Treatment Of Pulmonary Arterial Hypertension Research Articles

The Importance of Dose Escalation in the Treatment of Pulmonary Arterial Hypertension with Treprostinil

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.

Sotatercept: A New Era in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by proliferative remodeling and obliterative narrowing of the pulmonary vasculature. While outcomes have improved with existing treatments targeting 3 main pathways, there remains a critical need for novel therapies that address different and novel mechanisms of PAH. Sotatercept, recently Food and Drug Administration (FDA) approved, is a groundbreaking fusion protein that binds to activin and growth differentiation factors, rebalancing antiproliferative and pro-proliferative signals to reverse remodeling in both the pulmonary vasculature and the right ventricle. This review highlights current evidence exploring the safety and efficacy of sotatercept in the 2 landmark trials, phase 2 Pulmonary Arterial Hypertension and Sotatercept Trial and Research and phase 3 Sotatercept Treatment in Expansion of Long-term Learning and Assessment in PAH trial, which were instrumental in securing FDA approval for adult PAH patients with WHO functional class II or III symptoms already receiving background pulmonary hypertension therapy. Overall, sotatercept represents a landmark advancement in PAH treatment, offering hope for patients and the potential to delay or avoid lung transplantation. Importantly, this marks the beginning of an era of targeted therapies aimed at reverse remodeling in PAH while improving outcomes.

Consensus recommendations for diagnosis and management of pulmonary arterial hypertension patients in Egypt

Background The burden of pulmonary arterial hypertension (PAH) in Egypt is quite comparable to the global burden. Nonetheless, there is a lack of clear national guidance on the screening, treatment, and diagnosis of PAH in Egypt. This consensus aimed at summarizing and adapting to the updated guidelines for the diagnosis and treatment of PAH by combining available evidence from the Egyptian practice according to Egyptian experts’ opinions. Methods A three-step modified Delphi method was adopted to develop the present consensus, which consisted of two rounds of voting and in-between virtual meeting. Seven specialized experts from Egyptian PH expert referral centers were invited. Results The consensus provided 71 statements for the screening, diagnosis, and management of PAH, which considered the resources availability and the infrastructure of the healthcare system in Egypt. Besides, the experts highlighted several unmet medical needs pertaining to the diagnosis and management of PAH in Egypt. Conclusion There is a need to establish a national registry that covers all Egyptian PAH centers as well as standardized patients’ databases in these centers. This should be coupled with the development of screening algorithms tailored to the Egyptian setting. To develop such national screening algorithms, cost-effectiveness studies should be conducted in Egypt to better understand optimal screening frequency and the best use of algorithms. Concerning the management of PAH in Egypt, experts emphasized the role of real-world evidence in investigating the current treatment options for PAH in Egypt to improve the understanding of using these therapies in the real world. Likewise, educational programs and workshops should ensure effective physician–patient communication to promote greater patient satisfaction and higher adherence to medications.

Soluble guanylyl cyclase stimulators and activators: promising drugs for the treatment of hypertension?

Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD.The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand.In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and BP. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.

Effect of famotidine on outcomes in pulmonary arterial hypertension: A randomized controlled trial.

Adaptation of the right ventricle is a key determinant of outcomes in pulmonary arterial hypertension (PAH). Despite a compelling rationale to develop targeted therapies for the right ventricle in PAH, no such treatments exist. H2-receptor antagonism is a potential myocardial-focused paradigm in heart failure. Do H2-receptor antagonists improve outcomes in participants with PAH? We conducted a 24-week, single-center, 1:1 randomized, double-blind, placebo-controlled trial of the H2-receptor antagonist famotidine in patients with a diagnosis of PAH. The primary outcome was change in six-minute walk distance (6MWD) at 24 weeks. Secondary endpoints included B-type natriuretic peptide levels, NYHA functional class, right ventricular parameters, health-related quality of life, and escalation in PAH-focused care. From May 2019 to July 2023, 80 participants were randomized with 79 receiving study drug. There was no significant difference in the primary outcome of 6MWD at 24 weeks, with an increase of 4.7 meters seen in the placebo arm versus a decrease of 17.0 meters in the famotidine arm (p = 0.24). There were also no differences in secondary endpoints at 24 weeks. Study drug was well tolerated, and safety profiles were similar between arms. Adherence and study conduct was good overall. Participants with methamphetamine-associated PAH were similar in all aspects to the study participants more broadly. The results of this trial do not support the routine use of famotidine 20 mg daily as an adjunct therapy for the treatment of PAH. The REHAB-PH trial argues against the practice of avoiding participants with methamphetamine-associated PAH in randomized clinical trials of novel therapies. The trial was registered at clinicaltrials.gov (NCT03554291).

Phase 1 Studies to Assess Inhaled Seralutinib as a Perpetrator or a Victim of Drug-Drug Interactions in Healthy Participants.

Seralutinib, an inhaled, small-molecule tyrosine kinase inhibitor in clinical development for the treatment of pulmonary arterial hypertension (PAH), was evaluated for its potential as a perpetrator or victim of a metabolic and transporter-based drug-drug interactions in 2 phase 1 studies. In study 1, 24 participants received a cocktail of probe substrates: caffeine (CYP1A2), montelukast (CYP2C8), flurbiprofen (CYP2C9), midazolam (CYP3A), and pravastatin (OATP1B1/1B3), plus digoxin (P-gp) with or without seralutinib. In study 2, 19 participants received seralutinib with/without itraconazole, a strong CYP3A inhibitor, or fosaprepitant, a weak CYP3A inhibitor. Geometric least-squares mean ratios and 90% confidence intervals for maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) were obtained. Safety was monitored throughout the studies. All adverse events were mild or moderate in severity. Seralutinib coadministration increased AUC for midazolam 3.03-fold and caffeine 1.32-fold. The coadministration increased digoxin Cmax 1.28-fold. Seralutinib did not meaningfully alter Cmax and AUC for montelukast, flurbiprofen, or pravastatin. Fosaprepitant and itraconazole increased seralutinib AUC 1.08- and 1.84-fold, respectively. Seralutinib is a moderate CYP3A inhibitor and a weak CYP1A2 inhibitor; it slightly inhibits P-gp. Seralutinib exposure is minimally affected by a weak CYP3A inhibitor but is substantially increased by a strong CYP3A inhibitor.

Population Pharmacokinetic/Pharmacodynamic and Exposure-Response Modeling Analyses of Sotatercept in Healthy Participants and Patients with Pulmonary Arterial Hypertension.

Sotatercept is a breakthrough, first-in-class biologic, recently approved by the Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension (PAH). Exposure-response (E-R) analyses and pharmacokinetic/pharmacodynamic (PK/PD) modeling were performed for sotatercept after intravenous and subcutaneous (SC) administrations. Clinical endpoints included 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), and probability of N-terminal pro-B natriuretic peptide (NT-proBNP) concentrations < 300 pg/mL for efficacy, and hemoglobin (Hgb) for safety from two Phase 1 studies, two Phase 2 studies, and one Phase 3 study. E-R models using nonlinear mixed effect modeling approach were developed for 6MWD and PVR, while Cox proportional hazards model and semi-mechanistic PK/PD model were used for NT-proBNP and Hgb. Covariate analyses were conducted to identify significant predictors of variability for each of these clinical endpoints. Modeling results showed that increasing sotatercept average concentration (Cavg) at week 24 is associated with increased predicted 6MWD, increased probability of NT-proBNP concentration < 300 pg/mL, decreased predicted PVR, and increased Hgb which was clinically manageable. All these responses approached their corresponding plateaus at a Cavg range associated with the dose of 0.7 mg/kg Q3W SC. Statistically relevant covariates included age and iron supplementation which slightly increased Hgb-mediated effect for 6MWD, PAH disease duration, and baseline therapy infusion with prostacyclin for PVR, and WHO functional class for NT-proBNP. The magnitudes of the impact of these covariates are not clinically meaningful. Taken together, these results support an appropriate benefit-risk profile for the FDA-approved target dose for sotatercept of 0.7 mg/kg Q3W SC.

New approaches to the treatment of pulmonary arterial hypertension

New approaches to the treatment of pulmonary arterial hypertension

Hypoxia-Induced and Glucuronic Acid-Modified Extracellular Vesicles from Mesenchymal Stromal Cells Treat Pulmonary Arterial Hypertension by Improving Vascular Remodeling.

Achieving precise delivery of extracellular vesicles (EVs) to treat pulmonary arterial hypertension (PAH) remains challenging. Here, we propose a strategy using hypoxia-induced and glucuronic acid (GA)-modified mesenchymal stromal-cell-derived EVs (MSC-EVs) to enhance their functionalities and therapeutic targeting. The hypoxia-induced EVs (Hypo-EVs) exhibit enriched exosomal signatures and display heightened inhibition of the proliferation of pulmonary arterial smooth muscle cells (PASMCs) compared to normoxic EVs (Norm-EV). We then modify Hypo-EVs by incorporating GA into their outer membrane, targeting glucose transporter-1 overexpressed on PASMCs. Our studies show that GA-EVs significantly enhance the therapeutic efficacy, both in vitro and in vivo, through improved targeted delivery to diseased PASMCs for improving vascular remodeling. Additionally, we identify miR-5119 involved in the PAH-associated calcium signaling pathway as a key contributor to GA-EVs' superior effects. This work provides a promising strategy for PAH treatment and advances the clinical potential of MSC-EV-based therapies.

Discovery and Optimization of Dihydroquinolin-2(1H)-ones as Novel Highly Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension.

Phosphodiesterase 5 (PDE5) is a cGMP-specific hydrolytic enzyme and widely distributed in versatile tissues. PDE5 has been identified as a valid therapeutic target for treating erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, a hit-to-lead structural optimizations were performed on the PDE1 inhibitor 10c, leading to compound 14b possessing great potency against PDE5A (IC50 = 3 nM) with high selectivity over PDE1, PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11 by more than 1125-fold, and remarkable safety properties. Furthermore, oral administration of 14b (5.0 mg/kg) exerted much better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate (10.0 mg/kg) in a monocrotaline-induced PAH rat model. Overall, these results proposed a novel highly selective PDE5 inhibitor 14b which could serve as a potential candidate for treatment of PAH.

Therapeutic Resolution of Pulmonary Arterial Hypertension (PAH) Using Natural Products

Pulmonary arterial hypertension (PAH) is a progressive and rare condition characterised by the occlusion of pulmonary arterioles, with clinical manifestations resulting from the cross-sectional area reduction of the small pulmonary arteries. The disease is driven by a combination of factors including vasoconstriction, thrombosis, inflammation, proliferation, and the obstructive remodelling of the pulmonary artery walls. Heterozygous mutations in the type II bone morphogenetic protein receptor (BMPR2) underlie the majority of the inherited and familial forms of PAH. Current evidence indicates that in PAH, the BMPR2-mediated-signalling is diminished and the TGFβ signalling is heightened. Even when managed with current therapeutic approaches, the disease eventually results in increased pulmonary vascular resistance, right heart failure, and premature death. Natural products act as vascular disease treatment agents and have been used in clinical practice following compelling clinical trials. The rationale for the selection of natural compounds derives from their multi-targeted approach and synergistic effects. Although novel medicines licenced by the FDA (USA) between 1981 and 2010, constitute approximately 34% natural products or derivatives of natural products, their potentials for the treatment of PAH are not fully explored. The objective of this review is to emphasise the significance of natural products in the therapeutic resolution of PAH.

A new perspective on targeting pulmonary arterial hypertension: Programmed cell death pathways (Autophagy, Pyroptosis, Ferroptosis).

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by elevated pulmonary vascular resistance, progressive increases in pulmonary artery pressures, ultimately leading to right-sided heart failure, and potentially mortality. Pulmonary vascular remodeling is pivotal in PAH onset and progression. While targeted drug therapies have notably ameliorated PAH prognosis, current medications primarily focus on vascular vasodilation, with limited ability to reverse pulmonary vascular remodeling fundamentally, resulting in suboptimal patient prognoses. Cellular death in pulmonary vasculature, once thought to be confined to apoptosis and necrosis, has evolved with the identification of pyroptosis, autophagy, and ferroptosis, revealing their association with vascular injury in PAH. These novel forms of regulated cellular death impact reactive oxygen species (ROS) generation, calcium stress, and inflammatory cascades, leading to pulmonary vascular cell loss, exacerbating vascular injury, and mediating adverse remodeling, inflammation, immune anomalies, and current emerging mechanisms (such as endothelial-mesenchymal transition, abnormal energy metabolism, and epigenetic regulation) in the pathogenesis of PAH. This review comprehensively delineates the roles of autophagy, pyroptosis, and ferroptosis in PAH, elucidating recent advances in their involvement and regulation of vascular injury. It juxtaposes their distinct functions in PAH and discusses the interplay of these programmed cell deaths in pulmonary vascular injury, highlighting the benefits of combined targeted therapies in mitigating pulmonary arterial hypertension-induced vascular injury, providing novel insights into targeted treatments for pulmonary arterial hypertension.

Pathway to care, treatment and disease burden of pulmonary arterial hypertension: a real-world survey of physicians and patients in Latin America

ObjectivesTo investigate clinical characteristics, symptom profile, testing practices, treatment patterns and quality of life (QoL) among patients with pulmonary arterial hypertension (PAH) in Latin America.DesignData from the Adelphi Real World...

Population pharmacokinetics of selexipag for dose selection and confirmation in pediatric patients with pulmonary arterial hypertension.

Selexipag is an oral selective prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH) in adults. To date, no treatment targeting the prostacyclin pathway is approved for pediatric patients. Our goal is to identify a pediatric dose regimen that results in comparable exposures to selexipag and its active metabolite JNJ-68006861 as those shown to be efficacious in adult PAH patients. Extrapolation from the population pharmacokinetic (PK) model developed in adults (GRIPHON study; NCT01106014) resulted in the definition of three different pediatric body weight groups (≥9 to <25 kg, ≥25 to <50 kg, and ≥50 kg) with corresponding starting doses (100, 150, and 200 μg twice daily) and maximum allowed doses (800, 1200, and 1600 μg twice daily). The proposed pediatric dose regimen was subsequently tested in a clinical study (NCT03492177), including 63 pediatric PAH patients ≥2 to <18 years of age and a body weight range of 9.9-93.5 kg. The body weight-adjusted dose regimen for selexipag resulted in comparable systemic exposures to selexipag and its active metabolite in pediatric patients as previously observed in adult PAH patients. Updating the adult selexipag population PK model provided overall consistent parameters and confirmed that the PK characteristics of selexipag and its active metabolite were comparable between pediatric and adult patients. The presented selexipag dose regimen for pediatric PAH patients is considered appropriate for continuing the clinical evaluation of the safety and efficacy of selexipag in pediatric patients ≥2 years of age.

MicroRNA-637/661 ameliorate hypoxic-induced pulmonary arterial hypertension by targeting TRIM29 signaling pathway

The pathogenesis of pulmonary arterial hypertension (PAH) is closely linked to the abnormal proliferation of pulmonary artery smooth muscle cells. Studies have demonstrated that microRNAs play pivotal roles in the progression of pulmonary hypertension. We found that microRNA-637 (miR-637) and microRNA-661 (miR-661) are expressed at low levels in the serum of PAH patients. Moreover, the overexpression of miR-637 or miR-661 inhibited human pulmonary artery smooth muscle cell (HPASMC) proliferation and migration in hypoxic culture. Mechanistically, we overexpressed these two microRNAs in HPASMCs, and the RNA-sequencing (RNA-seq) results demonstrated that TRIM29 mRNA was suppressed, indicating that TRIM29 is a substrate. TRIM29 accumulates in the serum of patients with PAH and promotes cell proliferation and migration by activating AKT/mTOR signalling. In addition, overexpression of miR-637 or miR-661 reversed TRIM29-mediated HPASMC proliferation and migration. This study revealed that miR-637 and miR-661 are able to inhibit the proliferation ability of HPASMCs under hypoxic conditions through targeting TRIM29, suggesting that the microRNA-637/661/TRIM29 axis may act as a target for PAH treatment.

Abstract 4135357: Activation of prostaglandin E receptor 4 attenuates pulmonary vascular remodeling and pulmonary hypertension in monocrotaline-exposed rats via non-inflammatory pathway

Backgrounds: The prostacyclin pathway plays a pivotal role in the treatment of pulmonary arterial hypertension (PAH). Meanwhile, there is evidence that the expression of IP, the target of prostacyclin, is scant in PAH patients, whereas the prostaglandin E receptor 4 (EP 4 ) remains stable. EP 4 , similar to IP, exerts vasodilative effect via cAMP. In addition, an orally administrable selective EP 4 agonist, KAG-308, has shown to exert anti-inflammatory effect in patients with ulcerative colitis and the mouse with surgically induced osteoarthritis. However, the effect of KAG-308 on pulmonary vasculature of PAH remains unknown. Hypothesis: EP4 agonist ameliorates pulmonary vascular remodeling and pulmonary hypertension (PH). Methods and Results: We investigated the effects of KAG-308 on hemodynamics and pulmonary vascular remodeling in a monocrotaline (MCT)-exposed rat model of PH. Compared to normal rats, MCT-exposed rats had higher right ventricular systolic pressure (RVSP), total pulmonary vascular resistance index (TPRI) and RV hypertrophy, together with medial wall thickening and increased activation of nuclear factor kappa B (NFkB) and inflammatory cytokines in the lungs on day 21 after MCT injection. Chronic oral administration of KAG-308 (1 mg/kg, twice daily, by gavage, day 0 to 21) lowered RVSP (53.1 ± 9.3 vs 81.0±18.5 mmHg, p &lt;0.01), TPRI (112.0 ± 16.6 vs 161.4 ± 37.0 mmHg/mL/min/g, p &lt;0.05) and RV hypertrophy (0.47 ± 0.04 vs 0.57±0.10, p &lt;0.05). Elastica van Gieson staining showed attenuation of medical wall thickening. Furthermore, KAG-308 significantly reduced NFkB activation and inflammatory cytokines such as Il6 , Mcp1 and Il1b in the lungs. In addition, chronic KAG-308 administration didn’t alter the level of cAMP in the lung, suggesting that the reduction of TPRI wasn’t the results of vasodilation. Interestingly, in human pulmonary artery smooth muscle cells (PASMCs) stimulated by TNFα 10ng/ml, pretreatment with KAG-308 significantly upregulated mRNA level of Il6 (5.9±0.1vs 1.0±0.1, p &lt;0.05), whereas downregulated Ki67 (0.4±0.1 vs 1.0±0.2, p &lt;0.05), suggesting anti-proliferative effect via non-inflammatory pathway. Conclusions: KAG-308 ameliorated pulmonary vascular remodeling and PH in MCT-exposed rat, whereas it didn’t show anti-inflammatory effect but anti-proliferative effect in human PASMCs. Although EP 4 agonist KAG-308 could be a potential therapeutic agent for the treatment of PAH, the mechanism of anti-proliferation remains to be elucidated.

Integrating Network Pharmacology and Experimental Verification to Explore the Pharmacological Mechanisms of Cordycepin against Pulmonary Arterial Hypertension in Rats.

Pulmonary Arterial Hypertension (PAH) is a fatal disease with high morbidity and mortality. Cordycepin has anti-inflammatory, antioxidant and immune enhancing effects. However, the role of Cordycepin in the treatment of PAH and its mechanism is not clear. The Cordycepin structure and PAH-related gene targets were obtained from public databases. The KEGG and GO enrichment analysis of common targets was performed in DAVID. PPI networks were also mapped using the STRING platform. AutoDock Vina, AutoDockTools, ChemBio3D and Pymol tools were selected for molecular docking of key targets. The therapeutic effects of Cordycepin on PAH were observed in Monocrotaline (MCT)-induced PAH rats and platelet-derived growth factor BB (PDGFBB)-induced rat pulmonary artery smooth muscle cells (PASMCs). The right ventricular systolic pressure (RVSP) was detected. HE staining, Western Blot, Scratch assay, EDU and TUNEL assays were used, respectively. Through Network Pharmacology and molecular docking, the Cordycepin-PAH core genes were found to be TP53, AKT1, CASP3, BAX and BCL2L1. In MCT-induced PAH rats, the administration of Cordycepin significantly reduced RVSP, and inhibited pulmonary vascular remodeling. In PDGFBB-induced PASMCs, Cordycepin reduced the migration and proliferation of PASMCs and promoted apoptosis. After the Cordycepin treatment, the protein expressions of TP53, Cleaved CASP3 and BAX were significantly increased, while the protein expressions of p-AKT1 and BCL2L1 were significantly decreased in MCT-PAH rats and PDGFBB-induced PASMCs. This study identified that TP53, AKT1, CASP3, BAX, and BCL2L1 were the potential targets of Cordycepin against PAH by ameliorating pulmonary vascular remodeling, inhibiting the abnormal proliferation and migration of PASMCs and increasing apoptosis of PASMCs. which provided a new understanding of the pharmacological mechanisms of Cordycepin in the treatment of PAH.

Treatment with Oral or Inhaled Treprostinil in Patients with Pulmonary Arterial Hypertension and Cardiovascular Comorbidities

BackgroundAn increasing number of patients with pulmonary arterial hypertension (PAH) have cardiovascular comorbidities. However, the effects of comorbidities on responses to PAH treatment are not well understood. Research QuestionDo cardiovascular comorbidities in patients with PAH influence the efficacy and tolerability of inhaled or oral treprostinil? Study Design and MethodsAll patients from phase 3 studies TRIUMPH (N = 235) and FREEDOM-EV (N = 690) were included in this post hoc analysis and were classified as having 0, ≥1, or ≥2 cardiovascular comorbidities of interest based on patients’ medical histories. The mean difference in 6-minute walk distance (6MWD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to Week 12 was assessed for TRIUMPH and the risk and incidence of clinical worsening was assessed for patients in FREEDOM-EV. Adverse events (AEs) were summarized for each comorbidity grouping for TRIUMPH and FREEDOM-EV. ResultsIn TRIUMPH, there were 79, 156, and 88 patients with 0, ≥1, and ≥2 comorbidities, respectively. Patients on inhaled treprostinil had improvements in 6MWD, with numerically similar improvements for comorbidity subgroups (0: 26 m, P = 0.020; ≥1: 22 m, P = 0.006; ≥2: 21.6 m, P = 0.043). Significant reductions in NT-proBNP were also seen in all subgroups. In FREEDOM-EV, there were 375, 315, and 166 patients with 0, ≥1, and ≥2 comorbidities, respectively. Regardless of comorbidities, patients on oral treprostinil had a significantly reduced risk of clinical worsening compared with placebo (0: 36% reduction, P = 0.034; ≥1: 41% reduction, P = 0.014; ≥2: 45% reduction, P = 0.026). In TRIUMPH and FREEDOM-EV, AE profiles were typical for this class of medication regardless of the number of comorbidities. A sensitivity analysis using a subset of comorbidities confirmed the findings of our primary analysis. InterpretationThis post hoc analysis suggests that patients with PAH and cardiovascular comorbidities can benefit from combination therapy with inhaled or oral treprostinil.

Positioning Imatinib for Pulmonary Arterial Hypertension (PIPAH) study

Abstract Introduction Pulmonary arterial hypertension (PAH) is characterised by pre-capillary pulmonary vascular remodelling. Imatinib, a tyrosine kinase inhibitor, was the first treatment investigated in PAH patients with the primary aim of targeting vascular remodelling. A Phase 3 study showed that imatinib 400mg daily reduces pulmonary vascular resistance and increases exercise capacity but only 43% of patients continued the drug for 6 months. Concerns about safety prevented regulatory approval. Purpose To identify a safe and tolerated dose of oral Imatinib and evaluate efficacy in the dose range 100-400mg daily. Methods Oral Imatinib was added to the background therapy of 17 patients with PAH; prior intracranial haemorrhage was excluded by cross sectional imaging and none were receiving an anticoagulant. The first patient started on 100mg daily. The next 12 patients were recruited serially at a minimum of 4 week intervals and started on 200mg, 300mg or 400mg, according to a Bayesian adaptive design (Continuous Reassessment Method, CRM). Patients 14-17 were recruited as an extension cohort to better understand the safety and tolerability of the 100mg and 200mg doses. The primary endpoint was safety and tolerability at 4 weeks. Imatinib was continued for up to 24 weeks. Thirteen patients had implanted devices that provided remote daily measurements of cardiopulmonary haemodynamics and heart rate and rhythm and physical activity. Non-invasive measures of systemic blood pressure, weight and oxygen saturations were made remotely. We compared the time-haemodynamic response relationship with that produced by licensed treatments in a similar patient cohort. Results The recommended starting dose from the CRM was 200mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (P&amp;lt;0.01), increased cardiac output (P=0.08) and reduced total pulmonary resistance (TPR, P&amp;lt;0.001, Figure). There was a clear dose-TPR response relationship (r2=0.52, p&amp;lt;0.01). A reduction in TPR was evident within the first week and plateaued at 4-5 weeks. Withdrawal of Imatinib led to an increase to baseline in TPR over 4-5 weeks. This contrasts with a sharp fall in TPR with licensed therapy and rapid increase on treatment withdrawal. There was a small reduction in systemic vascular resistance (P&amp;lt;0.05) with Imatinib that reached plateau before TPR. Conclusions Oral Imatinib 200mg daily is well tolerated and effective as an add-on treatment in PAH. The time course of the initial haemodynamic response and the gradual return to baseline on withdrawal distinguishes Imatinib from licensed treatments and is supportive of a mechanism of action beyond reliance on vasodilation. Remote monitoring enables the safe evaluation of the withdrawal of an investigational drug in patients established on best medical therapy.Figure 1.

Real-world evidence on pulmonary arterial hypertension: interim analysis from the Italian observational study INSPECTIO

Abstract Background Pulmonary arterial hypertension (PAH) is a rare, progressive disease leading to right-sided heart failure. The interest in risk assessment based on non-invasive parameters is growing, and insights from clinical practice are needed in this regard. INSPECTIO is an Italian observational study aimed at filling this knowledge gap. The results of an interim analysis at month 12 are presented below. Purpose The primary objective was to assess the change from baseline to month 12 in the number of the non-invasive low-risk parameters among World Health Organization functional class, 6-minutes walking distance, Brain Natriuretic Peptide (BNP) or N-terminal proBNP. Secondary objectives are the evaluation of echocardiographic and haemodynamic parameters, and the proportion of patients in which the therapy was optimized according to the guidelines. Methods Prospective, multicentre study on PAH patients at low/intermediate mortality risk treated with macitentan and/or selexipag as part of the oral combination therapy. Results Among 177 patients who were enrolled in 29 centres, 148 patients [median age 63.0 years (Q1/Q3: 53.5/73.0), 76.4% females] completed the 12-month follow up and were considered for this analysis. The median time from PAH diagnosis was 22.6 months (4.9/60.1). Sixty-four (43.2%) patients had idiopathic PAH; 4 (2.7%) heritable; 80 (54.1%) associated with other diseases [58 (72.5%) connective tissue disease, 11 (13.8%) congenital heart disease corrected for at least one year, 5 (6.3%) portal hypertension, 5 (6.3%) human immunodeficiency virus infection, 1 (1.3%) drug and toxins]. At baseline, 45.9% patients and 28.4% were in double and triple oral combination therapy, respectively. Primary objective: at month 12, the number of noninvasive low-risk parameters increased in 43 (29.1%) patients and remained stable in 80 (54.1%) patients [mean change 0.16 (p=0.017)]. The values at baseline, at month 12 and the change from baseline for each noninvasive parameter are shown in Table 1. Mean right atrial (RA) area (end-systole) and tricuspid annular plane systolic excursion (TAPSE) remained unchanged while a reduction of systolic pulmonary artery pressure (sPAP) was observed. Regarding the haemodynamic parameters, the mean pulmonary arterial pressure decreased [median change -4.5, (p=0.0346)], while cardiac index, pulmonary vascular resistance, and RA pressure remained stable (Table 2). The number of patients on triple therapy increased from 42 to 51 (+21.4%). Conclusions This study confirms that a noninvasive low-risk profile can be achieved with current combination PAH therapy. The modest or absent changes in echocardiographic and hemodynamic parameters suggest that treatment of PAH in real world is yet to be improved; on the other hand, the optimization of therapy in a significant portion of patients can possibly account for the improvement or stabilization observed.Noninvasive parametersEcho and hemodynamic parameters