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Objectives: To investigate the diagnostic and therapeutic landscape for patients with connective tissue disease (CTD) and CTD-associated pulmonary arterial hypertension (CTD-PAH) in acute-care general hospitals in Japan., Methods: We conducted a retrospective cohort study by analysing the Medical Data Vision (MDV) database from April 2008 to September 2020. CTD patients who prescribed immunosuppressants were included in cohort 1, and CTD-PAH patients extracted from cohort 1 were included in cohort 2. Patient characteristics, diagnostic screening frequencies for PAH, and initial PAH-specific treatment patterns were assessed., Results: Overall, 16,648 patients with CTD and 81 patients with CTD-PAH were included in cohorts 1 and 2, respectively. The frequencies of screening tests for PAH, including brain natriuretic peptide (BNP), transthoracic echocardiogram (TTE), and 'diffusing capacity' of the 'lungs for carbon monoxide' (DLCO), among CTD patients were 0.7, 0.3, and 0.1 tests/person-year, respectively. The most common initial PAH-specific treatment therapy was monotherapy (87.7%), followed by dual therapy (7.4%) and triple therapy (2.5%)., Conclusion: This is the first study to describe the patient flow from PAH diagnosis to initial PAH-specific treatment for real-world patients who were followed regularly due to CTD in Japanese clinical practice., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objectives: Real-world evidence regarding prevalence, patient characteristics, and treatment patterns for pulmonary arterial hypertension (PAH) related to systemic lupus erythematosus (SLE) in Japan is limited., Methods: We conducted a retrospective study analysing Japan's Medical Data Vision database from April 2008 to September 2020. Prevalence, incidence, patient characteristics, treatment patterns, and use of vasodilators by treatment line were evaluated., Results: The prevalence of PAH was 0.392% in SLE patients (n = 114/29,077). Cumulative incidence was 0.53% (3 years) and 0.77% (5 years). Of 114 SLE-PAH patients, 49% developed PAH <1 year from SLE diagnosis. SLE-PAH patients were predominantly females (88% vs. 72%), had a lower mean age at SLE diagnosis (53 vs. 56 years), and had more severe SLE (61% vs. 25%) than non-PAH-SLE patients. Glucocorticoids (58%) and vasodilators (27%) were preferred first-line monotherapy for SLE-PAH. A combination of glucocorticoids and immunosuppressants (19%) was the predominant first-line combination therapy. Endothelin receptor antagonists (40% and 44%) and nitric oxide analogues (31% and 40%) were dominant first- and second-line vasodilators., Conclusions: SLE-PAH patients were predominantly females, were younger at diagnosis, and had more severe SLE than non-PAH-SLE patients. Most were diagnosed <1 year of SLE diagnosis. In Japan's real-world practice, the initial treatment goal is SLE management, while vasodilators are preferred in advanced diseases, as per the Medical Data Vision database., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Background and Aims: Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity., Methods: A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways., Results: The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {β: 43.7 m [95% confidence interval (CI): 32.9, 54.4]}, nitric oxide pathway [β: 29.4 m (95% CI: 22.6, 36.3)], endothelin pathway [β: 25.3 m (95% CI: 19.8, 30.8)], and prostacyclin pathway [oral/inhaled β: 19.1 m (95% CI: 14.2, 24.0), intravenous/subcutaneous β: 24.4 m (95% CI: 15.1, 33.7)] significantly increased 6 min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease., Conclusions: Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH., Methods: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes., Results: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively)., Conclusions: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Preoperative intravenous epoprostenol therapy can cause thrombocytopaenia, which may increase the risk of perioperative bleeding during lung transplantation. This study aimed to determine whether lung transplantation can be safely performed in patients with epoprostenol-induced thrombocytopaenia., Methods: From June 2008 to July 2022, we performed 37 lung transplants in patients with pulmonary arterial hypertension (PAH), including idiopathic PAH (n = 26), congenital heart disease-associated PAH (n = 7), pulmonary veno-occlusive disease (n = 3) and peripheral pulmonary artery stenosis (n = 1) at our institution. Of these, 26 patients received intravenous epoprostenol therapy (EPO group), whereas 11 patients were treated with no epoprostenol (no-EPO group). We retrospectively analysed the preoperative and postoperative platelet counts and post-transplant outcomes in each group., Results: Preoperative platelet counts were relatively lower in the EPO group than in the no-EPO group (median EPO: 127 000 vs no-EPO: 176 000/μl). However, blood loss during surgery was similar between the 2 groups (EPO: 2473 ml vs no-EPO: 2615 ml). The platelet counts significantly increased over 1 month after surgery, and both groups showed similar platelet counts (EPO: 298 000 vs no-EPO: 284 000/μl). In-hospital mortality (EPO: 3.9% vs no-EPO: 18.2%) and the 3-year survival rate (EPO: 91.4% vs no-EPO: 80.8%) were similar between the 2 groups., Conclusions: Patients with PAH treated with intravenous epoprostenol showed relatively lower platelet counts, which improved after lung transplantation with good post-transplant outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: This descriptive report describes the process used to obtain access to providing ambrisentan from a health-system specialty pharmacy (HSSP) affiliated with a pulmonary hypertension Center of Comprehensive Care, develop a pulmonary arterial hypertension (PAH) care team at the HSSP, and characterize medication adherence and access metrics., Summary: PAH is a rare disease treated with several specialty medications requiring intensive monitoring. Historically, specialty medications used to treat PAH have been provided by only select specialty pharmacies due to restricted drug distribution channels. It is recommended that patients with PAH receive their care at centers with expertise in the diagnosis and management of this disorder, but the HSSPs at these expert centers are unable to provide specialty PAH medications. The current care model for PAH leads to patients receiving their medical and pharmaceutical care from separate entities. This descriptive report describes a multidisciplinary team's approach to gaining access to providing ambrisentan and developing a disease state care team within an established HSSP. After implementing this service, specialty pharmacy metrics were assessed, including proportion of days covered (PDC), time to first fill, patient contact rate, Risk Evaluation and Mitigation Strategy (REMS) program compliance, time to prior authorization (PA) approval, rate of optimal adherence (PDC of >80%), and PA renewal rate, to demonstrate a proof-of-concept HSSP model for PAH. In this model, the HSSP was able to demonstrate high-quality specialty pharmacy metrics with regard to medication adherence, medication access, and REMS program compliance., Conclusion: The development of a PAH care team to provide ambrisentan at an existing HSSP was associated with high adherence rates, efficient and reliable medication access, and REMS program compliance., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Nobiletin is a flavonoid found in the peel of Citrus sinensis (oranges). The purpose of this study is to investigate whether Nobiletin can alleviate the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and explore the underlying mechanisms., Methods: The PAH rat model was replicated by subcutaneous injection of MCT. Nobiletin (1, 5 and 10 mg/kg) was administered by gavage from day 1 to day 21. After 21 days of MCT injection, the mean pulmonary artery pressure, pulmonary vascular resistance, Fulton Index, pulmonary artery remodelling, blood routine parameters, liver and kidney functions was measured. The level of inflammatory cytokines and PI3K/Akt/STAT3 were detected by qPCR, ELISA and western blot, the proliferation of pulmonary artery smooth muscle cells (PASMCs) was evaluated by CCK-8., Key Findings: Nobiletin (10 mg/kg) inhibited the MCT-induced increase in mean pulmonary artery pressure and pulmonary vascular resistance, right ventricular hypertrophy and pulmonary artery remodelling in rats. Nobiletin decreased the levels of inflammatory cytokines and phosphorylation level of PI3K/Akt/STAT3 in lungs of MCT-treated rats. Nobiletin inhibited the proliferation and lowered the inflammatory cytokines level induced by PDGF-BB in PASMCs., Conclusion: Nobiletin attenuates MCT-induced PAH, and the potential mechanism is to inhibit inflammation through PI3K/Akt/STAT3 pathway., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.)

Objectives: Systemic sclerosis (SSc) is associated with pulmonary vascular disease and interstitial lung disease, making it difficult to differentiate pulmonary arterial hypertension and pulmonary hypertension (PH) due to lung diseases and/or hypoxia and to decide treatments. We aimed to predict the response to pulmonary vasodilators in patients with SSc and PH., Methods: Eighty-four SSc patients were included with 47 having PH. Chest computed tomography was evaluated using software to calculate the abnormal lung volume (ALV). To define the response to vasodilators, Δ mean pulmonary artery pressure (mPAP)/basal mPAP was used (cut-off value: 10%). The predictive value was evaluated by using the receiver operating characteristic curve., Results: The mean (±standard deviation) value of ALV was 26.8 (±32.2) %. A weak correlation was observed between ALV and forced vital capacity (FVC) (R = -0.46). The predictive value of ALV [area under curve (AUC) = 0.74] was superior to that of FVC (AUC = 0.62) for the response to vasodilators. No hemodynamic parameters differed between patients with high and low ALV, whereas survival was worse in high ALV., Conclusions: Quantitative chest computed tomography well predicted the response to vasodilators in patients with SSc and PH. Our results suggest its utility in differentiating the dominance of pulmonary vascular disease or interstitial lung disease., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Adult Still's disease (ASD) is rarely complicated by pulmonary hypertension (PH). A 76-year-old woman experienced ASD relapse with repeated exacerbation of PH and interstitial lung disease. Although she had been treated with immunosuppressive agents and pulmonary vasodilators, the ASD relapsed with fever, rash, increased inflammatory responses and exacerbated interstitial lung disease, and PH. The pathology of PH appeared to encompass groups 1 [pulmonary arterial hypertension (PAH)], 1' [pulmonary veno-occlusive disease (PVOD)], and 3. Remission induction therapy with high-dose glucocorticoid and tocilizumab was administered, and switching or adding pulmonary vasodilators was also attempted. As the disease activity of ASD decreased, the mean pulmonary arterial pressure and pulmonary vascular resistance improved. PH is an extremely rare form of organ dysfunction in individuals with ASD. Like other systemic autoimmune diseases, PH (PAH or PVOD) can determine the prognosis of ASD. Because of PH's rarity, it is important to sufficiently evaluate its pathology, considering the possibility that PH is not clinically classified as PAH (group 1), and to administer immunosuppressive therapy and vasodilators according to the pathology., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF., Methods and Results: The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by -0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred., Conclusion: The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period., Competing Interests: Conflict of interest: E.G. received grants/contracts from Bayer, MSD, United Therapeutics and OMT; consulting fees from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics; payments/honoraria from Bayer, Janssen and MSD; support for attending meetings and/or travel from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics. E.G. participated on data monitoring/advisory boards for Janssen, United Therapeutics, and Acceleron. I.P. has received honoraria for lectures from Orion, AOP Orphan and Amomed. D.B. received financial support for the present manuscript in form of an unrestricted research grant by Bayer (all payments were made to the Medical University of Vienna); research grants by Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi (all payments were made to the Medical University of Vienna); and payments/honoraria from Bayer AG, Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi, Astra Zeneca, Boehringer Ingelheim, Zoll, Janssen, AOP Orphan, and MSD. All other authors declare that there is no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

We present the case of a 54-year-old woman with a long history of pulmonary hypertension associated with mixed connective tissue disease. She was being treated with pulmonary vasodilators, including epoprostenol and bosetan, but her mean pulmonary arterial pressure (mPAP) gradually worsened. Although her mPAP began to improve with adding sildenafil, ascites occurred. Discontinuing newly initiated drugs and starting diuretics improved her ascites. This suggested that an intensification of the treatment with vasodilators might have led to ascites (on a background of a probable arteriovenous shunt formation) in this patient with a long history of pulmonary hypertension., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Epoprostenol and treprostinil are prostacyclins indicated for the treatment of pulmonary arterial hypertension (PAH). Although there is literature describing the conversion of intravenous (IV) epoprostenol to IV treprostinil or IV treprostinil to oral treprostinil, there is little data on the direct conversion of IV epoprostenol to oral treprostinil. In this case, we describe the direct conversion of IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil., Summary: A 39 year-old female with PAH was admitted for altered mental status and self-removal of her peripherally inserted central catheter (PICC) used for IV epoprostenol. Given the unplanned hospitalization, absence of a dedicated central line for IV prostacyclin therapy, and concern the patient may remove a future subcutaneous line, the patient was transitioned to oral treprostinil. Of note, despite triple PAH therapy, the patient was unable to reach a low risk group based on her prognostic risk assessment. A right heart catheterization four months prior found severe PAH with a pulmonary arterial pressure of 79/32 mmHg (mean, 49 mmHg) and pulmonary vascular resistance of 10.6 Wood units. To expedite the transition, the patient was directly converted from IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil. A target oral treprostinil dose of 5 mg TID was calculated based on 110% of the IV epoprostenol dose (19 ng/kg/min) utilizing the conversion recommended by the medication manufacturer. Every 8 hours, IV epoprostenol was decreased by 2 ng/kg/min and oral treprostinil was increased by 0.5 mg. The target oral treprostinil dose of 5 mg TID was reached 72 hours after conversion initiation. Three hours after the final titration, the patient was discharged home on room air., Conclusion: In this case, rapid transition from IV epoprostenol to oral treprostinil was achieved in 72 hours without reported adverse effects., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Some patients present with excessive pulmonary hypertension (PH) prior to pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). This study was performed to evaluate the clinical role of pretreatment before PEA in CTEPH patients., Methods: A total of 370 patients with CTEPH undergoing first PEA between 2003 and 2017 were divided into those receiving pretreatment with bosentan (group B: n = 119) and those without targeted pretreatment for PH (group C: n = 251). After selecting patients given bosentan (2-8 months) and using propensity score matching, comparable patient cohorts (n = 23 each) were created from both groups. PEA was performed in the standard manner, and the median number of extracted segments was 14., Results: There were no significant differences in perioperative demographic characteristics or 30-day mortality (overall 5.7%) between the groups before and after matching. In patients with preoperative pulmonary vascular resistance (PVR) ≥800 dynes s/cm5, a significantly larger decrease in PVR was found in group B (78%) compared to group C (68%) (P = 0.033). There was no significant difference in late survival between the groups after matching. The frequency of residual/persistent PH (mean pulmonary artery pressure >25 mmHg) was lower in group B than in group C, although the difference was not significant (22% vs 39%, respectively, P = 0.200). Advanced age and longer cardiopulmonary bypass time were independent predictors of both 30-day mortality and residual/persistent PH (odds ratio: age, 1.053, 1.013, cardiopulmonary bypass time, 1.065, 1.010, respectively)., Conclusions: Preoperative treatment of CTEPH patients with bosentan for 2-8 months can improve post-PEA PVR without adverse clinical events in patients with a high preoperative PVR. A temporary bridging regime appears beneficial in selected patients prior to PEA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Oxygen is a pulmonary vasodilator. Although treatment of pulmonary arterial hypertension (PAH) is focused on pulmonary vasodilation, treatment guidelines do not recommend O2 therapy for patients unless they develop hypoxaemia. These guidelines point to a lack of evidence of benefit of O2 therapy from randomized controlled trials (RCTs) and to evidence of lack of benefit in a single RCT involving patients with Eisenmenger syndrome. These guidelines did not identify major limitations with the Eisenmenger study or consider other evidence of therapeutic benefit. Recent advances in mechanistic understanding of O2 effects on pulmonary vascular tone, along with substantial evidence of acute effects of O2 in PAH patients, challenge the view that benefits of O2 arise only through correction of hypoxaemia. Evidence presented in this review shows that O2 acts as a pulmonary vasodilator in patients who are normoxaemic; that this probably involves an alveolar mechanism in addition to a blood-borne (oxyhaemoglobin) mechanism; and that therapeutic benefit of O2 does not depend on arterial O2 levels. This suggests that O2 has potential therapeutic benefit for all patients with PAH. Clinical guidelines and practice related to O2 therapy need to be reassessed, and further research is needed., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Purpose: Selexipag is an oral nonprostanoid IP prostacyclin receptor agonist that is indicated for treatment of pulmonary arterial hypertension (PAH). In patients with continued symptoms of PAH despite maximized oral therapy with selexipag and other oral therapies, a transition to parenteral prostacyclin may be warranted. There is a paucity of data regarding how to safely transition from oral selexipag to parenteral treprostinil. We describe rapid transition from oral selexipag to parenteral treprostinil in this case report., Summary: A 65-year-old female with mixed-etiology PAH as result of pulmonary fibrosis related to polymyositis was admitted to the intensive care unit to be transitioned from selexipag to treprostinil due to dyspnea at rest despite therapy with selexipag 1,600 mg twice daily and macitentan 10 mg daily for 3 years. At baseline the patient required oxygen support (4 L/min) at rest to maintain oxygen saturation at or above 90%. Right heart catheterization performed 8 weeks prior to admission revealed severe PAH, with a pulmonary arterial pressure of 73/27 mm Hg and pulmonary vascular resistance of 10 Wood units. On the day of admission the patient was given selexipag 800 µg at 9 am and simultaneously started on intravenous (i.v.) treprostinil at a dose of 2 ng/kg/min. The treprostinil dose was increased by 2 ng/kg/min every 3 hours until a target dose of 22 ng/kg/min was achieved, at which point the patient had experienced dyspnea improvement. She experienced a mild headache and flushing during rapid treprostinil dose escalation. After 30 hours of i.v. treprostinil infusion, the patient was transitioned to subcutaneous treprostinil therapy and discharged., Conclusion: In this case the patient was rapidly transitioned from oral selexipag to i.v. and then subcutaneous treprostinil therapy over a 30-hour period, with minimal adverse effects., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Real-world data (RWD) are increasingly used for pharmacoepidemiology and regulatory innovation. Our objective was to compare adverse drug event (ADE) rates determined from two RWD sources, electronic health records and administrative claims data, among children treated with drugs for pulmonary hypertension., Materials and Methods: Textual mentions of medications and signs/symptoms that may represent ADEs were identified in clinical notes using natural language processing. Diagnostic codes for the same signs/symptoms were identified in our electronic data warehouse for the patients with textual evidence of taking pulmonary hypertension-targeted drugs. We compared rates of ADEs identified in clinical notes to those identified from diagnostic code data. In addition, we compared putative ADE rates from clinical notes to those from a healthcare claims dataset from a large, national insurer., Results: Analysis of clinical notes identified up to 7-fold higher ADE rates than those ascertained from diagnostic codes. However, certain ADEs (eg, hearing loss) were more often identified in diagnostic code data. Similar results were found when ADE rates ascertained from clinical notes and national claims data were compared., Discussion: While administrative claims and clinical notes are both increasingly used for RWD-based pharmacovigilance, ADE rates substantially differ depending on data source., Conclusion: Pharmacovigilance based on RWD may lead to discrepant results depending on the data source analyzed. Further work is needed to confirm the validity of identified ADEs, to distinguish them from disease effects, and to understand tradeoffs in sensitivity and specificity between data sources., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Pulmonary hypertension (PH) is a life-threatening lung disease. PH with concomitant lung diseases, e.g., idiopathic pulmonary fibrosis, is associated with poor prognosis. Development of novel therapeutic vasodilators for treatment of these patients is a key imperative. We evaluated the efficacy of dual activation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) using an active, small-molecule phosphodiesterase (PDE4)/PDE5 dual inhibitor (Compound A). Compound A increased both cAMP and cGMP levels in WI-38 lung fibroblasts and suppressed the expressions of type-1 collagen α1 chain and fibronectin. Additionally, compound A reduced right ventricular weight/left ventricular weight+septal weight ratio, brain natriuretic peptide expression levels in right ventricle, C─C motif chemokine ligand 2 expression levels in lung, and plasma surfactant protein D. Our data indicate that dual activation of cAMP/cGMP pathways may be a novel treatment strategy for PH.

Congenital heart disease (CHD) is the most common inborn defect. Due to advances in paediatric care, surgical, and catheter procedures the number of adults with CHD has grown remarkably in recent years. Most of these patients, however, have residua from their original operation/s and require life-long care, many of them are subjected to further haemodynamic and electrophysiological interventions during adulthood. While such re-do surgical or catheter interventions together with device therapy and transplantation play a key therapeutic role, increasingly, adults with CHD require drug therapy for late complications namely heart failure (HF), arrhythmias, pulmonary and systemic hypertension, thromboembolic events, etc. Unlike other cardiovascular areas, drug therapy in adult CHD is based on scarce clinical data and remains largely empiric. Consequently, pharmacological therapies are individualized to ameliorate patients' symptoms and/or degree of haemodynamic impairment. Thus far, recommendations have been difficult to make and formalized guidelines on drug therapy are lacking. We review herewith the rationale, limited evidence and knowledge gaps regarding drug therapy in this growing cardiovascular field and discuss pharmacotherapy options in specific conditions namely HF, arrhythmias, thrombosis, pulmonary arterial hypertension, contraception, and pregnancy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Background: The shift of metabolism from mitochondrial oxidative phosphorylation to glycolysis and mitochondria binding partner of hexokinase are features common to cancer. These have been seen in pulmonary hypertension (PH) as well. An inhibitor of hexokinase 2 (HK 2), the small molecule 3-bromopyruvate (3-BrPA) is an incredibly powerful and swift-acting anticancer agent. However, whether it could be of potential benefit to PH has still been unknown., Methods: Sprague-Dawley rats with monocrotaline (MCT)-induced PH were administered 2 oral doses of 3-BrPA (15 and 30 mg/kg/day, respectively) for 14 days. Hemodynamic parameters were obtained by right heart catheterization. Histopathology, immunohistochemistry, transmission electron microscopy, flow cytometry, and assessments of relative protein expressions were conducted., Results: Compared with MCT treatment, 3-BrPA decreased mean pulmonary arterial pressure and pulmonary vascular resistance, and increased cardiac output. 3-BrPA significantly suppressed proliferation in addition to enhancing apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodeling and right ventricular hypertrophy. Treatment with 3-BrPA markedly reduced the mitochondrial membrane potential and restored mitochondrial structure. Furthermore, 3-BrPA significantly inhibited HK 2 expression but not HK 1. The expression of both pyruvate dehydrogenase kinase and lactate dehydrogenase was decreased whereas that of pyruvate dehydrogenase and cytosolic cytochrome c was upregulated with 3-BrPA administration., Conclusion: This study demonstrates the reversal of PH by 3-BrPA is related to alteration in glycolysis and improved mitochondria function, indicating the "metabolic targeting" as a rational therapeutic strategy for PH., (© American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: The Delphi method was used to develop best practice recommendations (BPR) for safe use of pulmonary hypertension (PH) pharmacotherapies and to describe the pharmacist's role in provision of care., Methods: A core group reviewed PH medication-safety literature and developed initial BPR. Pharmacists practicing at PH-accredited Centers of Comprehensive Care who met defined PH expert criteria were invited to participate on an expert panel. In round 1 of a 4-round Delphi process, expert input was provided on the BPR. Feedback was incorporated into BPR for the next round. Round 2 proceeded in identical fashion to round 1. In round 3, BPR were deliberated in a teleconference and underwent voting at the cessation of the round using a 5-point Likert scale. Median scores of < 2.5, 2.5-3.75, and > 3.75 resulted in a best practice statement being rejected, reviewed in round 4, or accepted in the final BPR, respectively. In round 4, the remaining BPR were discussed and underwent voting. BPR were assigned a level of evidence and strength of recommendation based on voting results., Results: Eleven PH experts agreed to participate and met expert inclusion criteria, along with 2 pharmacists from the core group, bringing the total number of expert panel members to 13. To guide safe use of PH pharmacotherapies, 26 BPR were developed, categorized into 5 practice domains, comprising the PH Care Center accreditation process, inpatient practice, formulary management, diagnostics, and ambulatory care. BPR included provisions for safe use of parenteral prostacyclin agents and healthcare practitioner education., Conclusion: The Delphi method was used to develop BPR to guide safe use of PH pharmacotherapies.

Purpose: Safe transition of patients with pulmonary arterial hypertension (PAH) from parenteral treprostinil to oral selexipag therapy in both inpatient and outpatient settings is described., Summary: There is a paucity of published data on how to safely transition patients to oral therapy in the event of complications and problems during parenteral administration of prostacyclins, which can include bloodstream infections, injection-site pain (with use of subcutaneous treprostinil), infusion pump malfunction, and dosing errors due to incorrect dose preparation. This case series describes the transition of 4 patients with World Health Organization (WHO) group I PAH (WHO functional classes II-IV) from i.v. ( n = 3) and subcutaneous ( n = 1) treprostinil infusion therapy to oral selexipag use. The transition process was completed through the use of 2 cross-titration methods (rapid and slow). A rapid approach was used in 2 cases involving inpatients, with parenteral-to-oral transition completed over 8-13 days; a slow transition method was used in 2 cases, in which outpatients completed the transition over 19-25 weeks. Adverse events during the transitions were headache, nausea, vomiting, diarrhea, and jaw pain., Conclusion: Four patients with WHO group I PAH who were not candidates for continued parenteral treprostinil therapy were safely transitioned to oral selexipag in both inpatient and outpatient settings., Competing Interests: DisclosuresDr. Janmohamed is the primary investigator in clinical research sponsored by Actelion Pharmaceuticals. The authors have declared no other potential conflicts of interest., (Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Background: Newer endothelin receptor antagonists (ERAs) used to treat patients with pulmonary arterial hypertension (PAH) are associated with fewer drug-drug interactions than bosentan and require less monitoring. This, combined with a pharmacokinetic basis for improved efficacy, means there may be a clinical rationale for changing therapies. However, this can be challenging and few data on its safety in patients with PAH are available., Aims: At the Royal Free Hospital in London, UK, home-based medication transitioning has been standard practice since 2009 to avoid unnecessary hospital visits for patients, unless there is a clinical imperative. In this audit of standard practice we evaluated the consequences of adopting such a strategy when transitioning PAH patients between ERA therapies., Methods and Results: Using a Clinical Nurse Specialist-led, home-based transitioning strategy, 92 patients with PAH were transitioned from bosentan to macitentan or ambrisentan. Observational data were analysed retrospectively. The majority of patients were female with PAH associated with connective tissue disease and their ERA was changed in the hope of improving efficacy. The process was well tolerated with no adverse events associated with the process. Seventeen patients died during the study (macitentan, n = 5; ambrisentan, n = 12). None of the deaths was considered related to ERA treatment. The majority of patients remained clinically stable, based on WHO functional class and exercise capacity., Conclusion: An established home-based transitioning strategy can be adopted safely for patients with PAH changing ERA therapies. Most patients remained stable and the therapy change was well tolerated.

Background: Phosphodiesterase type 5 inhibitors (PDE5is), a treatment for erectile dysfunction, pulmonary hypertension (pHTN), and lower urinary tract symptoms (LUTS), have been implicated in melanoma development., Aim: We sought to determine the association between PDE5i use and melanoma development among patients with erectile dysfunction, pHTN, and LUTS., Methods: This was a retrospective cohort study of subjects contained within the Truven Health MarketScan claims database, which provides information on insurance claims in the United States for privately insured individuals, from 2007-2015. Individuals taking PDE5i were identified through pharmacy claims. A comparison group of men diagnosed with conditions for which PDE5i are prescribed was assembled., Outcomes: Cox proportional hazard models were used to estimate the hazard ratio (HR) (95% CI) of incident melanoma, basal cell carcinoma, and squamous cell carcinoma., Results: Of 610,881 subjects prescribed PDE5i, 636 developed melanoma (0.10%). The control group had 8,711 diagnoses of melanoma. There was an association between increased PDE5i tablet use and melanoma (HR 1.05, 95% CI 1.05-1.09). This association was also present between PDE5i use and basal cell carcinoma (HR 1.04, 95% CI 1.02-1.07) and squamous cell carcinoma (HR 1.04, 95% CI 1.01-1.07). In patients with pHTN and LUTS prescribed PDE5is, there was no relationship between exposure and melanoma incidence (HR 0.74, 95% CI 0.48-1.13; and HR 1.03, 95% CI 0.97-1.10, respectively)., Clinical Implications: There is little evidence for a clinically relevant association between PDE5i use and melanoma incidence., Strengths & Limitations: Our current work represents the largest study to date evaluating the relationship between PDE5i use and melanoma risk, and the first to examine all current indications of PDE5i use among men and women. Limitations include a patient population limited to commercially insured individuals, unknown patient medication compliance, and lack of information on patient skin type, lifestyle, and sun-exposure habits., Conclusion: There is a slight association between higher-volume PDE5i use and development of melanoma, basal cell carcinoma, and squamous cell carcinoma. This association among all skin cancers implies that confounding may account for the observed association. Shkolyar E, Li S, Tang J, et al. Risk of Melanoma With Phosphodiesterase Type 5 Inhibitor Use Among Patients With Erectile Dysfunction, Pulmonary Hypertension, and Lower Urinary Tract Symptoms. J Sex Med 2018;15:982-989., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: A case of life-threatening cardiovascular collapse after inadvertent subcutaneous injection of undiluted treprostinil is reported., Summary: A 29-year-old, 76-kg woman with group 1 pulmonary arterial hypertension managed with subcutaneous treprostinil infusion arrived at the emergency department (ED) with headache, nausea, vomiting, and a syncopal episode. Her vital signs were stable on presentation. Admission orders were placed, and the appropriate 3-mL syringe containing 7.5 mg of treprostinil intended for use with the patient's home microinfusion pump was sent from inpatient pharmacy to the ED. The order in the electronic medical record stated to administer treprostinil as a subcutaneous injection rather than an infusion. The patient's nurse transferred the 7.5 mg (3 mL) of undiluted treprostinil to a standard syringe and administered it as a single subcutaneous injection. Within minutes the patient experienced cardiovascular collapse, with a blood pressure nadir of 50/20 mm Hg. Aggressive resuscitation measures were immediately implemented. Initial management included fluids, bolus-dose vasopressors, multiple high-dose vasopressor infusions, ondansetron, acetaminophen, and loperamide. Hemodynamic stability was achieved, and vasopressors were discontinued 16 hours after the overdose event. Subcutaneous treprostinil was restarted at a reduced dose 12 hours after the overdose event and was adjusted to the patient's home dose 24 hours after the initial event. She was discharged in stable condition 30 hours after the overdose event., Conclusion: A patient who received an inadvertent overdose of subcutaneous treprostinil experienced cardiovascular collapse requiring aggressive resuscitation measures. Successful management of the patient was largely supportive, including fluids, bolus-dose vasopressors, multiple high-dose vasopressor infusions, ondansetron, acetaminophen, and loperamide., (Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Aims: Pulmonary hypertension (PH) is common in severe symptomatic left-sided valvular disease, particularly in aging populations. Inconsistent results have been reported concerning the association between PH and adverse outcomes after aortic valve replacement for aortic stenosis (AS). We therefore retrospectively investigated the prognostic significance of PH using peak tricuspid regurgitation velocity (TRV), as defined by the current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines, in a large cohort of patients with severe AS., Methods and Results: One thousand and nineteen patients (541 men; mean age 74 ± 11 years) with severe AS (aortic valve area (AVA) <1 cm2 and/or indexed AVA <0.6 cm2/m2 of body surface area) and LV ejection fraction ≥50% were included. Patients were divided into three groups according to the level of their peak TRV at the time of enrolment: Group 1 (n = 695, 68%) when TRV was ≤2.8 m/s; Group 2 (n = 212, 21%) when TRV was between 2.9 m/s and 3.4 m/s and Group 3 (n = 112, 11%) when TRV was > 3.4 m/s. Median overall follow-up was 31 [6-182] months. On univariate analysis, overall mortality during follow-up was globally different between groups (P < 0.001). On multivariate analysis, Group 3 (TRV >3.4 m/s) exhibited significant excess mortality after adjustment for covariates of prognostic importance (P = 0.032) and after further adjustment for surgery (P = 0.012), using Group 1 as the reference group. Dividing the whole population into two groups with a 3.4 m/s TRV threshold, overall mortality during follow-up was higher in the PH group [hazard ratio (HR) 1.87; 95% confidence interval [1.37-2.56]; P < 0.001)]. On multivariate analysis, after covariate adjustment, including surgery, Group 3 exhibited major excess mortality (adjusted HR 1.46 [1.10-1.95], P = 0.009)., Conclusion: This study demonstrates the negative impact of pulmonary pressure, as assessed by current ESC/ERS guidelines, on long-term outcome of patients with severe AS, irrespective of functional status, chronic obstructive pulmonary disease, AS severity and surgery. Baseline TRV should therefore be taken into account in the management of severe AS.

Aims: We aimed to determine whether treatment with sildenafil improves outcomes of patients with persistent pulmonary hypertension (PH) after correction of valvular heart disease (VHD)., Methods and Results: The sildenafil for improving outcomes after valvular correction (SIOVAC) study was a multricentric, randomized, parallel, and placebo-controlled trial that enrolled stable adults with mean pulmonary artery pressure ≥ 30 mmHg who had undergone a successful valve replacement or repair procedure at least 1 year before inclusion. We assigned 200 patients to receive sildenafil (40 mg three times daily, n = 104) or placebo (n = 96) for 6 months. The primary endpoint was the composite clinical score combining death, hospital admission for heart failure (HF), change in functional class, and patient global self-assessment. Only 27 patients receiving sildenafil improved their composite clinical score, as compared with 44 patients receiving placebo; in contrast 33 patients in the sildenafil group worsened their composite score, as compared with 14 in the placebo group [odds ratio 0.39; 95% confidence interval (CI) 0.22-0.67; P < 0.001]. The Kaplan-Meier estimates for survival without admission due to HF were 0.76 and 0.86 in the sildenafil and placebo groups, respectively (hazard ratio 2.0, 95% CI = 1.0-4.0; log-rank P = 0.044). Changes in 6-min walk test distance, natriuretic peptides, and Doppler-derived systolic pulmonary pressure were similar in both groups., Conclusion: Treatment with sildenafil in patients with persistent PH after successfully corrected VHD is associated to worse clinical outcomes than placebo. Off-label usage of sildenafil for treating this source of left heart disease PH should be avoided. The trial is registered with ClinicalTrials.gov, number NCT00862043.

Purpose: The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosing and administration, and place in therapy of selexipag, an orally administered selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension (PAH), are reviewed., Summary: The first-in-class oral prostacyclin IP receptor agonist selexipag (Uptravi, Actelion Pharmaceuticals) was approved by the Food and Drug Administration in December 2015. Selexipag is rapidly hydrolyzed to a long-acting metabolite that binds with high selectivity to IP receptors, resulting in vasodilation, inhibition of platelet aggregation, and antiinflammatory effects. Results of a long-term, placebo-controlled, clinical outcomes-driven trial showed that selexipag significantly reduced the occurrence of the composite primary outcome (all-cause mortality and development of PAH-related complications). Selexipag is indicated for use in patients with World Health Organization functional class (FC) II or III disease. The recommended initial selexipag dosage is 200 μg twice daily. Like prostanoid analogs, selexipag has a dose-dependent adverse-effect profile that includes nausea, vomiting, diarrhea, headache, and musculoskeletal pain. Although selexipag offers distinct pharmacologic advantages over other agents for the treatment of PAH, important issues of cost and access must be considered., Conclusion: Selexipag is an oral prostacyclin IP receptor agonist approved for use as monotherapy or in combination with other therapies to slow PAH progression and reduce the risk of hospitalization in patients with FC II or III symptoms. Its stability and relatively long half-life offer conveniences over conventional prostanoid therapies., Competing Interests: DisclosuresThe authors have declared no potential conflicts of interest., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Aims: The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored., Methods and Results: Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28-0.86; HR 0.72, 95% CL 0.42-1.22; and HR 0.22, 95% CL 0.15-0.33, respectively)., Conclusions: For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality., (© The Author 2017. Published on behalf of the European Society of Cardiology)

Purpose: The stability of sildenafil in combination with heparin and dopamine was evaluated., Methods: A stability-indicating high-performance liquid chromatography method with ultraviolet detection was developed for sildenafil citrate and validated. The method was applied to the investigation of sildenafil alone, sildenafil with heparin, sildenafil with dopamine, and sildenafil with heparin and with dopamine, all in 5% dextrose injection at room temperature and under refrigeration for 30 days. Samples of 100 μL were pulled from each storage bottle on each sampling day, diluted in mobile phase, and assayed in duplicate. Samples were tested on days 0, 1, 2, 3, 4, 5, 7, 9, 12, 14, 21, and 30. Each preparation was visually inspected for precipitation and color change. The percent recovery in each study sample was determined by comparing the peak area of sildenafil in the sample with the peak area of sildenafil from a freshly prepared 100-μg/mL standard in mobile phase., Results: The sildenafil alone, sildenafil with heparin, and sildenafil with dopamine remained within 90-110% of the expected sildenafil potency for at least 30 days at both temperatures. The preparation of sildenafil with both heparin and dopamine fell below 90% potency after 3 days at room temperature and 21 days in the refrigerator., Conclusion: Sildenafil prepared in 5% dextrose injection alone, with heparin, and with dopamine retained over 90% potency after 30 days of storage at room temperature and under refrigeration. Sildenafil prepared with both heparin and dopamine had a potency of <90% after 3 days of storage at room temperature and 21 days of storage under refrigeration., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Objectives: To investigate the effects of intravenous iloprost on pulmonary artery hypertension (PAH) in infants undergoing congenital heart surgery., Methods: In this prospective, randomized study, the study group (n = 15) received a continuous infusion of iloprost (2.0 ng/kg/min) that was delivered immediately after weaning from cardiopulmonary bypass and continued for 72 h postoperatively. Patients in the control group (n = 12) were managed conventionally. The groups were compared in terms of postoperative data, including systolic and mean pulmonary artery (PA) pressures, PA/systemic pressure ratio, lactate level, PAH crisis, ventilation time, reintubation and lengths of intensive care unit (ICU) and hospital stay. Transthoracic echocardiography was used to assess PA pressures at 1 day, 7 days and 30 days after surgery., Results: No mortality occurred. PAH crisis occurred in 2 (16.6%) patients in the control group and 4 (26.7%) patients in the study group (P = 0.53). Postoperative PA pressures and PA/systemic pressure ratios were similar between the groups (P > 0.05). The durations of ICU (P = 0.40) and hospital (P = 0.98) stays were similar between the groups. Echocardiographic studies demonstrated a significant decrease in postoperative PA pressures in the control (P = 0.001) and study (P = 0.0001) groups. However, no significant change was observed between the groups (P > 0.05). The Tukey multiple comparison test showed a significant decrease in PA pressures at each follow-up in both groups (P < 0.05)., Conclusions: Intravenous iloprost demonstrated no additional benefit over the conventional management of infants with PAH after repair of intracardiac defects. Clinicians may prefer other alternative agents in infants with a high risk of PAH crisis., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: Children conceived by assisted reproductive technology (ART) display vascular dysfunction. Its underlying mechanism, potential reversibility and long-term consequences for cardiovascular risk are unknown. In mice, ART induces arterial hypertension and shortens the life span. These problems are related to decreased vascular endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis. The aim of this study was to determine whether ART-induced vascular dysfunction in humans is related to a similar mechanism and potentially reversible. To this end we tested whether antioxidants improve endothelial function by scavenging free radicals and increasing NO bioavailability., Methods and Results: In this prospective double-blind placebo controlled study in 21 ART and 21 control children we assessed the effects of a four-week oral supplementation with antioxidant vitamins C (1 g) and E (400 IU) or placebo (allocation ratio 2:1) on flow-mediated vasodilation (FMD) of the brachial artery and pulmonary artery pressure (echocardiography) during high-altitude exposure (3454 m), a manoeuver known to facilitate the detection of pulmonary vascular dysfunction and to decrease NO bioavailability by stimulating oxidative stress. Antioxidant supplementation significantly increased plasma NO measured by ozone-based chemiluminescence (from 21.7 ± 7.9 to 26.9 ± 7.6 µM, p = 0.04) and FMD (from 7.0 ± 2.1 to 8.7 ± 2.0%, p = 0.004) and attenuated altitude-induced pulmonary hypertension (from 33 ± 8 to 28 ± 6 mm Hg, p = 0.028) in ART children, whereas it had no detectable effect in control children., Conclusions: Antioxidant administration to ART children improved NO bioavailability and vascular responsiveness in the systemic and pulmonary circulation. Collectively, these findings indicate that in young individuals ART-induced vascular dysfunction is subject to redox regulation and reversible., (© The European Society of Cardiology 2014.)

Background: Heart failure with preserved ejection fraction (HFpEF), with associated pulmonary hypertension is an increasingly large medical problem. Phosphodiesterase (PDE)-5 inhibition may be of value in this population, but data are scarce and inconclusive., Methods and Results: In this single centre, randomized double-blind, placebo-controlled trial, we included 52 patients with pulmonary hypertension [mean pulmonary artery pressure (PAP) >25 mmHg; pulmonary artery wedge pressure (PAWP) >15 mmHg] due to HFpEF [left ventricular ejection fraction (LVEF) ≥45%]. Patients were randomized to the PDE-5 inhibitor sildenafil, titrated to 60 mg three times a day, or placebo for 12 weeks. The primary endpoint was change in mean PAP after 12 weeks. Secondary endpoints were change in mean PAWP, cardiac output, and peak oxygen consumption (peak VO2). Mean age was 74 ± 10 years, 71% was female, LVEF was 58%, median NT-proBNP level was 1087 (535-1945) ng/L. After 12 weeks, change in mean PAP was -2.4 (95% CI -4.5 to -0.3) mmHg in patients who received sildenafil, vs. -4.7 (95% CI -7.1 to -2.3) mmHg in placebo patients (P = 0.14). Sildenafil did not have a favourable effect on PAWP, cardiac output, and peak VO2. Adverse events were overall comparable between groups., Conclusion: Treatment with sildenafil did not reduce pulmonary artery pressures and did not improve other invasive haemodynamic or clinical parameters in our study population, characterized by HFpEF patients with predominantly isolated post-capillary pulmonary hypertension. (ClinicalTrials.gov, number NCT01726049)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Objective: To document changes in pulmonary arterial systolic pressure (PASP) in patients with SLE who have received CYC for any indication., Methods: Twenty-four patients with SLE pulmonary arterial hypertension (PAH) with a PASP of >30 mmHg by transthoracic echocardiography received i.v. CYC (n = 24) or steroids (n = 24) with or without vasodilators (n = 20). Baseline clinical characteristics and PASP were evaluated before and after therapy at 6 months. Responders were defined as those who had a decrease in PASP of >15 mmHg from baseline along with improvement in their New York Heart Association functional class., Results: There were 11 responders (45.83%), with a decrease in mean PASP from 59.33 mmHg at baseline to 43.29 mmHg at the end of 6 months (P < 0.0001). The decrease in mean PASP from 39.75 mmHg at baseline to 34.4 mmHg at the end of 6 months was significant in four patients who received immunosuppression alone (P = 0.04). There was no difference in baseline PASP and disease activity between responders and non-responders. Two deaths were noted., Conclusion: Immunosuppression and vasodilators produced significant improvement in SLE PAH over 6 months., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: Imatinib mesylate, as add-on therapy in patients with pulmonary arterial hypertension (PAH) who remain inadequately treated despite receiving at least two PAH-specific drugs, improves exercise capacity and haemodynamics. We evaluated whether 24 weeks of add-on therapy with imatinib compared with placebo also improves right ventricular (RV) function assessed by echocardiography., Methods and Results: Echocardiograms were obtained at baseline, 12 weeks, and 24 weeks in 74 patients randomized to imatinib or placebo in the Imatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study (IMPRES) trial. Right ventricular function was assessed by tissue Doppler tricuspid annular peak systolic velocity (TA S'), tricuspid annular plane systolic excursion (TAPSE), RV Tei index, and RV fractional area change. Between-treatment-group differences in the changes from baseline to week-24 were assessed using an ANCOVA with the last observation carried forward. At week-24 patients randomized to imatinib demonstrated greater improvements in TA S' (1.6 ± 2.3 imatinib vs. 0.5 ± 2.4 cm/s placebo, P = 0.007) and RV Tei index (-0.11 ± 0.18 imatinib vs. 0.05 ± 0.18 placebo, P = 0.005) compared with placebo, but not in TAPSE (0.07 ± 0.44 imatinib vs. 0.03 ± 0.32 cm placebo, P = 0.08). Imatinib therapy was also associated with significant reduction in peak tricuspid regurgitation velocity, increase in LV size, and improvement in LV early diastolic relaxation velocity., Conclusions: Among patients with advanced PAH who remain symptomatic on at least two PAH-specific drugs, treatment with imatinib compared with placebo is associated with significant improvements in echocardiographic measures of RV function, in addition to LV size and LV early diastolic relaxation., Clinical Trial Registration: NCT00902174 (Clinicaltrials.gov)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Pulmonary hypertension (PH), which is classified as group 5 in the clinical classification of PH, is sometimes a complication of Pulmonary langerhans cell histiocytosis (PLCH), and is associated with high mortality. A 36-year-old woman had suffered from severe dyspnea 9 years previously and was diagnosed with PLCH and was on a waiting list for a lung transplant. Right heart failure had been observed and the mean pulmonary artery pressure was over 40 mmHg. The patient was diagnosed as PLCH with PH. After combined treatment with exercise rehabilitation and bosentan for 6 months, the cardiothoracic ratio, brain natriuretic peptide, and bodyweight were significantly decreased (cardiothoracic ratio from 43 to 38%, brain natriuretic peptide from 284 to10 pg/ml and bodyweight from 63 to 58 kg). Six-minute walk test also improved from 214 to 275 meters and the SF36 score for screening of depressive and anxiety disorders was improved. This is the report demonstrating the efficacy and safety of cardiac rehabilitation in combination with bosentan in a single patient with PLCH associated with PH., (© The European Society of Cardiology 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Purpose: The pharmacology, pharmacokinetics, clinical efficacy, safety, and role in therapy for riociguat are reviewed., Summary: Riociguat is the first member of a new class of medications, soluble guanylate cyclase stimulators. Riociguat is indicated for patients with resistant or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy who have World Health Organization (WHO) functional class IV pulmonary arterial hypertension (PAH) and in patients with inoperable CTEPH, regardless of WHO functional class, to improve exercise capacity and WHO functional class. Riociguat is indicated in patients with WHO functional class II PAH to improve exercise capacity, improve functional class, and delay clinical worsening. The mechanism of action of riociguat is within the nitric oxide pathway in the pulmonary vasculature. Clinical trials have demonstrated improvements in exercise capacity as measured by the six-minute walk distance test and in pulmonary arterial hemodynamics as measured by invasive pulmonary monitoring. Riociguat must be administered three times daily and requires dosage adjustments. Riociguat is a pregnancy category X drug and interacts with numerous medications. The two most serious adverse effects related to riociguat are hypotension and bleeding. Riociguat's role in the therapy of both PAH and CTEPH will be determined as more clinical experience and data are collected. Riociguat will likely cost approximately $90,000 annually., Conclusion: Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of CTEPH and PAH. It can be considered first-line therapy for the treatment of CTEPH and should be considered as an alternative to phosphodiesterase type-5 inhibitors in patients with PAH., (Copyright © 2014 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Hypertension, commonly recognized as high blood pressure, is a serious disease that affects millions of people worldwide. Similar to many physiological disorders, hypertension consists of several different cellular signaling pathways that involve various molecular messengers. Recent studies have shown that reactive oxygen species (ROS) play a substantial role in the development of both systemic and pulmonary hypertension, contributing to the pathology of this disease. However, the exact molecular mechanism of ROS in hypertension is not completely understood. In this review, we extensively examine and discuss the most recent experimental findings regarding the role of ROS in both pulmonary and systemic hypertension. Current studies show that excessive ROS not only promote JAK/STAT (janus kinase/signal transducers and activators of transcription)-mediated vascular remodeling in an angiotensin (ANG) II-induced hypertension model but also decrease the nitric oxide bioavailability. Furthermore, it has been shown that ROS generation can be mitigated through the inhibition of upstream ANG II or by blocking key ROS generators, such as nicotinamide adenine dinucleotide phosphate oxidase. Thus, various treatment options have been explored. Yet, as discussed in the current review, the regulation of ROS via novel antioxidant therapies may provide an alternative treatment for hypertension in the future.

Objectives: Pulmonary hypertension in paediatric patients with ventricular septal defect remains one of the most important determinants of perioperative morbidity and mortality. Sildenafil is an oral, well-tolerated pulmonary vasodilator with few drug interactions. We studied the effect of oral sildenafil, when given before and after surgical closure compared with starting it postoperatively, on the pulmonary artery pressure and patients' outcome., Methods: We enrolled 101 infants with large ventricular septal defects who had moderate-to-severe pulmonary hypertension scheduled for surgical closure. They were randomly assigned to the sildenafil group (n = 51, mean age 10 months and mean weight 6.5 kg), in which oral sildenafil was started 2 weeks before surgery to be continued postoperatively, and to the control group (n = 50, mean age 11 months and mean weight 7.3 kg), in which sildenafil was started only postoperatively. It was started at 0.5 mg/kg and increased gradually to a maximum dose of 2 mg/kg in both groups., Results: Overall hospital mortality was 4.9%. Mean pulmonary artery pressure decreased significantly at all time points of recording in both groups (P < 0.0001). In the sildenafil group, it decreased preoperatively after sildenafil administration from 75.4 to 59.4 mmHg and postoperatively from 50.4 mmHg immediate post-cardiopulmonary bypass to reach 44.2 mmHg before discharge. In the control group, it decreased from 74.6 mmHg to 51 mmHg immediate post-cardiopulmonary bypass to reach 42.7 mmHg before discharge. No adverse effects have been recorded. Although there was no difference in the duration of mechanical ventilation and hospital stay between the two groups, intensive care unit stay was significantly shorter in the sildenafil group. Dobutamine doses were significantly higher in the sildenafil group; however, milrinone and epinephrine have been used more significantly in the control group., Conclusions: The low cost, the oral availability and the good tolerability of sildenafil make it a suitable and simple alternative therapy for secondary pulmonary hypertension including persistent postoperative pulmonary hypertension associated with ventricular septal defect in resource limited places. However, starting sildenafil early before surgery does not add a great benefit in terms of improving postoperative pulmonary hypertension or patients' outcome.