Randomized Trial of Macitentan/Tadalafil Single-Tablet Combination Therapy for Pulmonary Arterial Hypertension.

BACKGROUND: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).

A sham-controlled randomised trial of pulmonary artery denervation for Group 1 pulmonary arterial hypertension: one-year outcomes of the PADN-CFDA trial.

BACKGROUND: Long-term clinical outcomes after pulmonary artery denervation (PADN) in patients with Group 1 pulmonary arterial hypertension (PAH) have not been reported. AIMS: We aimed to investigate the effect of PADN on 1-year outcomes in patients with PAH. METHODS: In the multicentre PADN-CFDA trial, 128 patients with Group 1 PAH were randomly assigned to PADN plus a phosphodiesterase-5 inhibitor (PDE-5i) versus a sham PADN procedure plus a PDE-5i. The principal endpoint of interest for the present study was clinical worsening at 1 year after randomisation, the composite of worsening of PAH (increase in WHO functional class, need for additional PAH treatments or PAH-related hospitalisation), atrial septostomy, listing for lung transplantation, or all-cause death. RESULTS: One-year clinical follow-up was available in all patients. At 1 year, clinical worsening had occurred in 3 (4.8%) patients in the PADN plus PDE-5i group and in 15 patients (23.1%) in the sham plus PDE-5i group (adjusted hazard ratio: 0.17; 95% confidence interval [CI]: 0.05-0.60; p=0.006), driven by significantly increased rates of PAH-related hospitalisations, worsening functional class and the requirement for additional PAH treatments in the sham group. Results were consistent in high-risk, intermediate-risk and low-risk patients (pinteraction=0.186). Patients treated with PADN plus PDE-5i had an improvement in the between-group change in the six-minute walking distance (6MWD) from baseline to 1 year of 81.2 m (95% CI: 50.3-112.2; p<0.001) compared with PDE-5i treatment alone. CONCLUSIONS: In this multicentre sham-controlled randomised trial, PADN treatment for Group 1 PAH significantly reduced clinical worsening and improved the 6MWD during 1-year follow-up in patients treated with a PDE-5i.

Maresin-1 protects against pulmonary arterial hypertension by improving mitochondrial homeostasis through ALXR/HSP90α axis.

AIMS: Pulmonary arterial hypertension (PAH) is a progressive and lethal disease characterized by continuous proliferation of pulmonary arterial smooth muscle cell (PASMCs) and increased pulmonary vascular remodeling. Maresin-1 (MaR1) is a member of pro-resolving lipid mediators and exhibits protective effects on various inflammation-related diseases. Here we aimed to study the role of MaR1 in the development and progression of PAH and to explore the underlying mechanisms. METHODS AND RESULTS: We evaluated the effect of MaR1 treatment on PAH in both monocrotaline (MCT)-induced rat and hypoxia+SU5416 (HySu)-induced mouse models of pulmonary hypertension (PH). Plasma samples were collected from patients with PAH and rodent PH models to examine MaR1 production. Specific shRNA adenovirus or inhibitors were used to block the function of MaR1 receptors. The data showed that MaR1 significantly prevented the development and blunted the progression of PH in rodents. Blockade of the function of MaR1 receptor ALXR, but not LGR6 or RORα, with BOC-2, abolished the protective effect of MaR1 against PAH development and reduced its therapeutic potential. Mechanistically, we demonstrated that the MaR1/ALXR axis suppressed hypoxia-induced PASMCs proliferation and alleviated pulmonary vascular remodeling by inhibiting mitochondrial accumulation of heat shock protein 90α (HSP90α) and restoring mitophagy. CONCLUSION: MaR1 protects against PAH by improving mitochondrial homeostasis through ALXR/HSP90α axis and represents a promising target for PAH prevention and treatment.

Treatment effects of pulmonary artery denervation for pulmonary arterial hypertension stratified by REVEAL risk score: Results from PADN-CFDA trial.

BACKGROUND: The differential treatment effect of pulmonary artery denervation (PADN) in pulmonary arterial hypertension (PAH) patients with different risk burdens remains unclear. This study aimed to determine the effectiveness of PADN in low vs intermediate-high-risk PAH patients. METHODS: In total, 128 patients with treatment naive PAH included in the PADN-CFDA trial were categorized into low-risk and intermediate-high-risk patients. The primary endpoint was the between-group difference in the change in 6-min walk distance (6 MWD) from baseline to 6 months. RESULTS: In the intermediate-high-risk group, those treated with PADN and PDE-5i had a greater improvement in 6 MWD from baseline to 6 months as compared to those treated with sham plus PDE-5i. From baseline to 6 months, pulmonary vascular resistance (PVR) was reduced by -6.1 ± 0.6 and -2.0 ± 0.7 Wood units following PADN plus PDE-5i and sham plus PDE-5i, respectively, along with the significant reduction of NT-proBNP in the intermediate-high-risk group. However, there were no significant differences in 6 MWD, PVR, and NT-proBNP between the PADN plus PDE-5i and sham plus PDE-5i groups among low-risk patients. Moreover, the right ventricular function was equally improved by PADN treatment across the low-, intermediate-, and high-risk groups. Clinical worsening was less with PADN plus PDE-5i treatment during the 6-month follow-up. CONCLUSIONS: In patients with pulmonary arterial hypertension, pulmonary artery denervation plus PDE-5i improved exercise capacity, NT-proBNP, hemodynamic, and clinical outcomes during the 6-month follow-up among intermediate-high risk patients.

Pulmonary Artery Denervation for Pulmonary Arterial Hypertension: A Sham-Controlled Randomized PADN-CFDA Trial.

BACKGROUND: World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH) is a progressive, debilitating disease. Previous observational studies have demonstrated that pulmonary artery denervation (PADN) reduces pulmonary artery pressures in PAH. However, the safety and effectiveness of PADN have not been established in a randomized trial. OBJECTIVES: The aim of this study was to determine the treatment effects of PADN in patients with group 1 PAH. METHODS: Patients with WHO group 1 PAH not taking PAH-specific drugs for at least 30 days were enrolled in a multicenter, sham-controlled, single-blind, randomized trial. Patients were assigned to receive PADN plus a phosphodiesterase-5 inhibitor or a sham procedure plus a phosphodiesterase-5 inhibitor. The primary endpoint was the between-group difference in the change in 6-minute walk distance from baseline to 6 months. RESULTS: Among 128 randomized patients, those treated with PADN compared with sham had a greater improvement in 6-minute walk distance from baseline to 6 months (mean adjusted between-group difference 33.8 m; 95% CI: 16.7-50.9 m; P < 0.001). From baseline to 6 months, pulmonary vascular resistance was reduced by -3.0 ± 0.3 WU after PADN and -1.9 ± 0.3 WU after sham (adjusted difference -1.4; 95% CI: -2.6 to -0.2). PADN also improved right ventricular function, reduced tricuspid regurgitation, and decreased N-terminal pro-brain natriuretic peptide. Clinical worsening was less (1.6% vs 13.8%; OR: 0.11; 95% CI: 0.01-0.87), and a satisfactory clinical response was greater (57.1% vs 32.3%; OR: 2.79; 95% CI: 1.37-5.82) with PADN treatment during 6-month follow-up. CONCLUSIONS: In patients with WHO group 1 PAH, PADN improved exercise capacity, hemodynamic status, and clinical outcomes during 6-month follow-up. (Safety and Efficacy of Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension [PADN-CFDA]; NCT03282266).

Chemical Constituents With Antiproliferative Activity From Pogostemon cablin (Blanco) Benth.

Two new patchoulene sesquiterpenoid glycosides (1-2), a natural patchoulane-type sesquiterpenoid (3) and a natural cadinene-type sesquiterpenoid (4), were isolated from the aerial parts of Pogostemon cablin (Blanco) Benth., together with eleven known sesquiterpenoids (5-15) and eleven known flavonoids (16-26). Their chemical structures were elucidated on the basis of spectroscopic methods, including NMR, HRESIMS, IR, and CD spectroscopic data analysis, as well as chemical hydrolysis. The isolated compounds 1-13 and 15-26 were tested for inhibitory effects on the proliferation of HepG2 cancer cells. Among them, compounds 17 and 19 displayed anti-proliferative effects against HepG2 cells with IC50 values of 25.59 and 2.30 µM, respectively. Furthermore, the flow cytometry analysis and Western blotting assays revealed that compound 19 significantly induced apoptosis of HepG2 cells by downregulating the ratio of Bcl-2/Bax and upregulating the expression of cleaved caspase-3 and cleaved caspase-9. Therefore, the potential pharmaceutical applications of P. cablin would be applied according to our study findings.

Validation and promise of a TCR mimic antibody for cancer immunotherapy of hepatocellular carcinoma.

Monoclonal antibodies are at the vanguard of the most promising cancer treatments. Whereas traditional therapeutic antibodies have been limited to extracellular antigens, T cell receptor mimic (TCRm) antibodies can target intracellular antigens presented by cell surface major histocompatibility complex (MHC) proteins. TCRm antibodies can therefore target a repertoire of otherwise undruggable cancer antigens. However, the consequences of off-target peptide/MHC recognition with engineered T cell therapies are severe, and thus there are significant safety concerns with TCRm antibodies. Here we explored the specificity and safety profile of a new TCRm-based T cell therapy for hepatocellular carcinoma (HCC), a solid tumor for which no effective treatment exists. We targeted an alpha-fetoprotein peptide presented by HLA-A*02 with a highly specific TCRm, which crystallographic structural analysis showed binds directly over the HLA protein and interfaces with the full length of the peptide. We fused the TCRm to the γ and δ subunits of a TCR, producing a signaling AbTCR construct. This was combined with an scFv/CD28 co-stimulatory molecule targeting glypican-3 for increased efficacy towards tumor cells. This AbTCR + co-stimulatory T cell therapy showed potent activity against AFP-positive cancer cell lines in vitro and an in an in vivo model and undetectable activity against AFP-negative cells. In an in-human safety assessment, no significant adverse events or cytokine release syndrome were observed and evidence of efficacy was seen. Remarkably, one patient with metastatic HCC achieved a complete remission after nine months and ultimately qualified for a liver transplant.

An Effective Protocol for Management of International Arrivals at Risk in COVID-19 Pandemic: Experience From the Pre-Hospital Covid-19 Response Teams at Xi'an, China.

Background: The coronavirus disease 2019 (COVID-19) outbreak within China has been well controlled and stabilized since early April 2020. Therefore, the current major focus in China is to prevent the introduction of COVID into China from international arrivals. To achieve this, pre-Hospital COVID-19 Response Teams (pHCRTs) have been established. Context: The pHRCTs were established in Xi'an, China in early 2020. During the 12 months covered in this report, there were 356 international flight arrivals with over 5,000 COVID-19 Nucleic Acid Test (NAT) positive people, 500 of them with symptomatic COVID-19 and requiring admission to special hospitals. All other arrivals were managed in dedicated facilities by pHRCTs. The outcome measure of this report was the number of positive cases among the pHRCT members. Details: Four hundred forty-two staff worked in the pHCRTs during the reporting period. Despite multiple throat swab PCR tests during their pHRCTs tour of duty, and the subsequent mandatory 14-day quarantine required before return to the general community, no staff became NAT positive. Conclusion: The prevention of community transmission from imported cases is a vital part of the strategy to maintain the low numbers of cases in countries which have achieved control, or suppression of local internal cases. The program of pHCRTs described in this article gives successful protocols for transportation of patients who are infectious based on the minimal transmission of virus and staff safety. The strategies employed may prove useful in future pandemics.

Long-term mortality after pulmonary artery denervation stratified by baseline functional class in patients with pulmonary arterial hypertension: Long-term mortality after PADN stratified by functional class.

Aims: This study aimed to assess the long-term effects of pulmonary artery denervation (PADN) on mortality in patients with pulmonary arterial hypertension (PAH). Methods and results: Between March 2012 and March 2018, a total of 120 patients with PAH, who underwent PADN treatment and were prospectively followed up, were analysed. Patients were classified into World Health Organization (WHO) Functional Class I and II (FC 1-2; n=46) and Functional Class III and IV (FC 3-4; n=74) according to their FC prior to PADN. The primary endpoint was lung transplantation-free mortality until March 2021. The secondary endpoint was a change in the six-minute walk distance (6MWD). During the median of 4.8 years of follow-up, 23 (19.2%) patients died, predominantly from the FC 3-4 group (25.7%), compared to 8.7% in the FC 1-2 group (p=0.034). The mortality rate at one year (2.2% vs 12.2%, p=0.087) and three years (6.5% vs 17.6%, p=0.102) was numerically low in the FC 1-2 group versus the FC 3-4 group, respectively. The median net increase of 6MWD was +29 m in the FC 1-2 group, compared to +60.5 m in the FC 3-4 group (p=0.037). Conclusions: PADN results in significant improvements in survival at long-term follow-up, especially in patients with PAH in FC 3-4. This study was the continuation of the PADN-1 study which was registered at URL: http://www.chictr.trc.com.cn. Unique identifier: chiCTR-ONC-12002085.

Clinical features and survival in Takayasu's arteritis-associated pulmonary hypertension: a nationwide study.

AIMS: This study aimed to assess the clinical characteristics and long-term survival outcome in patients with Takayasu's arteritis-associated pulmonary hypertension (TA-PH). METHODS AND RESULTS: We conducted a nationally representative cohort study of TA-PH using data from the National Rare Diseases Registry System of China. Patients with pulmonary artery involvement who fulfilled the diagnostic criteria of Takayasu's arteritis and pulmonary hypertension were included. The primary outcome was the time from diagnosis of TA-PH to the occurrence of all-cause death. Between January 2007 and January 2019, a total of 140 patients were included, with a mean age of 41.4 years at diagnosis, and a female predominance (81%). Patients with TA-PH had severely haemodynamic and functional impairments at diagnosis. Significant improvements have been found in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and haemodynamic profiles in patients with TA-PH receiving drugs approved for pulmonary arterial hypertension. The overall 1-, 3-, and 5-year survival rates in TA-PH were 94.0%, 83.2%, and 77.2%, respectively. Predictors associated with an increased risk of all-cause death were syncope [adjusted hazard ratio (HR) 5.38 (95% confidence interval 1.77-16.34), P = 0.003], NT-proBNP level [adjusted HR 1.04 (1.03-1.06), P < 0.001], and mean right atrial pressure [adjusted HR 1.07 (1.01-1.13), P = 0.015]. CONCLUSION: Patients with TA-PH were predominantly female and had severely compromised haemodynamics. More than 80% of patients in our cohort survived for at least 3 years. Medical treatment was based on investigators' personal opinions, and no clear risk-to-benefit ratio can be derived from the presented data.

LncRNA TUG1 acts as a competing endogenous RNA to mediate CTGF expression by sponging miR-133b in myocardial fibrosis after myocardial infarction.

Myocardial fibrosis (MF) is one of the basic causes of many cardiovascular diseases. Noncoding RNAs (ncRNAs), including microRNA (miRNA) and long noncoding RNA (lncRNA), have been reported to play an indispensable role in MF. The current work is focused on investigating the biological role of lncRNA taurine upregulation gene 1 (TUG1) in activating cardiac myofibroblasts as well as the underlying mechanism. The outcome revealed that after myocardial infarction TUG1 expression increased and miR-133b expression decreased in the rat model of MF. The expression level of TUG1 increased following AngII treatment in cardiac myofibroblast. TUG1 knockdown inhibited the Ang-II induced cardiac myofibroblast activation and TUG1 overexpression increased proliferation and collagen generation of cardiac myofibroblasts. Bioinformatic prediction programs predicted that TUG1 had MRE directly combined with miR-133b seed sequence, luciferase activity, and RIP experiments indicated that TUG1, acted as a sponger and interacted with miR-133b in cardiac myofibroblasts. Furthermore, a target of miR-133b was CTGF and CTGF knockdown counteracted the promotion of MF by miR-133b knockdown. Collectively, our study suggested that TUG1 mediates CTGF expression by sponging miR-133b in the activation of cardiac myofibroblasts. The current work reveals a unique role of the TUG1/miR-133b/CTGF axis in MF, thus suggesting its immense therapeutic potential in the treatment of cardiac diseases.

Effect of different initial anticoagulant strategies on short-term outcome of patients with symptomatic DVT in China.

PURPOSE: In ambulant patients with lower limb DVT managed with Warfarin, there is a need for initial treatment and short time "bridging" with a rapidly acting anticoagulant until there is a stable therapeutic INR. In this study, results from bridging with subcutaneous low molecular weight heparin (LMWH) or oral Rivaroxaban were compared. METHODS: One hundred and twenty-four patients received LMWH and 98 patients received Rivaroxaban, both in addition to Warfarin. Patients were assessed at 1 and 4 weeks after treatment initiation for thrombus progression, bleeding, clinic attendance and INR. FINDINGS: The treatment groups were well matched. There were no significant differences between the treatment groups for any of the end-points at either 1 week or 4 weeks. IMPLICATIONS: In ambulant patients with DVT treated with Warfarin both Rivaroxaban and LMWH are suitable for use in the early phase of Warfarin treatment until therapeutic INR is achieved. Rivaroxaban is a suitable alternative to LMWH for patients who prefer not to have injections.

Sanguinarine Reverses Pulmonary Vascular Remolding of Hypoxia-Induced PH via Survivin/HIF1α-Attenuating Kv Channels.

Background: Similarities in the biology of pulmonary hypertension and cancer suggest that anticancer therapies, such as sanguinarine, may also be effective in treating pulmonary hypertension. This, along with underlying biochemical pathways, is investigated in this study. Methods: Rats were subjected to 4-week hypoxia (or control) with or without sanguinarine treatment. In addition, pulmonary artery smooth muscle cells (PASMCs) were examined after 24-48 h hypoxia (with normoxic controls) and with or without sanguinirine. Pulmonary artery pressures and plasma survivin levels were measured in vivo. Ex vivo tissues were examined histologically with appropriate staining. mRNA and protein levels of survivin, HIF-1α, TGFb1, BMPR2, Smad3, P53, and Kv 1.2, 1.5, 2.1 were determined by real-time PCR and Western blot in PASMCs and distal PAs tissue. PASMC proliferation and changes of TGFb1 and pSmad3 induced by sanguinarine were studied using MTT and Western blot. Electrophysiology for Kv functions was measured by patch-clamp experiments. Results: Four-week hypoxia resulted in an increase in serum survivin and HIF-1α, pulmonary artery pressures, and pulmonary vascular remodeling with hypertrophy. These changes were all decreased by treatment with sanguinarine. Hypoxia induced a rise of proliferation in PASMCs which was prevented by sanguinarine treatment. Hypoxic PASMCs had elevated TGFb1, pSmad3, BMPR2, and HIF1α. These increases were all ameliorated by sanguinarine treatment. Hypoxia treatment resulted in reduced expression and function of Kv 1.2, 1.5, 2.1 channels, and these changes were also modulated by sanguinarine. Conclusion: Sanguinarine is effective in modulating hypoxic pulmonary vascular hypertrophy via the survivin pathway and Kv channels.

MicroRNA-483 amelioration of experimental pulmonary hypertension.

Endothelial dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) and that exogenously administered microRNA may be of therapeutic benefit. Lower levels of miR-483 were found in serum from patients with idiopathic pulmonary arterial hypertension (IPAH), particularly those with more severe disease. RNA-seq and bioinformatics analyses showed that miR-483 targets several PAH-related genes, including transforming growth factor-ß (TGF-ß), TGF-ß receptor 2 (TGFBR2), ß-catenin, connective tissue growth factor (CTGF), interleukin-1ß (IL-1ß), and endothelin-1 (ET-1). Overexpression of miR-483 in ECs inhibited inflammatory and fibrogenic responses, revealed by the decreased expression of TGF-ß, TGFBR2, ß-catenin, CTGF, IL-1ß, and ET-1. In contrast, inhibition of miR-483 increased these genes in ECs. Rats with EC-specific miR-483 overexpression exhibited ameliorated pulmonary hypertension (PH) and reduced right ventricular hypertrophy on challenge with monocrotaline (MCT) or Sugen + hypoxia. A reversal effect was observed in rats that received MCT with inhaled lentivirus overexpressing miR-483. These results indicate that PAH is associated with a reduced level of miR-483 and that miR-483 might reduce experimental PH by inhibition of multiple adverse responses.

Beraprost Upregulates KV Channel Expression and Function via EP4 Receptor in Pulmonary Artery Smooth Muscle Cells Obtained from Rats with Hypoxia-Induced Pulmonary Hypertension.

The reduced expression and function of voltage-dependent potassium (KV) channels have been involved in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH), leading to pulmonary vasoconstriction and vascular remodeling, while the upregulation of KV channels is of therapeutic significance for pulmonary hypertension. Beraprost sodium (BPS) has been shown to be effective in patients with pulmonary hypertension. However, the effect of BPS on O2-sensitive KV channels in pulmonary artery smooth muscle cells (PASMCs) remains unclear. In the present study, the effect of BPS on rats with HPH was observed, and the influence of BPS on the expression and function of O2-sensitive KV channels in PASMCs was investigated. The results revealed that BPS reduced mean pulmonary artery pressure, suppressed right ventricular hypertrophy, and attenuated the remodeling of pulmonary arteries in rats exposed to discontinuous hypoxia for 4 weeks (8 h/day). This was accompanied with the significantly upregulated expression of KV channel α-subunits (KV1.2, KV1.5 and KV2.1) and O2-sensitive voltage-gated K+ (KV) channel current (IK(V)) in small pulmonary arteries in HPH model rats, as well as in hypoxia-induced PASMCs. Furthermore, in vitrostudies have revealed that the upregulation of BPS on O2-sensitive KV channels was significantly inhibited after treatment with prostaglandin E2 receptor subtype EP4 antagonist GW627368X. Taken together, these results suggest that BPS attenuates the development of HPH through the upregulation of O2-sensitive KV channels, which was probably via the EP4 receptor-related pathway.

Sarpogrelate attenuates pulmonary arterial hypertension via calcium/calcineurin axis.

Pulmonary arterial hypertension (PAH) is a syndrome caused by restricted blood flow in the pulmonary circulation, which results in a poor patient prognosis. The serotonin (5-HT), TRPC1 (Transient receptor potencial channel 1), TRPC6 (Transient receptor potencial channel 6), calcineurin A, and NFATc3 (an isoform of nuclear factor of activated T-cells family) are involved in cell proliferation and hypertrophy and the crosstalk between these molecules may play an essential role in the pathogenesis of pulmonary arterial hypertension. We hypothesized that 5-HT promotes PAH by affecting TRPC channels. We investigated the effects of sarpogrelate, a 5-HT2A receptor antagonist, on pulmonary arterial pressure, cardiac remodeling, pulmonary artery remodeling, and TRPC1, TRPC6, calcineurin A, and NFATc3 expression in pulmonary arteries from rats with PAH. The results showed that sarpogrelate reduced pulmonary arterial pressure, cardiac remodeling, pulmonary artery remodeling, and expression of TRPC1, TRPC6, calcineurin A, and NFATc3 in pulmonary arteries. In conclusion, Sarpogrelate reduced the severity of PAH in rat model and decreased the expression of TRPC1, TRPC6, calcineurin A, and NFATc3 in pulmonary arteries.

The relationship between maternal anxiety and cortisol during pregnancy and birth weight of chinese neonates.

BACKGROUND: To determine the relationship between maternal anxiety and cortisol values and birth weight at various stages of pregnancy. METHODS: Two hundred sixteen pregnant Chinese women were assessed for anxiety and depression and had measurement of morning fasting serum cortisol. Women were assessed either in the first (71), second (72) or third (73) trimester. Birth weights of all children were recorded. RESULTS: There were significant negative correlations between anxiety level and birth weight of - 0.507 (p < 0.01) and - 0.275 (p < 0.05) in trimesters 1and 2. In trimester 3 the negative relation between anxiety and birth weight of -.209 failed to reach significance (p = 0.070). There was no relation between depression and birth weight in any trimester (p > 0.5 for all). Maternal cortisol was significantly inversely related to birth weight in trimester 1 (r = - 0.322) and with borderline significance in trimester 2 (r = - 0.229). Anxiety score and maternal cortisol were significantly correlated in each trimester (r = 0.551, 0.650, 0.537). When both anxiety score and maternal cortisol were simultaneously included in multiple regression analyses only anxiety score remained significant. CONCLUSION: Whilst both maternal anxiety score and maternal cortisol are inversely related to birth weight the associations with anxiety score were more robust perhaps indicating the importance of mechanisms other than, or in addition to, maternal cortisol in mediating the effects of anxiety. The findings indicate the importance of measures to reduce maternal anxiety, particularly of a severe degree, at all stages of pregnancy. TRIAL REGISTRATION: The study was approved by the Ethics Committee of the 1st Affiliated Hospital of Xi'an Jiaotong University.

Mechanism of Beraprost Effects on Pulmonary Hypertension: Contribution of Cross-Binding to PGE2 Receptor 4 and Modulation of O2 Sensitive Voltage-Gated K+ Channels.

Background: The purpose of this study is to elucidate mechanism(s) by which the orally active PGI2 analog, Beraprost (BPS), ameliorates pulmonary hypertension (PH). Prostaglandins are an important treatment for PH. Mechanisms of their action are not fully elucidated in relation to receptor subtype and effects on O2 sensitive Kv channels. Methods: Distal (3rd order and beyond) pulmonary arteries from chronically hypoxic rats and from humans with established PH were studied. Measurements included pulmonary haemodynamics and histology, vascular reactivity, prostanoid receptor expression and activity of the O2 sensitive Kv channels. Results: Prostacyclin receptor (IP), prostaglandin receptor E3 (EP3) and prostaglandin receptor E4 (EP4) are the main pulmonary artery receptor subtypes in both rat and human pulmonary arteries. Circulating levels of PGI2 and PGE2 were reduced in PH. PH was also associated with reduced receptor expression of IP but not of EP4. The effects on IP expression were overcome with BPS. Dilatory responses in PH to BPS were reduced in the presence of EP4 blockade. Expression and activity of oxygen sensitive Kv channels were reduced in pulmonary artery smooth muscle cell from rats with PH and humans with PAH and were also overcome by administration of BPS. Effects of BPS on oxygen sensitive Kv channels were reduced in the presence of EP4 blockade implicating the EP4 receptor, as well as the IP receptor, in mediating BPS effects. Conclusion: Reduced expression of pulmonary IP receptors and reduced activity of O2 sensitive Kv channels are found in PH in both humans and rats. The orally active prostacyclin analogue, BPS, is able to reverse these changes, partly through binding to the EP4 receptor.

Rivaroxaban in the Treatment of PICC-associated Upper Extremity Venous Thrombosis.

PURPOSE: Peripherally inserted central catheters (PICCs) are frequently used for prolonged drug administration, but their use is commonly complicated by the development of upper extremity deep venous thrombosis (UEDVT) requiring anticoagulation. Here, we compared the efficacy and safety profile of rivaroxaban (20 mg/d) with low molecular weight (LMW) heparin and vitamin K antagonists in the treatment of PICC-associated UEDVT. METHODS: Patients (N = 84) with PICC-associated UEDVT were studied. All had UEDVT identified by ultrasound scanning. Further ultrasound images were obtained at 1, 2, and 3 months after the start of treatment. Forty-four patients were treated with rivaroxaban and 40 with initial LMW heparin and vitamin K antagonist with continuation of vitamin K antagonists alone once international normalized ratio was therapeutic FINDINGS: In the rivaroxaban group mean (SD) age was 51 (16) years and 57% were men, whereas in the other group respective values were 50 (16) years and 56%. All patients were receiving treatment for cancer. Resolution of thrombus had occurred in 53.5% at 1 month, 76.1% at 2 months, and 92.6% at 3 months in the rivaroxaban-treated patients. Corresponding values in the LMW heparin/vitamin antagonist-treated patients were 34.2%, 55.5%, and 88.5%, respectively. Differences between groups were significant at 1 month (P < 0.01) and 2 months (P < 0.05). There were no major bleeds in either group, and cumulative bleeding rates by 3 months were 7.3% in the rivaroxaban group and 11.4% in the LMW heparin/vitamin K antagonist group. IMPLICATIONS: Rivaroxaban led to faster resolution of PICC-associated UEDVT than LMW/vitamin K antagonists without any increase in bleeding.