Aim    Analysis of survival and the impact of etiology, adverse prognosis factors, and therapy on the survival of patients with pulmonary arterial hypertension associated with immune-mediated inflammatory rheumatic diseases (PAH-IIRD).Material and methods    The study included 95 patients: 76 with systemic scleroderma (SSc), 9 with mixed connective tissue disease (MCTD), 8 with systemic lupus erythematosus (SLE), one with rheumatoid arthritis, and one with Sjogren's disease with diagnosed PAH. All patients were prescribed PAH-specific therapy and followed up for at least 5 years during this treatment. The endpoint of the study was all-cause death.Results    During the 5-year follow-up period, 37 patients with PAH-SSc and 4 with PAH-MCTD (43%) died. There were no fatal outcomes in PAH-SLE. One-, two-, three-, and five-year survival rates in the overall group of patients were 91%, 80%, 73%, and 57%, respectively. In patients with PAH-SSc, one-, two-, three-, and five-year survival rates were worse than in PAH-MCTD (88%, 76%, 68%, 51% and 100%, 89%, 89%, 56%, respectively). The factors associated with a fatal outcome included age, gender, functional class, 6-minute walk test distance, right atrial pressure, cardiac output, pulmonary vascular resistance, and biomarker (uric acid and N-terminal pro-brain natriuretic peptide) concentrations. The use of macitentan and/or riociguat, as monotherapy or in combination with another PAH-specific drug, significantly reduced the 5-year risk of fatal outcome (OR 0.38 [0.16; 0.89], p=0.027).Conclusion    The survival of patients with PAH-IIRD remains low. Further studies aimed at finding new pathogenetic targets are needed; the use of modern PAH-specific drugs (macitentan and/or riociguat) modifies the course of the disease, increasing the survival.

Few studies have evaluated macitentan alongside other endothelin receptor antagonists (ERAs) in patients with pulmonary arterial hypertension (PAH). This retrospective, observational, real-world, comparative effectiveness analysis assessed outcomes in PAH with macitentan versus other ERAs.

Adults (≥18 years) were included from the de-identified Optum Clinformatics Data Mart database (January 2014-December 2023). Index date was first ERA prescription. Patients were continuously enrolled in the database for ≥12 months before index (baseline), with pulmonary hypertension/PAH diagnosis and right-heart catheterization during baseline. Primary endpoint was time to first PAH-related hospitalization (Cox proportional-hazards). Secondary endpoints included healthcare resource utilization.

Overall, 518 patients receiving macitentan and 379 other ERAs (ambrisentan, n = 370; bosentan, n = 9) were included. Mean age was 67 years and ∼70 % were female. Patients on macitentan versus other ERAs had higher baseline Charlson Comorbidity Index (P < 0.007). Risks of PAH-related and all-cause hospitalization were 19 % and 20 % lower, respectively, for macitentan versus other ERAs (hazard ratios: 0.81, P = 0.034; 0.80, P = 0.020, respectively). There were fewer all-cause and PAH-related intensive care unit (ICU) stays for macitentan versus other ERAs (P = 0.009, P = 0.013, respectively). Overall duration of all-cause ICU stay per patient per year was significantly shorter for macitentan versus other ERAs (7.0 vs 7.7 days; P = 0.003), as was the duration of all-cause ICU stay per visit (2.4 vs 3.7 days; P = 0.003).

Macitentan was associated with a significantly reduced risk of PAH-related and all-cause hospitalization, with lower ICU healthcare resource utilization, versus other ERAs.

Adverse drug events (ADEs) for endothelin receptor antagonists (ERAs) and prostacyclin-related drugs (PRDs) have been reported in clinical trials, but large-scale, real-world evaluations for respiratory, thoracic, and mediastinal disorders (RTMD) remain scarce.

A pharmacovigilance analysis of the FAERS database (Q1 2004~Q2 2024) used the reporting odds ratio (ROR) method for disproportionality analysis to assess the adverse drug events (ADEs) of ERAs and PRDs in pulmonary arterial hypertension, focusing on risks related to RTMD.

Reports of ADEs for ERAs (bosentan, ambrisentan, and macitentan) were 15,286, 36795, and 17,497, respectively, and for PRDs (epoprostenol, treprostinil, iloprost, and selexipag) were 5,477, 57265, 3,247, and 5,504. Females exceeded males, with most cases in adults. The top PTs for ERAs were death, dyspnea, and pneumonia, with bosentan linked to liver impairment. PRDs commonly cause headaches, flushing, hypotension, edema, and fluid retention. Dyspnea was the most reported RTMD risk for all drugs, and nasal congestion was noted for all. Selexipag had the fewest RTMD-related PTs, and iloprost had the strongest signal for hemoptysis.

The analysis highlights the RTMD risks of ERAs and PRDs in treating PH and underscores the need for careful monitoring of ADEs to ensure their safe and effective use in clinical practice.

Pulmonary hypertension is a life-threatening condition characterized by elevated mean pulmonary arterial pressure and vascular resistance. Significant advances in diagnosis and treatment have been achieved over the 20th and 21st centuries, yet challenges remain in improving long-term outcomes.

This review discusses the historical milestones in understanding and pharmacotherapy of the pulmonary arterial hypertension (PAH). A comprehensive literature search was conducted to explore the earliest reports of each approved medication for pulmonary hypertension, along with historical papers detailing the pathophysiological and diagnostic development. Additionally, the search aimed to identify novel therapeutic strategies, including repositioned drugs and emerging targets.

While current therapies, such as prostacyclin analogs and PDE5 inhibitors, improve functional capacity and hemodynamics, they face limitations, including costs, administration, and a predominantly vasodilatory approach. Additionally, the limitations of current clinical trial designs for rare diseases like pulmonary arterial hypertension hinder the evaluation of potentially effective drugs. These challenges underscore the urgent need for translational research to optimize trial methodologies, accelerating the development of new therapies. Innovative approaches, such as drug repositioning and the exploration of novel molecular targets, are critical to overcoming these barriers and ensuring timely, effective, and affordable treatment options for patients with PAH.

Chronic obstructive pulmonary disease (COPD) can be complicated by pulmonary hypertension (PH), impacting prognosis and quality of life. Endothelin-1 (ET-1) is implicated in PH development and elevated in COPD patients. The impact of COPD treatments on ET-1 and COPD-related PH remains unclear. This study investigated changes in ET-1 levels after administration of inhaled COPD medications and explored underlying mechanisms.

Patients underwent pulmonary function tests, COPD Assessment Test, and plasma ET-1 measurement before and 4-12 weeks after treatment initiation. In mice, elastase-induced emphysema was treated with budesonide (BUD), glycopyrronium (GLY), and formoterol (FOR) combinations for 2 weeks. Plasma ET-1 concentration and cytokine expression were analysed. HULEC-5a cells were used to examine ET-1 expression after TNFα stimulation.

The study included 33 patients. COPD patients (n = 24) showed higher baseline plasma ET-1 levels compared to controls (n = 9) (2.12 pg/ml vs 1.54 pg/ml, p < 0.001). Plasma ET-1 levels decreased in COPD patients posttreatment (2.12-1.82 pg/ml, p = 0.004), with reductions observed across all disease stages and treatment regimens. Mice showed elevated ET-1 levels and expression of inflammatory cytokines after elastase instillation. BUD/GLY/FOR treatment significantly reduced ET-1 concentration and TNFα expression. Furthermore, TNFα stimulation upregulated ET-1 expression in HULEC-5a cells.

In COPD patients conventional treatment decreased ET-1 concentration. In mouse models TNFα expression was suppressed by BUD/GLY/FOR. In HULEC-5a cells, TNFα stimulation exerted an increased ET-1expression. These findings suggest that the suppressive effect of inhaler therapy on ET-1 expression is due to the anti-inflammatory effects of these drugs.

Health-related quality of life (HRQoL) in pulmonary arterial hypertension (PAH) is valued as an outcome measure by patients, clinicians and regulators. The selection of patient-reported outcome measures (PROMs) for measurement of HRQoL in PAH clinical trials lacks systematic evaluation of their suitability, accuracy and reliability.

We report a systematic review (PROSPERO ID: CRD42024484021) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of PROMs selected in PAH clinical trials. PROM measurement properties were then evaluated according to the 10-step COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist and graded by recommendation for use. Finally, HRQoL was modelled into a conceptual framework using patient interviews and surveys.

Screening of 896 records identified 90 randomised controlled trials. 43 trials selected PROMs, of which 20 were sufficiently validated to detect meaningful change. Of these, eight trials were adequately powered, using either EuroQol-five dimensions-five levels (EQ-5D-5L), Short-Form-36 (SF-36) or the Living with Pulmonary Hypertension Questionnaire (LPHQ). The COSMIN evaluation recommended EmPHasis-10 and the LPHQ for use (grade A); whereas, SF-36 and EQ-5D-5L require further study (grade B). A conceptual framework of HRQoL was developed from literature comprising 8045 patients. This framework can be used to visualise the different HRQoL concepts measured by different PROMs.

To improve patient-centred research, greater consistency in PROM selection is required. Three of 90 randomised controlled trials have selected COSMIN-recommended PROMs. Whilst the PROMs evaluated require development across the 10 areas of psychometric property measurement, EmPHasis-10 and the LPHQ can be recommended for use. The ratified conceptual framework can further support PROM selection by identifying the HRQoL concepts they are likely to capture.

Pulmonary hypertension (PH) is a serious and progressive disease, posing a significant challenge to patient survival and quality of life. However, current treatments have limited effectiveness. Tianlong Kechuanling (TL) is a traditional Chinese medicine (TCM) compound formulation commonly used in clinical practice for the treatment of pulmonary heart disease, but its underlying mechanism is unknown.

This study aimed to validate the mitigating effect of TL on PH and to further investigate its mechanism.

A rat model of PH was induced by SU5416 combined with hypoxia (SuHx). The effects of TL on PH were evaluated through right ventricular systolic pressure (RVSP), Right ventricular hypertrophy index (RVHI) and histopathological analysis. The serum levels of HIF-1α, VEGFA in rats were detected by ELISA; VEGFR2, Vimentin and CD31 were detected by immunohistochemistry to explore the mechanism of action of TL. Human pulmonary artery endothelial cells (HPAECs) were induced by hypoxia, and the effects of TL were confirmed by RT-PCR and Western Blotting. Liquid chromatography-mass spectrometry (LC-MS) analysis was used to identify the chemical composition of TL.

TL ameliorated PH through modulation of the HIF-1α/VEGFA pathway and endothelial-to-mesenchymal transition (End-MT). The study also identified the key chemical components responsible for these effects.

The study demonstrates that TL can improve PH by inhibiting End-MT, supporting the further development of TL as an effective therapeutic option for PH.

Primary pulmonary hypertension (PPH), now known as pulmonary arterial hypertension (PAH), has induced significant treatment breakthroughs in the past decade. Treatment has focused on improving patient survival and quality of life, and delaying disease progression. Current therapies are categorized based on targeting different pathways known to contribute to PAH, including endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE-5 inhibitors), prostacyclin analogs, soluble guanylate cyclase stimulators, and activin signaling inhibitors such as Sotatercept. The latest addition to treatment options is soluble guanylate cyclase stimulators, such as Riociguat, which directly stimulates the nitric oxide pathway, facilitating vasodilation. Looking to the future, advancements in PAH treatment focus on precision medicine involving the sub-stratification of patients through a deep characterization of altered Transforming Growth Factor-β(TGF-β) signaling and molecular therapies. Gene therapy, targeting specific genetic mutations linked to PAH, and cell-based therapies, such as mesenchymal stem cells, are under investigation. Besides prevailing therapies, emerging PH treatments target growth factors and inflammation-modulating pathways, with ongoing trials assessing their long-term benefits and safety. Hence, this review explores current therapies that delay progression and improve survival, as well as future treatments with curative potential.

High-altitude pulmonary hypertension (HAPH) occurs when blood pressure in the pulmonary arteries rises due to exposure to high altitudes above 2,500 m. At these elevations, reduced atmospheric pressure leads to lower oxygen levels, triggering a series of physiological responses, including pulmonary artery constriction, which elevates blood pressure. This review explored the complex pathophysiological mechanisms of HAPH and reviewed current pharmaceutical interventions for its management. Meanwhile, this review particularly emphasized on the emerging research concerning Chinese medicinal plants as potential treatments for HAPH. Traditional Chinese medicines are rich in diverse natural ingredients that show significant promise in alleviating HAPH symptoms. We reviewed both in vitro and in vivo studies to assess the efficacy, safety, and mechanisms of these natural medicines, along with their potential adverse effects. Additionally, this review highlighted new alternative natural remedies, underscoring the need for ongoing research to expand available treatment options for HAPH.

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disorder with complex causes. Calcium channel blockers have long been used in its treatment. Our study aimed to validate experimental results showing increased calcium ion concentration in PAH patients. We investigated the impact of genes related to calcium channel regulation on PAH development and developed an accurate diagnostic model. Clinical trial data from serum of 18 healthy individuals and 18 patients with PAH were retrospectively analyzed. Concentrations of calcium and potassium ions were determined and compared. Datasets were retrieved, selecting genes associated with calcium ion release. R packages processed the datasets, filtering 174 common genes, and conducting Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Six hub genes were identified, and nomogram and logistic regression prediction models were constructed. Random forest filtered cross genes, and a diagnostic model was developed and validated using an artificial neural network. The 174 intersection genes related to calcium ions showed significant correlations with biological processes, cellular components, and molecular functions. Six key genes were obtained by constructing a protein-protein interaction network. A diagnostic model with high accuracy (> 90%) and diagnostic capability (AUC = 0.98) was established using a neural network algorithm. This study validated the experimental results, identified key genes associated with calcium ions, and developed a highly accurate diagnostic model using a neural network algorithm. These findings provide insights into the role of calcium release genes in PAH and demonstrate the potential of the diagnostic model for clinical application. However, due to limitations in sample size and a lack of prognosis data, the regulatory mechanisms of calcium ions in PAH patients and their impact on the clinical prognosis of PAH patients still need further exploration in the future.

Resistant hypertension (RH) is the state of uncontrolled blood pressure in the face of ostensibly optimal pharmacological intervention. It accounts for roughly one in six cases of hypertension, and is associated with more severe morbidity and mortality outcomes than is non-RH. The prevalence of RH implies a currently unmanaged pathology, which may involve the potent vasoconstrictor endothelin. Several endothelin receptor antagonists are currently marketed for pulmonary arterial hypertension, but none so far has been marketed for RH. Aprocitentan is currently in development, an endothelin receptor antagonist that effectively produces clinically significant and sustained decreases in systolic and diastolic blood pressure in the setting of RH.

Pulmonary arterial hypertension is a disease of the pulmonary vasculature, resulting in elevated pressure in the pulmonary arteries and disrupting the physiological coordination between the right heart and the pulmonary circulation. Exercise intolerance is one of the primary symptons of pulmonary arterial hypertension, significantly impacting the quality of life. The pathophysiology of exercise intolerance in pulmonary arterial hypertension is complex and likely multifactorial. Although the significance of right ventricle impairment and perfusion/ventilation mismatch is widely acknowledged, recent studies suggest pathophysiology of the skeletal muscle contributes to reduced exercise capacity in pulmonary arterial hypertension, a concept explored herein.

Right ventricular failure contributes to the morbidity and mortality of acute myocardial function, massive pulmonary embolism, and chronic pulmonary hypertension. Understanding how the normal physiology of the right ventricle (RV) is disrupted is integral to managing patients who present with RV decompensation. Therapeutic advances in mechanical circulatory support, pharmacotherapies to reduce afterload, mechanical and chemical lytic therapies for acute pulmonary embolism have improved outcomes of patients by offloading the RV. In this report we provide an overview of the physiology of the RV, medical management (volume optimization, hemodynamic targets, rhythm management), along with critical care-specific topics (induction with mechanical ventilation, sedation strategies, and mechanical circulatory support) and provide a framework for managing patients who present with leveraging principles of preload, contractility, and afterload. Last, because of the complexity of right ventricular failure management, and the complexity of presentation, we also discuss the role of team-based approach (cardiogenic shock and pulmonary embolism response teams), and highlight its benefits at improving outcomes.

Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ETBR (endothelin receptor type B).

To address this, we studied multiple models: in vivo, in a mouse model of ET-1-associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells.

Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1-induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ETBR. In human endothelial cells, Ang-(1-7)-induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ETBR antagonist). A779 inhibited ET-1-induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ETBR. Binding sites for ETBR were mapped to MasR (amino acids 290-314). Binding sites for MasR on ETBR were identified (amino acids 176-200). Peptides that disrupt MasR:ETBR prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ETBR interaction, which we termed enhancers. Enhancers increased Ang-(1-7)-induced eNOS activity, NO production, and Ang-(1-7)-mediated vasorelaxation, and reduced contractile responses.

We identify cross talk between Ang-(1-7) and ET-1 through MasR:ETBR interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ETBR-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ETBR signaling may have therapeutic potential in conditions associated with vascular damage.

Substantial progress has been made in the management of pulmonary arterial hypertension (PAH) in the past 25 years, but the disease remains life-limiting. Established therapies for PAH are mostly limited to symptomatic relief by correcting the imbalance of vasoactive factors. The tyrosine kinase inhibitor imatinib, the first predominantly non-vasodilatory drug to be tested in patients with PAH, improved exercise capacity and pulmonary haemodynamics compared with placebo but at the expense of adverse events such as subdural haematoma. Given that administration by inhalation might reduce the risk of systemic adverse effects, inhaled formulations of tyrosine kinase inhibitors are currently in clinical development. Other novel therapeutic approaches for PAH include suppression of activin receptor type IIA signalling with sotatercept, which has shown substantial efficacy in clinical trials and was approved for use in the USA in 2024, but the long-term safety of the drug remains unclear. Future advances in the management of PAH will focus on right ventricular function and involve deep phenotyping and the development of a personalized medicine approach. In this Review, we summarize the mechanisms underlying PAH, provide an overview of available PAH therapies and their limitations, describe the development of newer, predominantly non-vasodilatory drugs that are currently being tested in phase II or III clinical trials, and discuss future directions for PAH research.

Challenges in drug development for rare diseases such as pulmonary arterial hypertension can be addressed through the use of mathematical modeling. In this study, a quantitative systems pharmacology model of pulmonary arterial hypertension pathophysiology and pharmacology was used to predict changes in pulmonary vascular resistance and six-minute walk distance in the context of oral treprostinil clinical studies. We generated a virtual population that spanned the range of clinical observations and then calibrated virtual patient-specific weights to match clinical trials. We then used this virtual population to predict the results of clinical trials on the basis of disease severity, dosing regimen, time since diagnosis, and co-administered background therapies. The virtual population captured the effect of changes in trial design and patient subpopulation on clinical response. We also demonstrated the virtual trial workflow's potential for enriching populations based on clinical biomarkers to increase likelihood of trial success.

Background: Treprostinil, which is administered via continuous subcutaneous or intravenous infusion, is a medication applied in the treatment of pulmonary arterial hypertension (PAH). The dose of treprostinil is adjusted on an individual basis for each patient. A number of factors determine how well patients respond to treatment. Objectives: The aim of this study was to identify factors that may influence the clinical response to the dose of treprostinil at 3 months after the start of therapy. Methods: The factors influencing treatment response were analyzed in consecutive PAH patients who started receiving treprostinil treatment. The treatment efficacy was assessed as improvement in 6 min walk distance (6MWD) and WHO functional class (WHO FC), a reduction in N-terminal prohormone of brain natriuretic peptide (NTproBNP), and the percentage of patients achieving low-risk status after 12 months of treatment. Results: A total of 83 patients were included in this analysis. Classification of patients according to the tertiles of treprostinil dose achieved at 3 months after drug inclusion shows that after 12 months of follow-up, the median WHO FC in the highest dose group was lower than that in the intermediate dose group (WHO FC II vs. WHO FC III, p = 0.005), the median NTproBNP was lower (922 pg/mL, vs. 1686 pg/mL, p = 0.036) and 6MWD was longer (300 m vs. 510 m, p = 0.015). The French Noninvasive Criteria (NIFC) scale score was higher (2 vs. 0, p = 0.008), and the Reveal scale score was lower (5.0 vs. 8.5, p = 0.034). In the group of patients who exceeded a dose of 19.8 ng/kg/min within 3 months, an improvement in 6MWD was observed significantly more often after one year of therapy, and they were more likely to show an increase in NIFC scale scores after one year of therapy than the group of patients who received the lower dose (65% vs. 30%, p = 0.02). In the group of patients younger than 50 years of age, a statistically significant correlation was observed between the dose of treprostinil achieved after three months of treatment and the parameters assessed after 12 months of treatment, including WHO FC, 6MWD, and NIFC prognostic scale scores (all p < 0.05). Conclusions: The clinical effect of treatment is critically dependent on the rapid escalation of the treprostinil dose during the first three months of treatment.

Despite increasing therapeutic options and evolving treatment strategies, including targeting 3 therapeutic pathways, in the management of pulmonary arterial hypertension (PAH), morbidity and mortality have remained unacceptably high. Sotatercept is a first-in-class, novel activin signaling inhibitor approved for treating PAH based on evolving efficacy and safety evidence. This state-of-the-art review summarizes the current understanding of the mechanism of action, the impact on outcomes that improve how patients feel, function, and survive, and the safety and adverse event profile to inform readers of this breakthrough novel therapy.

Pulmonary arterial hypertension (PAH) is a long-term condition characterised by increased resistance to blood flow in the pulmonary circulation. The disease has a progressive course and is associated with a poor prognosis. Without treatment, PAH is associated with mortality in <3 years. Over the past decade, many advances have been made in revising the haemodynamic definition, clinical classification, risk calculation score, treatment options etc. Suggestions from the Sixth World Symposium on Pulmonary Hypertension were incorporated into a literature review that was included in the European Society of Cardiology/European Respiratory Society (ESC/ERS)'s most recent iteration of their guidelines in 2022. The traditional cut-off for pulmonary hypertension (PH), i.e., mean pulmonary artery pressure (mPAP) >25 mm Hg, has been challenged by observational cohort studies, which have shown poor outcomes for values of 21-24 mmHg; the new consensus is that PH is defined at mPAP >20 mm Hg. Although the gold standard for diagnosis and the major source of therapy guidance continues to be right cardiac catheterisation, echocardiography remains the initial test of choice. A multidisciplinary approach is highly recommended when treating PH patients and careful evaluation of patients will aid in proper diagnosis and prognosis. Pharmacotherapy for PAH has seen a paradigm shift with the successful use of newer agents in more extensive, longer and more inclusive trials driven by hard endpoints. Macitentan, selexipag and riociguat are three oral agents that have shown astounding success in PAH randomised studies in the past decade. Upfront combination therapy with two agents is now becoming the norm (following the AMBITION, OPTIMA and ITALY trials) and the momentum is shifting towards triple therapy as for essential hypertension. More recently, inhaled treprostinil was shown to improve exercise capacity in PH associated with interstitial lung disease in the phase III INCREASE study and has been granted regulatory approval for World Health Organization group 3 PH. A new class of drug, sotatercept (a tumour growth factor-β signalling inhibitor), has also been recently approved by the Food and Drug Administration for management of PAH based on positive results from the phase III STELLAR study. Pulmonary artery denervation and balloon pulmonary angioplasty have emerged as viable alternatives in PH that are resistant to drug therapy. This article aims to summarise the key changes and recent advances in diagnosis and managing PH in general, with an emphasis on certain subgroups.

Endothelin receptor antagonists are commonly used in clinical practice, with concerns about their hepatotoxicity.

This study aimed to conduct a comprehensive pharmacovigilance study based on FDA adverse event reporting system data to evaluate the possible association between endothelin receptor antagonists and drug-induced liver injury.

Adverse event reports from FDA adverse event reporting system between January 2004 and December 2022 were analyzed. Disproportionality algorithms, including reporting odds ratio and information component, were used to evaluate the association between endothelin receptor antagonists and liver injury. Sex- and age-stratified analyses of drug-induced liver injury events were also conducted in relation to endothelin receptor antagonists.

Significant associations between bosentan, macitentan, and liver injury were identified. Bosentan showed a strong link with liver injury, with reporting odds ratios for cholestatic injury at 7.59 (95% confidence interval: 6.90-8.35), hepatocellular injury at 5.63 (5.29-6.00), and serious drug-related hepatic disorders events at 1.33 (1.24-1.43). Drug-induced liver injury signals associated with bosentan were detected in all age groups. Macitentan was associated with liver injury, with reporting odds ratios for hepatic failure at 1.64 (1.39-1.94), cholestatic injury at 1.62 (1.43-1.83), and serious drug-related hepatic disorders events at 1.40 (1.29-1.51). No drug-induced liver injury signal was detected for ambrisentan, and no significant sex differences were observed in drug-induced liver injury events.

Both bosentan and macitentan are associated with liver injury. Routine monitoring of serum aminotransferase levels is recommended, especially in patients at higher risk of liver injury. Further research into drug-drug interactions involving endothelin receptor antagonists is warranted.

Pulmonary arterial hypertension (PAH) is a form of precapillary pulmonary hypertension caused by a complex process of endothelial dysfunction and vascular remodeling. If left untreated, this progressive disease presents with symptoms of incapacitating fatigue causing marked loss of quality of life, eventually culminating in right ventricular failure and death. Patient management is complex and based on accurate diagnosis, risk stratification, and treatment initiation, with close monitoring of response and disease progression. Understanding the underlying pathophysiology has enabled the development of multiple drugs directed at different targets in the pathological chain. Vasodilator therapy has been the mainstay approach for the last few years, significantly improving quality of life, functional status, and survival. Recent advances in therapies targeting dysfunctional pathways beyond endothelial dysfunction may address the fundamental processes underlying the disease, raising the prospect of increasingly effective options for this high-risk group of patients with a historically poor prognosis.

Despite the innovations introduced in the 2022 European Society of Cardiology/European Respiratory Society Guidelines on Pulmonary Hypertension, risk discrimination and management of pulmonary arterial hypertension (PAH) patients at intermediate risk still represents a grey zone. Additionally, clinical evidence derived from currently available studies is limited. This expert panel survey intends to aid physicians in choosing the best therapeutic strategy for patients at intermediate risk despite ongoing oral therapy. An expert panel of 24 physicians, specialized in cardiology and/or pulmonology with expertise in handling all drugs available for the treatment of PAH participated in the survey. All potential therapeutic options for patients at intermediate risk were explored and analyzed to produce graded consensus statements regarding: the switch from endothelin receptor antagonist (ERA) or phosphodiesterase 5 inhibitor (PDE5i) to another oral drug of the same class; the addition of a drug targeting the prostacyclin pathway administered by different routes; the switch from PDE5i to riociguat.

Background/Objectives: The extensive range of instruments designed for evaluating functional performance (FP) in chronic respiratory diseases (CRD) other than chronic obstructive pulmonary disease (COPD) presents a challenge in selecting the most appropriate one. Therefore, this systematic review aimed to summarise FP instruments, their measurement properties, their minimum clinically important differences, and their associations with CRD course-related events or prognosis in non-COPD CRD. Methods: Studies employing patient-reported or performance-based instruments to assess FP in non-COPD CRD were systematically identified in the PubMed, PEDro, Embase, and Cochrane Library databases. COPD-exclusive studies or those solely reporting exercise capacity tests were excluded. Examination focused on measurement properties and associations with CRD course-related events or prognosis. The risk of bias was evaluated using the COSMIN, Downs and Black, and PEDro checklists based on the study design. Results: A total of 216 studies across seven CRD categories [asthma, bronchiectasis, cystic fibrosis, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), pre-/post-lung-transplantation] from various study types were included. Thirty-three instruments were identified, with the SF-36 questionnaire's physical function domain being the most commonly used patient-reported tool. The 1 min sit-to-stand test was the most extensively studied performance-based measure, with its measurement properties frequently reported in non-COPD CRD studies. Associations with events were infrequently documented, primarily in ILD and PAH studies related to mortality. Conclusions: Despite the prevalent use of FP instruments, limited information exists concerning their measurement properties and clinical implications. This review furnishes a concise summary of available evidence, aiding informed clinical decisions when selecting FP tools for non-COPD CRD.

Letairis (ambrisentan), an endothelin receptor antagonist (ERA), is a critical medication for pulmonary arterial hypertension (PAH). Despite its efficacy, its safety profile is under scrutiny, warranting a detailed analysis.

This study leveraged the FDA Adverse Event Reporting System (FAERS) from Q1 2007 to Q4 2023, focusing on Letairis as the primary suspect in adverse events. Employing advanced data mining techniques, such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), the study aimed to uncover safety signals.

A total of 43,774 cases were identified, with Letairis implicated in 16,038,963 adverse event reports. There was a notable predominance of female patients (75.30%), with a median age around 64 years. Severe outcomes, including hospitalization (51.63%) and fatalities (20.44%), were prevalent. Signal strength analysis highlighted concerns in infections and infestations, as well as cardiac disorders.

The analysis underscores the need for vigilant pharmacovigilance and highlights Letairis's potential to induce serious AEs, particularly in female and elderly populations. These findings are instrumental in guiding clinical practice and future drug safety assessments.

Pulmonary hypertension (PH) is a severe and chronic disease characterized by increased pulmonary vascular resistance and remodeling, often precipitating right-sided heart dysfunction and death. Although the condition is progressive and incurable, current therapies for the disease focus on multiple different drugs and general supportive therapies to manage symptoms and prolong survival, ranging from medications more specific to pulmonary arterial hypertension (PAH) to exercise training. Moreover, there are multiple studies exploring novel experimental drugs and therapies including unique neurostimulation, to help better manage the disease. Here, we provide a narrative review focusing on current PH treatments that target multiple underlying biochemical mechanisms, including imbalances in vasoconstrictor-vasodilator and autonomic nervous system function, inflammation, and bone morphogenic protein (BMP) signaling. We also focus on the potential of novel therapies for managing PH, focusing on multiple types of neurostimulation including acupuncture. Lastly, we also touch upon the disease's different subgroups, clinical presentations and prognosis, diagnostics, demographics, and cost.

Pulmonary arterial hypertension leads to significant impairment in haemodynamics, right heart function, exercise capacity, quality of life and survival. Current therapies have mechanisms of action involving signalling via one of four pathways: endothelin-1, nitric oxide, prostacyclin and bone morphogenetic protein/activin signalling. Efficacy has generally been greater with therapeutic combinations and with parenteral therapy compared with monotherapy or nonparenteral therapies, and maximal medical therapy is now four-drug therapy. Lung transplantation remains an option for selected patients with an inadequate response to therapies.

Over the last decades, significant progress has been achieved in the pulmonary hypertension (PH) field. Pathophysiology of PH has been studied, leading to the classification of PH patients into five groups, while the hemodynamic definition has been recently revised. A diagnostic algorithm has been established and awareness has been raised in order to minimize diagnosis delay. The pulmonary arterial hypertension (PAH) treatment strategy includes the established three pathways of endothelin, nitric oxide-phosphodiesterase inhibitor, and prostacyclin pathway, but new therapeutic options are now being tested. The aim of this review is to summarize the existing practice and to highlight the novelties in the field of PH.

Pulmonary arterial hypertension (PAH) is a complex fatal condition that requires aggressive treatment with close monitoring. Significant progress has been made over the last three decades in the treatment of PAH, but, despite this progress, survival has remained unacceptably low. In the quest to improve survival, therapeutic interventions play a central role. In the last few years, there have been remarkable attempts to identify novel treatments. Finally, we have had a breakthrough with the discovery of the fourth treatment pathway in PAH. Activin signaling inhibition distinguishes itself as a potential antiproliferative intervention as opposed to the traditional therapies, which mediate their effect primarily by vasodilatation. With this novel treatment pathway, we stand at an important milestone with an exciting future ahead and the natural question of when to use an activin signaling inhibitor for the treatment of PAH. In this state-of-the-art review, we focus on the placement of this novel agent in the PAH treatment paradigm, based on the available evidence, with special focus on the U.S. patient population. This review also provides an expert opinion of the current treatment algorithm in important subgroups of patients with comorbidities from the U.S. perspective.

Getting the dose right is a key challenge in drug development; model-informed drug development (MIDD) provides powerful tools to shape dose strategies and inform decision making. In this tutorial, the case study of the ZENITH trials showcases how a set of clinical pharmacology and MIDD approaches informed an impactful dose strategy. The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, has yielded a robust and significant albuminuria reduction in the Phase IIb trial ZENITH-CKD and is being investigated for reduction of kidney function decline in a high-risk chronic kidney disease population in the Phase III trial ZENITH High Proteinuria. Endothelin antagonist treatment has, until now, been limited by the class effect fluid retention. ZENITH-CKD investigated a wide range of zibotentan doses based on pharmacokinetics in renal impairment, competitor-data exposure-response modeling, and clinical trial simulations. Recruitment delays reduced interim analysis data availability; here, supportive dose-response modeling recovered decision-making confidence. At trial completion, the low-dose arm enabled Phase III dose selection between Phase IIb doses. Dose-response modeling of efficacy and Kaplan-Meier analyses of tolerability identified a kidney-function-based low-dose strategy of 0.25 or 0.75 mg zibotentan (with 10 mg dapagliflozin) to balance benefit/risk in ZENITH High Proteinuria. The applied clinical pharmacology and MIDD principles enabled successful Phase IIb dose finding, rationalized and built confidence in the innovative Phase III dosing strategy and identified a potential therapeutic window for zibotentan/dapagliflozin, providing the opportunity for a significant improvement in the treatment of chronic kidney disease with high proteinuria.

Pulmonary hypertension is a common comorbidity in patients with chronic kidney disease (CKD), but therapeutic options are limited. We discuss the epidemiology of pulmonary hypertension in patients with CKD and review therapies for pulmonary hypertension with a focus on emerging treatments for pulmonary arterial hypertension (PAH).

The definition of pulmonary hypertension has been updated to a lower threshold of mean pulmonary artery pressures of more than 20 mmHg, potentially leading to more patients with CKD to qualify for the diagnosis of pulmonary hypertension. Endothelin receptor antagonists, a class of medications, which demonstrated efficacy in patients with PAH, have been shown to slow progression of CKD, but their efficacy in lowering pulmonary artery pressures and their effects on reducing cardiovascular mortality in this population remains unproven. Sotatercept, a novel activin signaling inhibitor, which was previously studied in dialysis patients has been shown to increase exercise capacity in patients with PAH. These studies may lead to new specific therapies for pulmonary hypertension in patients with CKD.

Pulmonary hypertension is common in patients with CKD. Although our understanding of factors leading to pulmonary hypertension in this population have evolved, evidence supporting disease-specific therapy in CKD is limited arguing for larger, long-term studies.

Newer medications and devices, as well as greater understanding of the benefits and limitations of existing treatments, have led to expanded treatment options for patients with lung disease. Treatment advances have led to improved outcomes for patients with asthma, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary hypertension, and cystic fibrosis. The risks and benefits of available treatments are substantially variable within these heterogeneous disease groups. Defining the role of newer therapies mandates both an understanding of these disorders and overall treatment approaches. This section will review general treatment approaches in addition to focusing on newer therapies for these conditions..

Endothelins and their receptors, ETA and ETB, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ETA antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ETA in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ETA antagonist, respectively. Notably, a specialized anti-ETA antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ETA and ETB, and the agonist BQ3020-bound ETB, in complex with Gq, unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ETA. Furthermore, our results suggest that ECL2 in ETA can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors.

In the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy.

Patients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition.

Of 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg, p = 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan (p < 0.0001).

In SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.

There is no clinical evidence of differences in drugs associated with long-term survival in patients with pulmonary arterial hypertension (PAH) due to the small population and lack of information on death in Japanese medical database systems. This study evaluated whether patient data from a spontaneous reporting database could be used for comparing the effects of pulmonary vasodilators on long-term survival in PAH patients. PAH patient data reported in the Japanese Adverse Drug Event Report (JADER) database from April 2004 to July 2022 were extracted. Kaplan-Meier curves were used to compare survival times. Adjusted hazard ratios (aHRs) for all-cause mortality were determined using Cox proportional hazards models. Of 1969 PAH patients reported in the JADER database, 1208 were included in the survival analyses. The patient demographics were similar to those of the PAH population reported in the Japan Pulmonary Hypertension Registry. Among drugs targeting the prostacyclin pathway, epoprostenol was most associated with long-term survival (aHR, 0.38; 95% confidence interval (CI), 0.23-0.64). The PAH patients treated with endothelin receptor antagonists had improved survival, especially among the macitentan users (aHR, 0.30; 95% CI, 0.22-0.42). Sildenafil was associated with a poor prognosis in the PAH patients (aHR, 1.56; 95% CI, 1.19-2.04). Although our results must be interpreted with caution due to several limitations inherent to spontaneous reporting databases, our approach using the JADER database for survival analysis may provide useful information in limited situations such as the treatment of rare diseases including PAH.

Health-related quality of life (HRQOL) is frequently impaired in pulmonary arterial hypertension. However, little is known about HRQOL in other forms of pulmonary hypertension (PH).

Does HRQOL vary across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system?

This cross-sectional study included patients with PH from the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort study. HRQOL was assessed by using emPHasis-10 (e-10), the 36-item Medical Outcomes Study Short Form survey (physical component score [PCS] and mental component score), and the Minnesota Living with Heart Failure Questionnaire. Pearson correlations between HRQOL and demographic, physiologic, and imaging characteristics within each WSPH group were tested. Multivariable linear regressions compared HRQOL across WSPH groups, adjusting for demographic characteristics, disease prevalence, functional class, and hemodynamics. Cox proportional hazards models were used to assess associations between HRQOL and survival across WSPH groups.

Among 691 patients with PH, HRQOL correlated with functional class and 6-min walk distance but not hemodynamics. HRQOL was severely depressed across WSPH groups for all measures except the 36-item Medical Outcomes Study Short Form survey mental component score. Compared with Group 1 participants, Group 2 participants had significantly worse HRQOL (e-10 score, 29 vs 24 [P = .001]; PCS, 32.9 ± 8 vs 38.4 ± 10 [P < .0001]; and Minnesota Living with Heart Failure Questionnaire score, 50 vs 38 [P = .003]). Group 3 participants similarly had a worse e-10 score (31 vs 24; P < .0001) and PCS (33.3 ± 9 vs 38.4 ± 10; P < .0001) compared with Group 1 participants, which persisted in multivariable models (P < .05). HRQOL was associated in adjusted models with survival across Groups 1, 2, and 3.

HRQOL was depressed in PH and particularly in Groups 2 and 3 despite less severe hemodynamics. HRQOL is associated with functional capacity, but the severity of hemodynamic disease poorly estimates the impact of PH on patients' lives. Further studies are needed to better identify predictors and treatments to improve HRQOL across the spectrum of PH.

Pulmonary hypertension (PH) is a known complication of certain connective tissue diseases (CTDs), with systemic sclerosis (SSc) being the most common in the Western world. However, PH in association with non-SSc CTD such as systemic lupus erythematous, mixed connective tissue disease, and primary Sjögren's syndrome constitutes a distinct subset of patients with inherently different epidemiologic profiles, pathophysiologic mechanisms, clinical features, therapeutic options, and prognostic implications. The purpose of this review is to inform a practical approach for clinicians evaluating patients with non-SSc CTD-associated PH.The development of PH in these patients involves a complex interplay between genetic factors, immune-mediated mechanisms, and endothelial cell dysfunction. Furthermore, the broad spectrum of CTD manifestations can contribute to the development of PH through various pathophysiologic mechanisms, including intrinsic pulmonary arteriolar vasculopathy (pulmonary arterial hypertension, Group 1 PH), left-heart disease (Group 2), chronic lung disease (Group 3), chronic pulmonary artery obstruction (Group 4), and unclear and/or multifactorial mechanisms (Group 5). The importance of diagnosing PH early in symptomatic patients with non-SSc CTD is highlighted, with a review of the relevant biomarkers, imaging, and diagnostic procedures required to establish a diagnosis.Therapeutic strategies for non-SSc PH associated with CTD are explored with an in-depth review of the medical, interventional, and surgical options available to these patients, emphasizing the CTD-specific considerations that guide treatment and aid in prognosis. By identifying gaps in the current literature, we offer insights into future research priorities that may prove valuable for patients with PH associated with non-SSc CTD.

Persistent pulmonary hypertension of the newborn is a life-threatening condition that affects about 1-2 per 1,000 live births worldwide. Bosentan is an oral dual endothelin receptor antagonist that may have a beneficial effect on persistent pulmonary hypertension of the newborn by reducing pulmonary vascular resistance and improving oxygenation. However, its role in persistent pulmonary hypertension of the newborn remains unclear.

To systematically evaluate the efficacy and safety of bosentan as an adjuvant therapy for persistent pulmonary hypertension of the newborn in newborns.

We searched six English and two Chinese databases from their inception to 1 January 2023 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomised controlled trials and retrospective studies that compared bosentan with placebo or other drugs for persistent pulmonary hypertension of the newborn in newborns. We performed a meta-analysis using random-effects models and assessed the risk of bias and heterogeneity in the included studies.

We included 10 studies with a total of 550 participants. Bosentan significantly reduced the treatment failure rate (relative risk = 0.25, P < 0.001), pulmonary artery pressure (mean difference = -11.79, P < 0.001), and length of hospital stay (mean difference = -1.04, P = 0.003), and increased the partial pressure of oxygen (mean difference = 10.02, P < 0.001) and blood oxygen saturation (SpO2) (mean difference = 8.24, P < 0.001) compared with a placebo or other drugs. The occurrence of adverse reactions was not significantly different between bosentan and a placebo or other drugs.

Bosentan is effective in the treatment of persistent pulmonary hypertension of the newborn but adverse reactions such as abnormal liver function should be observed when using it.

Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and may be associated with a variety of cardiovascular and respiratory diseases. Pulmonary hypertension due to left heart disease (PH-LHD) currently lacks targeted therapies, while Pulmonary arterial hypertension (PAH), despite approved treatments, carries considerable residual risk. Metabolic dysfunction has been linked to the pathogenesis and prognosis of PH through various studies, with emerging metabolic agents offering a potential avenue for improving patient outcomes. Sodium-glucose cotransporter 2 inhibitor (SGLT-2i), a novel hypoglycemic agent, could ameliorate metabolic dysfunction and exert cardioprotective effects. Recent small-scale studies suggest SGLT-2i treatment may improve pulmonary artery pressure in patients with PH-LHD, and the PAH animal model shows that SGLT-2i can reduce pulmonary vascular remodeling and prevent progression in PAH, suggesting potential benefits for patients with PH-LHD and perhaps PAH. This review aims to succinctly review PH's pathophysiology, and the connection between metabolic dysfunction and PH, and investigate the prospective mechanisms of action of SGLT-2i in PH-LHD and PAH management.