolic dimension(LVDs),peak velocity of the pulmonary valve(PV),peak velocities from the early phase of the mitral inflow(MVE),bidirectional shunting and pericardial effusion were associated with a correctable shunt.When adjusted in multivariable model,only PV and bidirectional shunting remained statistically significant.The ROC curve found that PV exhibits good discriminative ability for correctable shunt(AUC[area under the curve]:0.779,95%CI:0.676-0.871)with a cut-off value of 1.465 m/s.The predictive performance of bidirectional shunting was not satisfactory,with a low AUC of 0.669(95%CI:0.571-0.766).Conclusions PV and bidirectional shunting are simple and clinically available parameters from echocardiogram in predicting PH severity,which not only avoids the repeated unnecessary cardiac catheterization,but also provides a reference basis for follow-up evaluation.