Treatment Of Pulmonary Arterial Hypertension Research Articles

GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of EIF2AK4 gene (encoding general control nonderepressible 2 kinase, GCN2) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely in patients with PAH. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here, we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and patients with idiopathic PAH. Unexpectedly, loss of GCN2 kinase activity in Eif2ak4-/- mice with genetic disruption of the kinase domain induced neither PVOD nor pulmonary hypertension (PH) but inhibited hypoxia-induced PH. RNA-sequencing analysis suggested endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2α. Restored Edn1 expression in ECs of Eif2ak4-/- mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss-of-function mutations.

Safety and efficacy of rodatristat ethyl for the treatment of pulmonary arterial hypertension (ELEVATE-2): a dose-ranging, randomised, multicentre, phase 2b trial

The role of serotonin in pulmonary arterial hypertension has been extensively studied in recent decades, with preclinical data strongly indicating involvement in disease pathogenesis; however, clinical studies have yielded mixed results. ELEVATE-2 was a phase 2b dose-ranging, randomised, double-blind, placebo-controlled, multicentre trial investigating rodatristat ethyl as a treatment for patients with pulmonary arterial hypertension. The study was conducted at 64 sites across 16 countries in Europe and North America. Eligible participants were aged 18 years or older, had pulmonary arterial hypertension with WHO functional class II or III symptom severity, and had received a stable dose and regimen of one or more pulmonary arterial hypertension treatments for at least 12 weeks. Participants were randomly assigned 1:1:1 to receive two placebo tablets, one placebo and one rodatristat ethyl 300 mg tablet, or two rodatristat ethyl 300 mg tablets twice daily using an interactive response system. Participants, investigators, site personnel, and sponsors were masked to treatment allocation. Participants who completed the 24 week treatment period were invited to continue in an open-label extension. The primary endpoint was percent change in pulmonary vascular resistance (PVR) from baseline to week 24. Primary efficacy analyses were conducted on the intention-to-treat population and analyses of harms were conducted in the safety population, which included all patients who received any amount of the study drug. This trial is registered with ClinicalTrials.gov, NCT04712669, and is now complete. Between March 18, 2021 and Dec 13, 2022, 108 participants were enrolled and randomly assigned. 36 participants received placebo, 36 received rodatristat ethyl 300 mg, and 36 received rodatristat ethyl 600 mg twice daily. Overall, 85 (79%) of participants were female and 23 (21%) were male. The mean age was 52·8 years (SD 14·7) in the full analysis set. In the open-label extension phase, 62 (82%) of participants were female and 14 (18%) were male, and the mean age was 52·8 years (SD 14·7); this phase was terminated following sponsor review of unmasked main study results. Least-squares mean percent change in PVR from baseline to week 24 favoured placebo and was 5·8% (SE 18·1) for the placebo group, 63·1% (18·5) for the rodatristat ethyl 300 mg group, and 64·2% (18·0) for the rodatristat ethyl 600 mg group. Treatment-emergent adverse events (TEAE) were reported for 29 (81%) patients in the placebo group, 33 (92%) patients in the rodatristat ethyl 300 mg group, and all 36 (100%) patients in the rodatristat ethyl 600 mg group. TEAE leading to study discontinuation were reported for three (8%) patients in the placebo group, four (11%) patients in the rodatristat ethyl 300 mg group, and four (11%) in the rodatristat ethyl 600 mg group. There was one (3%) TEAE leading to death in the rodatristat ethyl 300 mg group. Our results indicate that reducing peripheral serotonin concentrations via rodatristat ethyl has a negative effect on pulmonary haemodynamics and cardiac function in patients with pulmonary arterial hypertension. This finding suggests that manipulating this pathway might not be a suitable option for pulmonary arterial hypertension therapy. Enzyvant Therapeutics (now Sumitomo Pharma America).

Pulmonary Arterial Hypertension and TGF-β Superfamily Signaling: Focus on Sotatercept.

Pulmonary arterial hypertension (PAH) is a rare and progressive disease that continues to remain highly morbid despite multiple advances in medical therapies. There remains a persistent and desperate need to identify novel methods of treating and, ideally, reversing the pathologic vasculopathy that results in PAH development and progression. Sotatercept is a first-in-class fusion protein that is believed to primarily inhibit activin signaling resulting in decreased cell proliferation and differentiation, though the exact mechanism remains uncertain. Here, we review the currently available PAH therapies, data highlighting the importance of transforming growth factor-β (TGF-β) superfamily signaling in the development of PAH, and the published and on-going clinical trials evaluating sotatercept in the treatment of PAH. We will also discuss preclinical data supporting the potential use of the fusion protein KER-012 in the inhibition of aberrant TGF-β superfamily signaling to ameliorate the obstructive vasculopathy of PAH.

Diagnosis and Management of Pulmonary Hypertension: New Insights.

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.

MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study.

MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation. The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks. The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH. 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg). In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect.

High relative humidity environment alleviates hypoxia-induced pulmonary arterial hypertension in mice

The environment has long been considered a crucial factor influencing the onset and progression of pulmonary diseases. Environmental therapy is also a practical treatment approach for many conditions. While research has explored the effects of factors like air pressure and oxygen concentration on pulmonary arterial hypertension (PAH), the impact of air humidity on PAH has not been investigated. In this study, we examined the role of different air humidity levels in a mouse model of PAH by controlling relative humidity. We induced PAH in mice using 10 % hypoxia, which led to significant thickening of the pulmonary vasculature, elevated right ventricular systolic pressure, and an increased right ventricular hypertrophy index (RVHI). However, when exposed to an environment with 80–95 % relative humidity, there was a marked reduction in the extent of pulmonary vascular remodeling, decreased vascular thickening, and lower RVHI, effectively preserving right heart function. Notably, changes in the Bmpr2/Tgf-β signaling pathway were significant and may play a pivotal role in this protective effect. In summary, our findings indicate that high relative humidity confers a protective effect on hypoxia-induced PAH in mice, providing novel insights into potential treatments for PAH.

Allosteric site identification, virtual screening and discovery of a sulfonamide Hsp110-STAT3 interaction inhibitor for the treatment of hypoxic pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disorder marked by vascular remodeling, which is linked to the malignant phenotypes of pulmonary vascular cells. The prevailing therapeutic approaches for PAH tend to neglect the potential role of vascular remodeling, leading to the clinical prognosis remains poor. Previously, we first demonstrated that heat shock protein (Hsp110) was significantly activated to boost Hsp110-STAT3 interaction, which resulted in abnormal proliferation and migration of human pulmonary arterial endothelial cells (HPAECs) under hypoxia. In the present study, we initially postulated the allosteric site of Hsp110, performed a virtual screening and biological evaluation studies to discover novel Hsp110-STAT3 interaction inhibitors. Here, we identified compound 29 (AN-329/43448068) as the effective inhibitor of HPAECs proliferation and the Hsp110-STAT3 association with good druggability. In vitro, 29 significantly impeded the chaperone function of Hsp110 and the malignant phenotypes of HPAECs. In vivo, 29 remarkably attenuated pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-induced PAH rats (i.g). Altogether, our data support the conclusion that it not only provides a novel lead compound but also presents a promising approach for subsequent inhibitor development targeting Hsp110-STAT3 interaction.

ORENITRAM’s decadal journey: unveiling safety profiles and adverse event through a real-world pharmacovigilance study of FAERS events

ABSTRACT Background ORENITRAM, an oral treprostinil formulation, was approved in 2013 for pulmonary arterial hypertension (PAH) treatment, necessitating ongoing safety monitoring. Research design and methods This retrospective analysis used FDA Adverse Event Reporting System data from Q4 2013 to Q4 2023, employing disproportionality analysis and the reporting odds ratio (ROR) to identify adverse events (AEs) linked with ORENITRAM. Results Out of 15,660,695 reports, ORENITRAM was the primary suspect in 10,125 cases. We identified 174 significant adverse events across 27 organ systems, with notable issues like pulmonary edema, ascites, and ventricular fibrillation. Females reported more AEs (75.6%) than males (24.0%), suggesting potential metabolic differences. AEs were most common within 30 days of starting treatment or after one year. Conclusions The study indicates significant safety issues with ORENITRAM, including serious unexpected events such as pulmonary edema, ascites, and ventricular fibrillation. These findings highlight the necessity for careful clinical monitoring and effective risk management, particularly with observed gender differences in AE profiles. The study’s retrospective nature and reliance on spontaneous reports may affect result generalizability.

Mechanisms underlying age-associated exacerbation of pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is a rare but severe form of pulmonary hypertension characterized by the obstruction of pulmonary arteries and veins, causing increased pulmonary artery pressure and leading to right ventricular (RV) heart failure. PVOD is often resistant to conventional pulmonary arterial hypertension (PAH) treatments and has a poor prognosis, with a median survival time of 2-3 years after diagnosis. We previously showed that the administration of a chemotherapy agent mitomycin C (MMC) in rats mediates PVOD through the activation of the eukaryotic initiation factor 2 (eIF2) kinase protein kinase R (PKR) and the integrated stress response (ISR), resulting in the impairment of vascular endothelial junctional structure and barrier function. Here, we demonstrate that aged rats over 1 year exhibit more severe vascular remodeling and RV hypertrophy than young adult rats following MMC treatment. This is attributed to an age-associated elevation of basal ISR activity and depletion of protein phosphatase 1, leading to prolonged eIF2 phosphorylation and sustained ISR activation. Pharmacological blockade of PKR or ISR mitigates PVOD phenotypes in both age groups, suggesting that targeting the PKR/ISR axis could be a potential therapeutic strategy for PVOD.

Upregulation of Angiomotin-Like 2 Ameliorates Experimental Pulmonary Arterial Hypertension by Inactivating YAP1 Signaling.

Angiomotin-like 2 (AMOTL2) is related to numerous physiological and pathological conditions by affecting signal transduction. However, whether AMOTL2 is linked to pulmonary arterial hypertension (PAH) has not been addressed. This work aimed to investigate the potential role of AMOTL2 in PAH. A decrease in AMOTL2 abundance was observed in the lungs of PAH rats. The upregulation of AMOTL2 significantly decreased right ventricle systolic pressure and right ventricular hypertrophy in PAH rats. Overexpression of AMOTL2 also led to a noteworthy decrease in vascular wall thickness, pulmonary artery area, and collagen deposition in rats with PAH. AMOTL2 was downregulated in hypoxia-stimulated pulmonary arterial smooth muscle cells (PASMCs). Moreover, AMOTL2 overexpression impeded hypoxia-evoked proliferation, migration, and phenotypic transformation in rat PASMCs. Mechanistic investigation revealed that Yes-associated protein 1 (YAP1) activation in PAH rats or hypoxia-stimulated PASMCs was markedly inhibited by AMOTL2 overexpression, which was associated with increased large tumor suppressor 1/2 phosphorylation. The inhibition of large tumor suppressor 1/2 reversed the AMOTL2-mediated inactivation of YAP1. Restoring the activity of YAP1 reversed the inhibitory effect of AMOTL2 on hypoxia-evoked proliferation, migration, and phenotypic transformation of PASMCs. Collectively, these results suggest that AMOTL2 can ameliorate PAH in a rat model by interfering with pulmonary arterial remodeling via the inactivation of YAP1 signaling. Our work indicates that AMOTL2 may be a candidate target for novel drug development for the treatment of PAH.

Pulmonary hypertension associated with lung diseases.

Pulmonary hypertension (PH) associated with chronic lung disease (CLD) is both common and underrecognised. The presence of PH in the setting of lung disease has been consistently shown to be associated with worse outcomes. Recent epidemiological studies have advanced understanding of the heterogeneity of this patient population and shown that defining both the specific type of CLD as well as the severity of PH (i.e. deeper phenotyping) is necessary to inform natural history and prognosis. A systematic diagnostic approach to screening and confirmation of suspected PH in CLD is recommended. Numerous uncontrolled studies and one phase 3 randomised, controlled trial have suggested a benefit in treating PH in some patients with CLD, specifically those with fibrotic interstitial lung disease (ILD). However, other studies in diseases such as COPD-PH showed adverse outcomes with some therapies. Given the expanding list of approved pharmacological treatments for pulmonary arterial hypertension, developing a treatment algorithm for specific phenotypes of CLD-PH is required. This article will summarise existing data in COPD, ILD and other chronic lung diseases, and provide recommendations for classification of CLD-PH and approach to the diagnosis and management of these challenging patients.

Современные подходы к лечению легочной артериальной гипертензии

Pulmonary arterial hypertension (PAH) is a rare, progressive, life-threatening disease that leads to the right ventricular heart failure and premature death. Available specific therapies act primarily as vasodilators and have a limited effect on the biological cause of the disease, that is, the uncontrolled proliferation of vascular endothelial and smooth muscle cells. Currently used drugs for the treatment of PAH, as well as potential drugs that are in various phases of clinical trials are reviewed in the article. The authors discuss also the issue of drug provision for patients with PAH.

Improvement of Bioavailability of Sildenafil Citrate Through Taste Masked Orodispersible Film for Pulmonary Hypertension Management.

The oral bioavailability of sildenafil citrate is approximately 43%, primarily limited by the low aqueous solubility and first-pass effect. Considering the drug properties and biopharmaceutical considerations, this study aimed to develop an immediate release, taste masked orodispersible film (ODF) of sildenafil citrate for the efficient management of pulmonary arterial hypertension (PAH). The optimization was done by applying 32 full-factorial design. The drug-loaded film was prepared and evaluated for the physical and mechanical parameters like; thickness, disintegration time, tensile strength, elongation, swelling index, content uniformity, disintegration and in vitro drug release in pH 6.2 stimulated salivary fluid. The FTIR and DSC data proved excellent compatibility between the drug and polymers used. The time taken for disintegration by the optimized film was about 62.66s, while the drug release was observed ~ 96% in 10min. Pharmacokinetic studies exhibited better sildenafil plasma level (p < 0.05) and Cmax (p < 0.001) of orally disintegrating film which is significantly higher than the oral drug solution. The AUC0-8 (24874.425 ± 1234.45ng. h/mL) in the oromucosal application was 1.2-fold more (p < 0.0001) than the control. The presence of sweetening and flavoring agents in the formulation masked the drug bitterness, resulting in a higher intake of the formulation in rats compared to the unmasked drug solution, as observed with in vivo taste masking studies. The importance of ODF as a feasible, effective, and optimal approach for delivering sildenafil citrate via oromucosal administration for the treatment of PAH was successfully highlighted by these results.

Discovery and Optimization of Hsp110 and sGC Dual-Target Regulators for the Treatment of Pulmonary Arterial Hypertension.

Currently, bifunctional agents with vasodilation and ameliorated vascular remodeling effects provide more advantages for the treatment of pulmonary arterial hypertension (PAH). In this study, we first screened the hit 1 with heat shock protein 110 (Hsp110) inhibition effect from our in-house compound library with soluble guanylate cyclase (sGC) activity. Subsequently, a series of novel bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced PAH rat models (i.g.). Notably, our study successfully demonstrated that the simultaneous regulation of Hsp110 and sGC dual targets was a novel and feasible strategy for PAH therapy, providing a promising lead compound for anti-PAH drug discovery.

Mechanisms and treatment of pulmonary arterial hypertension.

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.

Investigation of electrochemical behaviour and determination of Riociguat with bare GCE and molecularly imprinted polymer-based electrochemical sensor

Pulmonary Arterial Hypertension (PAH) causes death due to ventricular overload and heart failure. Calcium channel blockers, anticoagulants, digoxin and diuretics are the standards of care for PAH. Riociguat (RIO) is an oral soluble guanylate cyclase stimulator approved for the treatment of PAH by World Health Organization (WHO) Group 1 patients. In this study, the electrochemical behavior of RIO was investigated using a bare glassy carbon electrode (GCE). In addition, RIO was determined using GCE and a molecularly imprinted polymer (MIP)-based electrochemical sensor. The MIP-based electrochemical sensor was prepared by photopolymerization of methacrylic acid in the presence of a basic monomer, crosslinker, target molecule, and photoinitiator. The polymer film was characterised by a scanning electron microscope (SEM) and cyclic voltammetry (CV). Under the optimized conditions, the results obtained with GCE and MIP sensor were compared. The analytical performance of GCE and MIP-based electrochemical sensors was evaluated. The linear ranges of RIO were 1.0 × 10–6 – 1.0 × 10–4 M and 1.0 × 10–13 – 1.0 × 10–12 M, with a limit of detection (LOD) of 1.40 × 10–8 M and 2.12 × 10–14 by bare GCE and MIP-based electrochemical sensor using differential pulse voltammetry (DPV), respectively. The results show that the MIP sensor has higher sensitivity than the bare GCE. Both were applied to commercial human serum samples and pharmaceutical dosage forms. The recovery studies were performed, and the recovery% and RSD% results are within the acceptable range. Therefore, the GCE and MIP sensors have good selectivity, accuracy and precision.

Population pharmacokinetic modeling of sotatercept in healthy participants and patients with pulmonary arterial hypertension.

Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic (PopPK) model was developed using data from two phase 1 studies in healthy participants, and two phase 2 studiesand one phase 3 study in participants with PAH. The pooled sotatercept PK data encompassed single intravenous (IV) or subcutaneous (SC) doses ranging from 0.01 to 3.0 mg/kg, as well as multiple SC doses ranging from 0.03 to 1.0 mg/kg, with PK samples collected up to a maximum of ~150 weeks following Q3W and Q4W dosing regimens. The final PopPK analysis included 350 participants, with 30 and 320 participants receiving sotatercept IV and SC, respectively. A two-compartment model with a first-order absorption rate constant and a linear disposition from central compartment well-described sotatercept PK. The estimated bioavailability is ~66%; bioavailability, clearance (CL), and central volume (VC) have low to moderate inter-individual variability. Time-varying body weight and baseline albumin concentration were statistically significant predictors of PK; CL and VC were predicted to increase with increasing body weight, while CL was predicted to decrease with increasing baseline albumin concentration. However, the magnitude of covariate effects is not predicted to meaningfully alter the disposition of sotatercept. Altogether, the PopPK modeling results demonstrate favorable PK characteristics (low to moderate variability and typical bioavailability), supporting sotatercept as a SC biological agent for the treatment of patients with PAH.

New and Emerging Therapeutic Drugs for the Treatment of Pulmonary Arterial Hypertension: A Systematic Review.

Pulmonary arterial hypertension (PAH) is a serious, progressive, and potentially fatal lung disease characterized by a gradual increase in mean pulmonary arterial pressure to over 20 mmHg at rest. The pathogenesis of PAH is multifactorial. It involves dynamic obstruction of the pulmonary vasculature through vasoconstriction, structural obstruction due to adverse vascular remodeling, and pathological obstruction caused by vascular fibrosis and stiffening, which reduces compliance. PAH often presents with vague initial symptoms and is frequently diagnosed at an advanced stage. The increased pulmonary arterial pressure leads to vascular remodeling, eventually resulting in right ventricular hypertrophy and failure. PAH is a rare condition with a median life expectancy of three years, underscoring the need for effective treatment alternatives. Several FDA-approved therapeutic options are available, including prostacyclin analogs (epoprostenol, iloprost, and treprostinil), the non-prostanoid IP receptor agonist selexipag, selective endothelin receptor antagonists (ERA) (ambrisentan, bosentan, and macitentan), phosphodiesterase 5 inhibitors (sildenafil and tadalafil), and the soluble guanylate cyclase (sGC) stimulator riociguat. Despite these advancements, current medications do not provide a permanent cure. This study presents an overview of current and emerging PAH therapies through a systematic literature review. It involved an analysis of nine studies and a review of 800 papers from reputable journals published between 2013 and June 2023. The research focused on drug effects on the six-minute walk distance (6-MWD) and associated side effects in randomized controlled trials. The review found that while udenafil, imatinib, racecadotril, sotatercept, anastrozole, riociguat, tacrolimus, and ralinepag were evaluated, imatinib was notably associated with adverse side effects. Conversely, udenafil, racecadotril, sotatercept, anastrozole, riociguat, tacrolimus, and ralinepag were found to be safe, well-tolerated, and effective in improving hemodynamic measures and 6-MWDs. This study aims to summarize the developing treatment options currently under clinical trials, highlighting the need for further trials before their application in clinical practice.

Right ventricular stroke work index from echocardiography in patients with pulmonary arterial hypertension—the role in short-term follow-up assessment

Abstract Aims Right ventricular (RV) failure causes high mortality in patients with pulmonary arterial hypertension (PAH). RV stroke work index (RVSWi) poses as a potential predictor of outcome. We evaluated how RVSWi by echocardiography (ECHO) or right heart catheterization (RHC) is altered following PAH treatment and if RVSWi is an indicator of outcome in PAH. Methods and results Fifty-four patients with PAH performed ECHO and RHC (median, 0 days between examinations) at baseline and treatment follow-up. RVSWiRHC was computed as (mPAP-mRAP)×SViRHC, (mPAP, mean pulmonary arterial pressure; mRAP, mean right atrial pressure; SVi, stroke volume indexed to body surface area). ECHO-derived RVSWi was calculated as RVSWiECHO-Mean = TRmeanPG × SViECHO and RVSWiECHO-Max = TRmaxPG × SViECHO (TRmeanPG and TRmaxPG: tricuspid regurgitant mean and maximum pressure gradient). Invasive sPAP, mPAP, and pulmonary vascular resistance decreased and SVi increased from baseline to follow-up (P &amp;lt; 0.01 for all). RVSWiRHC and RVSWiECHO (Mean and Max) did not differ from baseline to follow-up (P &amp;gt; 0.05). Forty patients died during 109 ± 24 months. In univariate Cox proportional hazard analysis, age &amp;gt; 65 years, 6-minute-walk test &amp;lt; 160 m, WHO class III-IV and indexed right atrial volume were associated with long-term mortality, but none of the RVSWi methods. In multivariate analysis with clinical parameters, both RVSWiECHO methods were independently associated with mortality. Conclusion The RVSWi methods did not differ from baseline to short-term follow-up and were not associated with long-term outcomes in univariate analysis. However, baseline RVSWiECHO was associated with mortality when adjusting for clinical parameters.

Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study

BackgroundIn 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.MethodsPatients 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.ResultsOf 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).ConclusionIn 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.