Ventricle Systolic Pressure Research Articles

Effect of Cocaine on Pulmonary Vascular Remodeling and Hemodynamics in Human Immunodeficiency Virus-Transgenic Rats.

Human immunodeficiency virus (HIV)-related pulmonary arterial hypertension has been found to be more prevalent in intravenous drug users. Our earlier cell-culture findings reported down-regulation of bone morphogenetic protein receptors (BMPRs) in combination with enhanced proliferation of human pulmonary arterial smooth muscle cells (PASMCs) in the presence of HIV-Trans-activator of transcription (Tat) and cocaine compared with either treatment alone. Here, we report physiologic evidence of significant increases in mean pulmonary arterial pressure in HIV-transgenic (Tg) rats intraperitoneally administered 40 mg/kg body weight cocaine (HIV-cocaine group) once daily for 21 days when compared with HIV-Tg rats given saline (HIV group) or wild-type (WT) Fischer 334 rats treated with (WT-cocaine group) and without cocaine (WT group). In addition, right ventricle systolic pressure was also found to be significantly higher in the HIV-cocaine rats compared with the WT group. Significant down-regulation in protein expression of BMPR-2 and BMPR-1B was observed in total lung extract from HIV-cocaine rats compared with the other three groups. Furthermore, the PASMCs isolated from HIV-cocaine rats demonstrated a higher level of proliferation and lower levels of apoptosis compared with cells isolated from other rat groups. Interestingly, corroborating our earlier cell-culture findings, we observed higher expression of BMPR-2 and BMPR-1B messenger RNA and significantly lower levels of BMPR-2 and BMPR-1B protein in HIV-cocaine PASMCs compared with cells isolated from all other groups. In conclusion, our findings support an additive effect of cocaine and HIV on smooth muscle dysfunction, resulting in enhanced pulmonary vascular remodeling with associated elevation of mean pulmonary arterial pressure and right ventricle systolic pressure in HIV-Tg rats exposed to cocaine.

Fermented ginseng, GBCK25, ameliorates hemodynamic function on experimentally induced myocardial injury

In the present study, we investigated whether treatment with GBCK25 facilitated the recovery of hemodynamic parameters, left ventricle systolic pressure, left ventricular developed pressure, and electrocardiographic changes. GBCK25 significantly prevented the decrease in hemodynamic parameters and ameliorated the electrocardiographic abnormality. These results indicate that GBCK25 has distinct cardioprotective effects in rat heart.

The Effect Of Ischemic Preconditioning On Pulmonary Pressure And Gas Exchange During Exercise In Hypoxia

Elevations in pulmonary vascular pressure are common at high altitude and can influence respiratory gas exchange. PURPOSE: The purpose of this study was to determine the role of acute ischemic preconditioning (IPC) on pulmonary vascular pressures and gas exchange during hypoxic exercise in healthy individuals. METHODS: A total of 12 healthy subjects were randomly assigned to either treatment group (n=6, 22.4±4.2yrs) or the sham group (n=6, 27.3±9.7yrs). Pulmonary vascular pressure was estimated from right ventricle systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) via echocardiograph (General Electric, Duluth, GA). In addition, minute ventilation (VE), end tidal CO2 (PETCO2) and breathing efficiency for CO2 (VE/VCO2) were measured breath-by-breath (MGC Diagnostics, Saint Paul, MN). For baseline measurement, subjects exercised at 30W on an echocardiograph-ergometer (Ergoline, Germany) during hypoxia (FiO2=~12.5%) followed by IPC treatment. Between baseline measurement and IPC treatment, a 90min washout period was applied. For IPC, an arm cuff was placed on the upper arm and the procedure included 4 cycles of alternating between 5min inflation and 5min deflation. The cuff pressures were 200mmHg for the treatment group and 20mmHg for the sham group. Following treatment or sham, both groups rested for 90min and post measurements were made. RESULTS: The treatment group demonstrated a trend towards an improved RVSP (-28.8±27.5% vs. -1.1±20.8% respectively, p=0.055) and mPAP (-11.30±16.2% vs. 13.8±23.8% respectively, p=0.057) but sham did not. However, no significant difference in VE, PETCO2 and VE/VCO2 between groups was observed (p>0.05). CONCLUSION: In this small preliminary study, IPC reduced pulmonary vascular pressure during hypoxic exercise, however, it was not associated with altered respiratory gas exchange.

Rutaecarpine attenuates hypoxia-induced right ventricular remodeling in rats.

Rutaecarpine has been shown to exhibit wide pharmacological effects in the cardiovascular system via stimulation of calcitonin gene-related peptide (CGRP) release. In the present study, the effect of rutaecarpine on hypoxia-induced right ventricular (RV) remodeling and the underlying mechanisms were evaluated. RV remodeling was induced by hypoxia (10% O2, 3weeks) in rats. Rats were treated with rutaecarpine (20 or 40mg/kg) by intragastric administration. Proliferation of cardiac fibroblasts was induced by TGF-β1 (5ng/mL) and determined by MTS and EdU incorporation method. Cardiac fibroblasts were treated with exogenous CGRP (10 or 100nM). The concentrations of CGRP and TGF-β1 in plasma were measured by ELISA. The expression of eIF3a, p27, α-SMA, collagen-I/III, ANP, and BNP were measured by real-time PCR or western blot. Hypoxia induced an increase of right ventricle systolic pressure (RVSP), ration of RV/LV+S, and RV/tibial length in rats, while cardiac hypertrophy, apoptosis, and fibrosis were detected. The expression of ANP, BNP, α-SMA, collagen-I, collagen-III, eIF3a, and TGF-β1 was up-regulated, and the expression of p27 was down-regulated in the right ventricle of hypoxia-treated rats. The plasma concentration of CGRP was decreased and TGF-β1 was increased in hypoxia-treated rats. All of these effects induced by hypoxia were attenuated by rutaecarpine in a dose-dependent manner. In cultured cardiac fibroblasts, TGF-β1 significantly promoted the proliferation and up-regulated the expression of α-SMA and collagen-I/III, while the expression of eIF3a was up-regulated and the expression of p27 was down-regulated. The effects of TGF-β1 were attenuated by CGRP. CGRP8-37, a selective CGRP receptor antagonist, abolished the effects of CGRP. Rutaecarpine attenuates hypoxia-induced RV remodeling via stimulation of CGRP release, and the effects of rutaecarpine involve the eIF3a/p27 pathway.

Activation of AMPK Prevents Monocrotaline-Induced Extracellular Matrix Remodeling of Pulmonary Artery.

BackgroundThe current study was performed to investigate the effect of adenosine monophosphate (AMP) – activated protein kinase (AMPK) activation on the extracellular matrix (ECM) remodeling of pulmonary arteries in pulmonary arterial hypertension (PAH) and to address its potential mechanisms.Material/MethodsPAH was induced by a single intraperitoneal injection of monocrotaline (MCT) into Sprague-Dawley rats. Metformin (MET) was administered to activate AMPK. Immunoblotting was used to determine the phosphorylation and expression of AMPK and expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). Gelatin zymography was performed to determine the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9.ResultsActivation of AMPK by MET significantly reduced the right ventricle systolic pressure and the right ventricular hypertrophy in MCT-induced rat PAH model, and partially inhibited the ECM remodeling of pulmonary arteries. These effects were coupled with the decrease of MMP-2/9 activity and TIMP-1 expression.ConclusionsThis study suggests that activation of AMPK benefits PAH by inhibiting ECM remodeling of pulmonary arteries. Enhancing AMPK activity might have potential value in clinical treatment of PAH.

Non-muscle myosin light chain promotes endothelial progenitor cells senescence and dysfunction in pulmonary hypertensive rats through up-regulation of NADPH oxidase

Non-muscle myosin regulatory light chain (nmMLC20) is reported to exert transcriptional function in regulation of gene expression, and NADPH oxidase (NOX)-derived reactive oxygen species contribute to vascular remodeling of pulmonary artery hypertension (PAH). This study aims to determine if nmMLC20 can promote endothelial progenitor cells (EPCs) senescence and dysfunction through up-regulation of NOX in PAH rats. The rats were exposed to10% hypoxia for 3 weeks to establish a PAH model, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, and the accelerated senescence and impaired functions in EPCs, accompanied by an increase in Rho-kinase (ROCK) and NOX activities, p-nmMLC20 level, NOX expression and H2O2 content; these phenomena were reversed by fasudil, a selective inhibitor of ROCK. Next, normal EPCs were cultured under hypoxia to induce senescence in vitro. Consistent with the in vivo findings, hypoxia increased the senescence and dysfunction of EPCs concomitant with an increase in ROCK and NOX activities, p-nmMLC20 level, NOX expression and H2O2 content; these phenomena were reversed by fasudil. Knockdown of nmMLC20 showed similar results to that of fasudil except no effect on ROCK activity. Based on these observations, we conclude that nmMLC20 could promote the senescence and dysfunctions of EPCs in PAH through up-regulation of NOX in a phosphorylation-dependent manner.

Assessment of right ventricular function in patients with right ventricular overload using real-time three-dimensional echocardiography

Objective To evaluate global and segmental right ventricular (RV) systolic functions in patients with excessive volume or pressure load using real-time three-dimensional echocardiography(RT-3DE). Methods Forty-five patients with RV volume overload, 45 patients with RV pressure overload and 45 healthy subjects were underwent RT-3DE. RV global and segmental (inflow, body, outflow) end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV) and ejection fraction (EF) were analyzed with TomTec software. The correlations between EF with the three-dimensional method and two-dimensional parameters including right ventricle systolic pressure(RVSP) were discussed. Results Global EDV and ESV increased significantly in both patient groups compared with controls (all P 0.05). Compensated increase of SV was found in sixty percent of patients with volume overload but none with pressure overload (P<0.05). Global EF decreased significantly in both of patient groups (all P<0.05), which was more significant patients with pressure overload (P<0.05). Different patterns of the regional dysfunction were found among the different RV segments. No correlation was found between RVSP and global or segmental EF in patients with pressure overload. Conclusions RT-3DE could be used to assess global and segmental RV systolic function in patients with pressure and volume overload. Key words: Echocardiography, real-time three-dimensional; Ventricular function, right; Right ventricular overload

Association of different electrocardiographic patterns with shock index, right ventricle systolic pressure and diameter, and embolic burden score in pulmonary embolism.

Some electrocardiographic (ECG) patterns are characteristic for pulmonary embolism but exact meaning of the different ECG signs are not well known. The aim of this study was to determine the association between four common ECG signs in pulmonary embolism [complete or incomplete right bundle branch block (RBBB), S-waves in the aVL lead, S1Q3T3 sign and negative T-waves in the precordial leads] with shock index (SI), right ventricle diastolic diameter (RVDD) and peak systolic pressure (RVSP) and embolic burden score (EBS). The presence of complete or incomplete RBBB, S waves in aVL lead, S1Q3T3 sign and negative T-waves in the precordial leads were determined at admission ECG in 130 consecutive patients admitted to the intensive care unit of a single tertiary medical center in a 5-year period. Echocardiography examination with measurement of RVDD and RVSP, multidetector computed tomography pulmonary angiography (MDCT-PA) with the calculation of EBS and SI was determined during the admission process. Multivariable regression models were calculated with ECG parameters as independent variables and the mentioned ultrasound, MDCT-PA parameters and SI as dependent variables. The presence of S-waves in the aVL was the only independent predictor of RVDD (F = 39.430, p < 0.001; adjusted R2 = 0.231) and systolic peak right ventricle pressure (F = 29.903, p < 0.001; adjusted R2 = 0.185). Negative T-waves in precordial leads were the only independent predictor for EBS (F = 24.177, p < 0.001; R2 = 0.160). Complete or incomplete RBBB was the independent predictor of SI (F = 20.980, p < 0.001; adjusted R2 = 0.134). In patients with pulmonary embolism different ECG patterns at admission correlate with different clinical, ultrasound and MDCT-PA parameters. RBBB is associated with shock, Swave in the aVL is associated with right ventricle pressure and negative T-waves with the thrombus burden in the pulmonary tree.

BMPR2 gene delivery reduces mutation-related PAH and counteracts TGF-β-mediated pulmonary cell signalling.

Idiopathic, familial and secondary pulmonary arterial hypertension (PAH) are associated with reduced bone morphogenetic protein receptor type 2 (BMPR2) expression, and in some contexts, TGF-β upregulation. Our aims were to assess BMPR2 gene therapy in a PAH mouse model and to assess the impact on TGF-β signalling. Using a targeted in vivo gene delivery approach, we assessed the impact of BMPR2 gene delivery in a transgenic mouse model in which PAH was first induced by doxycycline driven expression of a dominant negative BMPR2 mutant (R899X). We also assessed the impact of BMPR2 gene delivery on TGF-β-induced changes in cell signalling in human pulmonary vascular endothelial and smooth muscle cells. In the mouse model, changes in TGF-β levels were not detected, but BMPR2 gene delivery reversed the increase in right ventricle systolic pressure (RVSP) and Fulton Index (FI), associated with a trend to increased pulmonary endothelial nitric oxide synthase (eNOS) gene expression. In vitro, BMPR2 gene transfer reduced TGF-β effects on Smad2, Smad1/5/8 and Erk1/2 phosphorylation in human pulmonary arterial smooth muscle cells (HPASMC). BMPR2 was also found to upregulate nitric oxide (NO) production in lung derived human microvascular endothelial cells (HMVEC-L). This study provides further evidence that BMPR2 modulation may have therapeutic potential. See Editorial, page 406.

Percutaneous CT guided lung biopsy in patients with pulmonary hypertension: Assessment of complications

PurposeTo assess the complications of CT-guided percutaneous transthoracic needle aspiration and/or core biopsy (PTNAB) of lung nodules in patients with pulmonary arterial hypertension (PHTN). Method and materialsWe analyzed PTNAB of 74 lung lesions (mean size: 3.6±2.1 cm) in 74 patients (M: F 38:36; age 68±15 years) with documented PHTN on cardiac ultrasound. 39 patients with lung lesions (M: F 24:15; age 65±14) who underwent PTNAB in the same period with right ventricle systolic pressure (RVSP) <35mmHg were selected as controls. Pulmonary arterial pressures were estimated on cardiac ultrasounds by using the tricuspid regurgitation jet method. Two thoracic radiologists reviewed the medical records and PTNAB images on a PACS station and documented nodule size, location, distance traversed in lung, technical success and complications. ResultsFine needle aspirates were obtained in all and core biopsy in 23% (17/74) of the nodules. 61% (45/74) of the nodules were in the middle and 39% (29/74) were in the outer third of lung. PHTN was mild, moderate and severe in 84% (62/74), 13% (10/74) and 3% (2/74) of the patients. Biopsy was complicated by hemorrhage in 26% (19/74), moderate hemoptysis in 1.3% (1/74), pneumothorax in 17% (12/74), chest tube in 1.3% (1/74) and hemothorax in 1.3% (1/74) of the patients. The complications rate in control group was similar, hemorrhage in 33% (19/39) (p=0.6), moderate hemoptysis in 5% (2/39) (p=0.3), pneumothorax in 28% (11/39) (p=0.2), chest tube in (0/39) (p=0.3), and hemothorax in 3% (1/39) of the patients (p=0.7). ConclusionPercutaneous needle biopsy of lung lesions in patients with mild to moderate PHTN can be performed without significant increase in complications.

Detection of Left Atrium Myopathy Using Two-Dimensional Speckle Tracking Echocardiography in Patients with End-Stage Renal Disease on Dialysis Therapy.

Left atrium (LA) deformation analysis by two-dimensional speckle tracking echocardiography (2DSTE) has recently been proposed to evaluate left ventricular (LV) filling pressure in dialysis patients. The purpose of this study was to study the LA function in dialysis patients using two-dimensional speckle tracking echocardiography correlated to prevalence of atrial fibrillation, echocardiographically pulmonary capillary wedge pressure, and right ventricle systolic pressure. Hundred adult patients aged 49.3 ± 13.9 years on regular hemodialysis and 40 healthy individuals were enrolled in the study. Left ventricular dimensions, ejection fraction, and mass index were studied. Left atrium volume index (LAVI) was calculated by dividing left atrium volumes by body surface area. Left ventricle filling pressure was evaluated according to E/E'. Left atrium global systolic strain (LASS) was studied using 2DSTE. Left atrium stiffness was calculated noninvasively based on the ratio of E/E' to LASS. Right ventricle systolic pressure was estimated with the Bernoulli equation formula. Left atrium diameter, left ventricle indexed mass, mitral (E/E'), and LA stiffness were increased in dialysis group 4.4 ± 0.2 cm, 126.5 ± 24.6 g/m(2) , 16.9 ± 4.4, and 0.5 ± 0.1, respectively, P < 0.001 for all. Left atrium systolic strain was significantly decreased in dialysis patients (26.6 ± 1.9 vs. 33.7 ± 2.1%, P < 0.001). Left atrium stiffness was significantly higher in dialysis patients with atrial fibrillation (AF) compared to those without AF. Assessment of LA deformation parameters predicts LV diastolic dysfunction and right ventricle systolic pressure in dialysis patients. Left atrium function in dialysis patients was impaired before the occurrence of left atrium dilatation.

Arginase inhibitor attenuates pulmonary artery hypertension induced by hypoxia.

Hypoxia-induced pulmonary arterial hypertension (HPAH) is a refractory disease characterized by increased proliferation of pulmonary vascular smooth cells and progressive pulmonary vascular remodeling. The level of nitric oxide (NO), a potential therapeutic vasodilator, is low in PAH patients. L-arginine can be converted to either beneficial NO by nitric oxide synthases or to harmful urea by arginase. In the present study, we aimed to investigate whether an arginase inhibitor, S-(2-boronoethyl)-L-cysteine ameliorates HPAH in vivo and vitro. In a HPAH mouse model, we assessed right ventricle systolic pressure (RVSP) by an invasive method, and found that RSVP was elevated under hypoxia, but was attenuated upon arginase inhibition. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions, and their proliferative capacity was determined by cell counting and flow cytometry. The levels of cyclin D1, p27, p-Akt, and p-ERK were detected by RT-PCR or Western blot analysis. Compared to hypoxia group, arginase inhibitor inhibited HPASMCs proliferation and reduced the levels of cyclin D1, p-Akt, p-ERK, while increasing p27 level. Moreover, in mouse models, compared to control group, hypoxia increased cyclin D1 expression but reduced p27 expression, while arginase inhibitor reversed the effects of hypoxia. Taken together, these results suggest that arginase plays an important role in increased proliferation of HPASMCs induced by hypoxia and it is a potential therapeutic target for the treatment of pulmonary hypertensive disorders.

Serum apelin as a novel non-invasive marker for subclinical cardiopulmonary complications in children and adolescents with sickle cell disease

BackgroundCardiovascular involvement represents a leading cause of mortality and morbidity in sickle cell disease (SCD). Apelin is a peptide involved in the regulation of cardiovascular function. AimTo determine serum apelin among 40 children and adolescents with SCD compared with 40 healthy controls and assess its relation to markers of hemolysis, iron overload as well as cardiopulmonary complications. MethodsSCD patients, in steady state and asymptomatic for heart disease, were studied stressing on hydroxyurea/chelation therapy, hematological profile, serum ferritin and apelin levels. Full echocardiographic study including assessment of biventricular systolic function and pulmonary artery pressure was done. ResultsApelin levels were significantly lower in SCD patients compared with controls (P<0.001). Cardiopulmonary complications were encountered in 30% of patients. Apelin was significantly decreased among patients with cardiopulmonary disease (P=0.006) whether those at risk of pulmonary hypertension (P=0.018) or patients with heart disease (P=0.043). Hydroxyurea-treated patients had higher apelin levels than untreated ones (P=0.001). Apelin was negatively correlated to lactate dehydrogenase, indirect bilirubin, serum ferritin, end systolic diameter, tricuspid regurgitant jet velocity, right ventricle systolic pressure, pulmonary vascular resistance and tissue Doppler imaging S wave. Apelin cutoff value of 1650ng/L could significantly detect the presence of cardiopulmonary complications in SCD with 90.9% sensitivity and 72.4% specificity. ConclusionApelin is a promising marker for screening of SCD patients at risk of cardiopulmonary disease because it is altered during the early subclinical stage of cardiac affection. A combination of apelin and echocardiography provides a reliable method to assess cardiopulmonary affection in young SCD patients.

Abstract 19126: Endothelial-specific Deletion of Prolyl Hydroxylase Domain Protein 2 (PHD2) Results in Severe Pulmonary Hypertension in Mice by Enhancing the HIF2alpha Signaling Pathway

Rationale: Sustained pulmonary vasoconstriction and excessive vascular remodeling are major causes of elevated pulmonary vascular resistance which leads to increased pulmonary arterial pressure in patients with pulmonary hypertension. Hypoxic-inducible factor (HIF) and its upstream regulators have been linked to the hypoxia response in vascular remodeling and the development of pulmonary hypertension. In this study, we aimed at defining whether increased HIF1α and/or HIF2α, due to endothelial cell specific deletion of prolyl hydroxylase domain protein 2 (PHD2) under normoxic condition are involved in or required for the initiation and progression of pulmonary hypertension. Methods: PHD2, HIF1α and HIF2α conditional knockout mice were created. Right ventricle systolic pressures (RVSP), right ventricular hypertrophy by RV/(LV+S) ratios, and small pulmonary artery smooth muscle layer thickness were measured. Pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs) were isolated from wild type (WT) or knockout (KO) mice, followed with cell-based assays. Results: We report here that mice with targeted deletion of PHD2 developed severe pulmonary hypertension under normoxic condition. Conditional and inducible deletion of HIF2α in endothelial cells, but not smooth muscle cells, dramatically protected mice from hypoxia-induced pulmonary hypertension. HIF2α KO mice had significantly lower RVSP, RV/(LV+S) ratios, and displayed less pulmonary vascular remodeling when exposed to hypoxia compared to their WT mice. Conclusion: This work shows that the endothelium is responsible for the development of pulmonary hypertension and it demonstrates a crucial role of PHD2/HIF signaling for hypoxic response in pulmonary hypertension. These findings unveil temporally and spatially distinct functions for HIFs in the development of pulmonary hypertension.

MiR-100 suppresses mTOR signaling in hypoxia-induced pulmonary hypertension in rats

Mammalian Target of Rapamycin (mTOR) is involved in the proliferation and survival of pulmonary artery smooth muscle cells (PASMCs) in human pulmonary hypertension (PH) and animal PH models, and miRNAs are reported to play a key role in modulation of the proliferation of PASMCs. The purposes of this study are to determine the functions of miR-100 and mTOR in cardiovascular remodeling of the hypoxic PH rats and to clarify the correlation between them. We established a rat model of hypoxic PH, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, accompanied by an up-regulation of mTOR and a down-regulation of miR-100. Next, we established an in vitro model of hypoxia-induced proliferation of PASMCs. Consistent with the in vivo findings, hypoxia induced proliferation of PASMCs, accompanied by a down-regulation of miR-100 and an up-regulation of mTOR; these phenomena were reversed by miR-100 mimics or the antagonist of mTOR. Finally, the dual-luciferase reporter gene assay was utilized to reveal the direct interaction between miR-100 and the 3 ′-UTR region of mTOR gene. Based on these observations, we conclude that miR-100 can modulate the proliferation of PASMCs in hypoxic PH rats through suppressing the mTOR expression.

Inhibition of Notch3 prevents monocrotaline-induced pulmonary arterial hypertension

ABSTRACTIt has been shown that activation of Notch3 signaling is involved in the development of pulmonary arterial hypertension (PAH) by stimulating pulmonary arteries remodeling, while the molecular mechanisms underlying this are still largely unknown. The aims of this study are to address these issues. Monocrotaline dramatically increased right ventricle systolic pressure to 39.0 ± 2.6 mmHg and right ventricle hypertrophy index to 53.4 ± 5.3% (P < 0.05 versus control) in rats, these were accompanied with significantly increased proliferation and reduced apoptosis of pulmonary vascular cells as well as pulmonary arteries remodeling. Treatment of PAH model with specific Notch inhibitor DAPT significantly reduced right ventricle systolic pressure to 26.6 ± 1.3 mmHg and right ventricle hypertrophy index to 33.5 ± 2.6% (P < 0.05 versus PAH), suppressed proliferation and enhanced apoptosis of pulmonary vascular cells as well as inhibited pulmonary arteries remodeling. Our results further indicated that level of Notch3 protein and NICD3 were increased in MCT-induced model of PAH, this was accompanied with elevation of Skp2 and Hes1 protein level and reduction of P27Kip1. Administration of rats with DAPT-prevented MCT induced these changes. Our results suggest that Notch3 signaling activation stimulated pulmonary vascular cells proliferation by Skp2-and Hes1-mediated P27Kip1 reduction, and Notch3 might be a new target to treat PAH.

Right ventricular failure and pulmonary hypertension at recurrent thromboembolism of small branches of the pulmonary artery in cancer patients

Aim. Develop new approaches to the diagnosis of right heart failure and pulmonary hypertension in recurrent thromboembolism of small branches of the pulmonary artery in patients with malignant tumors. &#x0D; Methods. 83 patients with malignant tumors of various localizations were examined and followed-up. The main group included 49 patients with malignant tumors of various localizations and related venous thrombosis. The control group included 34 patients who did not have venous thrombosis. Patients in both groups underwent ultrasonography of inferior vena cava system veins and echocardiography at intervals of 3-4 days during the diagnosis and treatment of malignant tumors. Right ventricle ejection fraction and systolic pressure in the pulmonary artery were calculated at echocardiography. &#x0D; Results. No signs of inferior vena cava system veins thromboses, right heart failure, pulmonary hypertension were identified in patients of the control group while setting up the diagnosis and treatment of malignancies. In 38 out of 49 patients of the main group, right ventricular failure and pulmonary hypertension of varying severity were detected. The condition of 46 patients of the main group gradually improved after treating with anticoagulants. &#x0D; Conclusion. Recanalization of venous thrombosis is accompanied by frequent rejection of micro thrombi and embolization of small branches of pulmonary artery, causing right heart failure and pulmonary hypertension, which can be promptly detected by repeated echocardiography.

Arginase inhibition protects against hypoxia‑induced pulmonary arterial hypertension.

The present study aimed to determine the role of arginase (Arg) in pulmonary arterial hypertension (PAH). In vitro, human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions with, or without, the Arg inhibitor, S‑(2‑boronoethyl)‑l‑cysteine (BEC), for 48 h, following which the proliferation of the HPASMCs was determined using MTT and cell counting assays. For the in vivo investigation, 30 male rats were randomly divided into the following three groups (n=10 per group): i) control group, ii) PAH group and iii) BEC group, in which the right ventricle systolic pressure (RVSP) of the rats was assessed. The levels of cyclin D1, cyclin‑dependent kinase (CDK)4 and p27 were measured in vitro and in vivo. The phosphorylation levels of Akt and extracellular‑related kinase (ERK) were also measured in HPASMCs. In vitro, compared with the hypoxia group, Arg inhibition reduced HPASMC proliferation and reduced the expression levels of cyclin D1, CDK4, phosphorylated (p‑)Akt and p‑ERK. By contrast, Arg inhibition increased the expression of p27. In vivo, compared with the control group, the expression levels of cyclin D1 and CDK4 were reduced in the PAH group, however, the expression of p27 and the RVSP increased. In the BEC group, the opposite effects were observed. Therefore, it was suggested that Arg inhibition may reduce the RVSP of PAH rats and reduce HPASMC proliferation by decreasing the expression levels of cyclin D1 and CDK4, increasing the expression of p27, and partly reducing the phosphorylation of Akt and ERK.

PP.21.18

Objective: Fixed drug combinations are increasingly used in antihypertensive therapy, so it is necessary to find the best combinations to achieve the best therapeutic effects not only in the control of arterial blood pressure (BP), but in other relevant aspects such as arterial stiffness (AS) of these patients (P). To evaluate the efficacy in reducing left ventricular hypertrophy (LVH) and arterial stiffness between two fixed combinations of antihypertensive drugs: olmesartan plus amlodipine (olm + aml) and valsartan plus amlodipine (val + aml) in patients with mild to moderate hypertension. Design and method: We studied 126 P (53 ± 9 years) with mild-moderate hypertension with LVH who received two fixed combinations of antihypertensive drugs to maintain BP below 140/90 Hgmm in the office: olm + aml group: 66 P and val + aml group: 60 P to whom an echocardiographic study to detect LVH was performed by measuring the walls of the left ventricle and central systolic and diastolic pressures (CSBP, CDBP) were measured, the augmentation index (AI) and pulse wave velocity (PWV) at baseline and 32 weeks of treatment. Results: Data from both groups were compared and are shown in the following table:Conclusions: Our data suggest that the combination of OLM + AML is significantly higher than VAL + AML in reducing LVH and in reducing arterial stiffness indices indicating that not only provide a benefit in the control of blood pressure but also in the significant reduction in cardiovascular risk and mortality, being the HVI an independent marker of mortality in hypertensive patients, which should influence the selection of a fixed combination antihypertensive comprehensive control of our patients.

Iptakalim attenuates hypoxia-induced pulmonary arterial hypertension in rats by endothelial function protection.

The present study aimed to investigate the protective effects of iptakalim, an adenosine triphosphate (ATP)-sensitive potassium channel opener, on the inflammation of the pulmonary artery and endothelial cell injury in a hypoxia-induced pulmonary arterial hypertension (PAH) rat model. Ninety-six Sprague-Dawley rats were placed into normobaric hypoxia chambers for four weeks and were treated with iptakalim (1.5 mg/kg/day) or saline for 28 days. The right ventricle systolic pressures (RVSP) were measured and small pulmonary arterial morphological alterations were analyzed with hematoxylin and eosin staining. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the content of interleukin (IL)-1β and IL-10. Immunohistochemical analysis for ED1(+) monocytes was performed to detect the inflammatory cells surrounding the pulmonary arterioles. Western blot analysis was performed to analyze the expression levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) and endothelial nitric oxide synthase (eNOS) in the lung tissue. Alterations in small pulmonary arteriole morphology and the ultrastructure of pulmonary arterial endothelial cells were observed via light and transmission electron microscopy, respectively. Iptakalim significantly attenuated the increase in mean pulmonary artery pressure, RVSP, right ventricle to left ventricle plus septum ratio and small pulmonary artery wall remodeling in hypoxia-induced PAH rats. Iptakalim also prevented an increase in IL-1β and a decrease in IL-10 in the peripheral blood and lung tissue, and alleviated inflammatory cell infiltration in hypoxia-induced PAH rats. Furthermore, iptakalim enhanced PECAM-1 and eNOS expression and prevented the endothelial cell injury induced by hypoxic stimuli. Iptakalim suppressed the pulmonary arteriole and systemic inflammatory responses and protected against the endothelial damage associated with the upregulation of PECAM-1 and eNOS, suggesting that iptakalim may represent a potential therapeutic agent for PAH.