Treatment Of Pulmonary Arterial Hypertension Research Articles

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.

Design, synthesis and optimization of pyrazolo[3,4-b] pyridine derivatives as Hsp110-STAT3 interaction disruptors for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive and fatal cardiovascular disorder that is characterized by pulmonary vascular remodeling. Our previous results demonstrated that heat shock protein (Hsp110) was significantly activated to induce vascular remodeling by enhancing the Hsp110-STAT3 interaction. The development of inhibitors that disrupt this association represents a novel strategy for the treatment of PAH. This study is committed to finding new inhibitors targeting the Hsp110-STAT3 interaction based on the structure of the lead compound 2h. A fusion design principle was employed in conjunction with structural optimization in the identification of the compound 10b. In vitro data indicates that 10b exhibited greater potency in the inhibition of pulmonary vascular cells malignant phenotypes via impeding the chaperone function of Hsp110 and the Hsp110-STAT3 interaction. In hypoxia-induced PAH rats, administration of 10b significantly attenuated vascular remodeling and right ventricular hypertrophy by inhibiting the Hsp110-STAT3 association. In short, this work identified a novel and promising lead compound for the development of anti-PAH drugs targeting the Hsp110-STAT3 interaction.

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.

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

Perspectives on Sotatercept in Pulmonary Arterial Hypertension.

Sotatercept acts as a type IIA-Fc activin receptor, thereby scavenging free activin from its physiological membrane receptor. Through this type of action, sotaterpect leads to a rebalancing of the proliferation and antiproliferation pathways of pulmonary smooth muscle cells in response to bone morphogenic protein (BMP). Although sotatercept has been approved as the fourth pillar of therapy for group 1 pulmonary arterial hypertension (PAH) in the United States and Europe, several studies are ongoing to broaden the application of the drug to non-Group 1 PAH. We provide an overview of the clinical and preclinical evidence of targeting the activation pathway by sotatercept in the treatment of PAH. We also discuss other potential applications of sotatercept in the context of pulmonary hypertension other than PAH group 1.

Sotatercept: The First FDA-Approved Activin A Receptor IIA Inhibitor Used in the Management of Pulmonary Arterial Hypertension.

This report illustrates the Food and Drug Administration (FDA) approval of first-in-its-class activin A receptor IIA inhibitor, sotatercept (Winrevair™), for the treatment of pulmonary arterial hypertension (PAH). Sotatercept is used to increase exercise capacity, improve WHO functional class, and decrease the risk of clinical worsening events in adults with PAH. One phase 2 trial, one phase 3 trial, and an ongoing open-label extension study is described in detail within the current text. Sotatercept significantly improved the 6-min walk distance in patients with PAH after 24 weeks with a mean change increase of 40.1 meters in the experimental group versus 1.4 meters decrease in the placebo group. Epistaxis, telangiectasia, increased hemoglobin, hematocrit, red blood cell levels, and dizziness were adverse events more frequently observed in the sotatercept group than in the placebo group. Sotatercept has shown significant benefits in the reduction of pulmonary vascular resistance and N-terminal pro b-type natriuretic peptide in patients with PAH. However, more studies are needed to evaluate the reduction in mortality. Limitations in practice include high cost and unknown long-term effects.

CS585, a novel prostacyclin receptor agonist, demonstrates sustained efficacy in vivo in the prevention of thrombosis

Abstract Background Uncontrolled platelet activity resulting from cardiovascular disease can lead to occlusive thrombi, culminating in myocardial infarction or stroke. Despite major advances in anti-platelet therapeutics, many patients remain at risk. Although prostacyclin (IP) receptor agonists are currently used for the treatment of pulmonary arterial hypertension (PAH), activation of the IP receptor has been shown to decrease platelet reactivity. However, engaging the IP receptor as a therapeutic target was previously considered unviable due to the lack of a sustained effect of current IP agonists in the blood. The development of an IP agonist with sustained effects in the blood would represent a novel prevention strategy in targeting platelet hyperreactivity and thrombosis. Purpose Assess the stability profile of CS585, an IV and orally bioavailable IP agonist, compared to FDA-approved IP agonists iloprost and selexipag, with regards to sustained activity in vivo in the blood in limiting platelet activation and thrombosis. Methods Using ex vivo and in vivo mouse models, we assessed the timeframe of effect of CS585, iloprost and selexipag in blood. Blood was drawn from wild-type mice 24 hours following a single IV dose of CS585, iloprost or selexipag. Platelet adhesion and blood clotting were measured using perfusion flow chamber at arterial shear and total thrombus activation system (T-TAS), respectively. In vivo, platelets and fibrin were labelled 24 hours post IV or oral administration of CS585, iloprost or selexipag, and accumulation at the site of injury was measured using the cremaster arteriole injury thrombosis assay. Results Blood drawn from mice administered CS585 was observed to show a decrease in platelet adhesion and clot formation in the perfusion flow chamber and T-TAS assays. The effects of iloprost and selexipag are no longer observed at 24 hours post-administration. Administration of CS585 resulted in sustained inhibition of platelet accumulation and fibrin formation in the laser-induced cremaster arteriole thrombosis assay up to 18 hours post-administration. In mice administered iloprost, a decrease in thrombus formation was observed 10 minutes post-administration, but thrombus size returned to vehicle levels by 4 hours. Selexipag-dosed mice demonstrated inhibition of thrombus formation up to 4 hours, but effects were no longer observed at 18 hours. Conclusions CS585, a novel IP agonist, inhibits platelet activation and clot formation up to 24 hours post-administration. In both in vivo and ex vivo models, we demonstrate the sustained effects of CS585. In contrast, current FDA-approved IP agonists do not possess an effect profile sufficient to target the IP receptor in blood. By overcoming the sustainability challenge facing IP agonists, CS585 represents a novel approach to anti-platelet treatment of thrombotic diseases, which could include thrombosis, VTE, secondary prevention after MI and stroke, and PAH.

The safety and efficacy of treprostinil for the treatment of pulmonary arterial hypertension: a systematic review and meta-analysis of randomized controlled trials

Abstract Introduction Pulmonary arterial hypertension (PAH) is a severe and life-threatening condition characterized by increased pulmonary vascular resistance and elevated mean pulmonary artery pressure. Treprostinil, a prostacyclin analog, has vasodilatory and anti-remodeling effects on pulmonary arterial smooth muscle cells, indicating promising benefits in enhancing exercise capacity, improving hemodynamics, and reducing morbidity in patients with PAH. Aim The primary objective of this systematic review and Meta-analysis is to assess the efficacy and safety of Treprostinil in patients with PAH. Methods We systematically searched PubMed, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov from inception until July 2023. Randomized controlled trials comparing Treprostinil with Placebo were selected. We used the mean values to compare continuous data and odds ratio (OR) for dichotomous outcomes with their 95% confidence interval (CI). Results We included 7 studies with a total of 2,447 patients. The Treprostinil group was favored over the control group in terms of 6-minute walk distance (6MWD) (Mean difference (MD), meters (m)) (MD = 15.16 m, 95% confidence interval (CI) (10.42 – 19.90 )). Subgroup analysis based on the route of administration revealed a 6MWD of (MD = 13.55 m (95% CI (7.82 – 19.28)) for oral administration and (MD = 17.49 m, 95% CI (6.01 – 28.89)) for intravenous (IV)/subcutaneous (SC) administration, indicating enhanced exercise capacity. When evaluating the efficacy of Treprostinil for oral administration, there was a slight but non-significant trend toward functional improvement (Odds Ratio (OR): 1.36; 95% CI: 0.95 to 1.93) and no significant change in maintaining functional status (OR: 0.94; 95% CI: 0.59 to 1.51). In terms of functional deterioration, the risk was also not significantly reduced (OR: 0.84; 95% CI: 0.36 to 1.98). Safety assessment of the drug was based on clinical, mortality, and adverse events outcomes. Clinically, Treprostinil demonstrated a protective effect against disease progression, evidenced by a reduced risk of clinical worsening (OR: 0.69; 95% CI: 0.52 to 0.91). Mortality rates were not significantly impacted by Treprostinil addition (OR: 0.95; 95% CI: 0.57 to 1.58 for oral, 0.80; 95% CI: 0.32 to 1.98 for IV/SC). However, the incidence of adverse events was notably higher among Treprostinil-treated patients, particularly with oral administration. Conclusion The addition of Treprostinil therapy for patients with PAH significantly improved exercise capacity, as evidenced by an increase in the 6MWD compared to control groups and demonstrated a reduced risk of clinical worsening. The incidence of adverse events was higher among Treprostinil-treated patients, especially with oral administration, potentially impacting quality of life.Forest plot of the 6MWD

Prognostic value of follow-up hemodynamics after initial treatment in pulmonary arterial hypertension

Abstract Background Hemodynamic variables such as right atrial pressure (RAP), cardiac index (CI) and mixed venous oxygen saturation (SvO2) have consistently been associated with survival in pulmonary arterial hypertension (PAH). The prognostic importance of hemodynamics after treatment initiation seems to be superior to baseline evaluation and stroke volume index (SVI) emerged as an independent prognostic parameter. New PAH treatments are, however, able to improve exercise capacity without increasing CI or SVI. Purpose The aim of this work was to define the prognostic role of follow-up hemodynamic parameters in a population of patients with idiopathic, hereditary, drug-induced PAH (I/H/D-PAH) and PAH associated with connective tissue disease (CTD-PAH) and congenital heart disease (CHD-PAH). Methods Treatment naïve PAH patients were assessed at baseline and at 1st follow-up (3-4 months after starting PAH-specific therapy; 1st F-UP) with 6-minute walk distance (6MWD), World Health Organization functional class (WHO-FC) and right heart catheterization (RHC). Collected hemodynamic parameters were: RAP, systolic, diastolic and mean pulmonary artery pressure (s/d/mPAP), CI, SVI, SvO2, pulmonary vascular resistance (PVR), pulmonary arterial compliance (PAC), cardiac efficiency (CE), pulmonary arterial elastance (Ea), resistance–compliance product (RC), right ventricular (RV) power, and RV stroke work index (RVSWI). The primary outcome was all cause death. We used stepwise Cox regression to assess variables obtained at baseline and at 1st F-UP. Results 794 patients with PAH were enrolled (54% I/H/D, 28% CTD, 18% CHD). A primary outcome occurred in 54% of patients over a median follow-up duration of 5.8 (2.4–11) years. In a multivariable model considering only baseline variables, no hemodynamic variables independently predicted prognosis but RAP. At first follow-up RHC (n=706), WHO-FC, 6-minute walk distance, RAP, and Ea were independently associated with death, adjusted for age, gender, and etiology of PAH. Because hemodynamic variables were highly correlated, we compared multivariable Cox regression models adding only variables with a correlation coefficient &amp;lt;0.6. In these models, RAP, Ea, PAC, CE, PVR, SvO2, CI, and SVI at follow-up RHC were independent predictors of death (Table). Conclusions Ea and right atrial pressure were the hemodynamic variables independently associated with death at 1st F-UP RHC after initial PAH treatment. These findings suggest that beyond improving RV function, RV afterload reduction can be considered a further treatment target.Table

Colchicine as a therapeutic option for the treatment of pulmonary arterial hypertension (PAH) in a rat model

Abstract Introduction Pulmonary arterial hypertension (PAH) is a cardiovascular disease that is characterized by severe structural and functional damages, resulting from the obstructive remodeling of the pulmonary vasculature and consequent right ventricular pressure overload. The current therapy mainly focuses on the pulmonary vascular system, with uncertain efficacy. Therefore, it is crucial to explore new therapeutic approaches. The mechanism of colchicine is complex and not-fully understood, but it has been proven to exert cardiopulmonary protective effects. Methods PAH induction was carried out in 8-week-old male WKY rats with a single subcutaneous injection of 60 mg/kg monocrotaline. Monocrotaline, a pyrrolizidine alkaloid, is metabolized in liver and induces inflammatory processes, which can cause PAH in rats. Starting from day 14 after MCT injection, the animals received three times a week intraperitoneal colchicine treatment at a dose of 0.5 mg/kg for two weeks. Echocardiographic examinations were performed during the study. At the end of the study, besides histological examination of the right ventricles and lungs [arterial wall thickness (WT%) and area (WA%)], the expression and phosphorylation levels of the proteins involved in cardiac remodeling were evaluated using Western blot. We assessed the pyruvate dehydrogenase (PDH) enzyme activity in the heart, which plays an important role in energy metabolism. We also examined the production of cytokines and chemokines in the right ventricle. Results The VW/BW ratio in the colchicine-treated group was significantly reduced compared to the MCT group (p&amp;lt;0.01). Echocardiographic parameters, EF% and E/e' ratio – characterizing the left ventricular function – did not differ considerably between the groups during the treatment. The TAPSE and PAT values characterizing right ventricular function improved in the MCT+C group (p&amp;lt;0.05). Collagen deposition and TGFβ level were significantly reduced by colchicine (p&amp;lt;0.05) in PAH animals. In the MCT+C group, the vascular remodeling (WT% and WA%) significantly decreased compared to the MCT group (p&amp;lt;0.01). The expression of α-SMA in vessel walls was most pronounced in the MCT group (p&amp;lt;0.01), which was significantly reduced by colchicine treatment. The phosphorylation of prosurvival signaling factors (ERK1/2, Akt1, GSK3β) was significantly increased in the MCT+C group (p&amp;lt;0.01) compared to the MCT group. In the right ventricle, PDH enzyme activity increased in the MCT+C group compared to the MCT group (p&amp;lt;0.01). According to cytokine array, cytokines involved in mediating fibrosis and inflammatory processes (TIMP-1, VEGF, L-selectin, CXCL7) showed increased secretion in the MCT group, which was moderately attenuated by colchicine treatment. Conclusion Colchicine treatment reduced the extent of fibrosis and inflammation, improved the structure of the pulmonary vasculature, and enhanced right ventricular function and energy supply.

Dual prostacyclin infusions: A case report of a patient symptom-driven transition from high-dose intravenous epoprostenol to subcutaneous treprostinil for the treatment of pulmonary arterial hypertension.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. A case of successful transition from high-dose epoprostenol to high-dose subcutaneous treprostinil for treatment of pulmonary arterial hypertension (PAH) is reported. PAH is a chronically progressive disease characterized by pulmonary artery luminal narrowing that causes increased pulmonary artery pressures leading to right ventricular failure. Parenteral prostacyclin analogues, such as epoprostenol and treprostinil, are direct vasodilators and are cornerstones of therapy for patients with severe disease that have been proven to reduce mortality and increase exercise tolerance. These agents must be administered continuously via intravenous or subcutaneous devices and are high-risk medications due to their potent vasodilatory actions. Chronic use of these medications requires constant attention from both providers and patients because of potential complications including central venous catheter infection, thromboembolism, therapy interruptions, and other undesirable consequences. This case report describes management of a 35-year-old male patient on high-dose outpatient intravenous epoprostenol (101ng/kg/min; dosing weight, 47kg) for treatment of PAH who was admitted to the hospital with a malfunctioning central venous catheter. Surrounding manipulation of the central catheter, the patient experienced an ischemic stroke that led to cognitive disability resulting in a lack of ability to manage his previously used home infusion device. The patient was successfully transitioned from intravenous epoprostenol to subcutaneous treprostinil (discharge dose, 200ng/kg/min) over 5 days by infusing both medications simultaneously and adjusting doses based upon patient-reported symptoms. This successful transition from high-dose epoprostenol to high-dose subcutaneous treprostinil demonstrates the importance in considering patient-specific factors during high-risk medication transitions, the value of a patient-directed flexible prostacyclin transition plan, and the benefit of institutional training and education in ensuring the safe use of parenteral prostacyclin analogues.

Metabolism and disposition of zamicastat in rats

The metabolism and disposition of zamicastat, a reversible dopamine β-hydroxylase (DβH) inhibitor, developed for treatment of Pulmonary Arterial Hypertension (PAH), were investigated in rats after oral and intravenous administration of [14C]-zamicastat. Zamicastat was rapidly absorbed and widely distributed to peripheral tissues, with total radioactivity almost completely recovered 168 h post-dose. Its main route of excretion was via faeces, whilst urine and expired air had minor roles. Maximum plasma concentration of zamicastat-related radioactivity occurred in the first hours, remaining quantifiable up to 144 h. The unchanged zamicastat plasma peak was 2 h post-dose and declined to low levels over 24 h. Zamicastat metabolism occurs largely during the first 8 h with only one metabolite identified in the latest time-point (96 h), the isocyanic acid/thiocyanic acid (tautomeric forms). Zamicastat metabolic pathway involved multiple reactions comprising desulphurisation, oxidative desulphurisation, N-debenzylation followed by further oxidation or N-acetylation, and the unexpected multistep metabolic pathway leading to isocyanic acid/thiocyanic acid.

A new day has come: Sotatercept for the treatment of pulmonary arterial hypertension

Despite increasing therapeutic options and evolving treatment strategies, including targeting three 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.

Nanoparticle delivery of VEGF and SDF-1α as an approach for treatment of pulmonary arterial hypertension.

Endothelial dysfunction is an underlying mechanism for the development of pulmonary arterial hypertension (PAH). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF) may help repair the dysfunctional endothelium and provide treatment for PAH. To examine this possibility, nanoparticles carrying human recombinant VEGF and SDF (VEGFNP and SDFNP) were aerosolized into the lungs of nude rats at Day 14 after monocrotaline (MCT) injection and analyses were performed at Day 28. The data show that the VEGFNP/SDFNP delivery led to a lower pulmonary arterial pressure and prevented right ventricular hypertrophy in the MCT rats: the right ventricular systolic pressure of the control, MCT, and MCT + VEGFNP/SDFNP treatment groups were 29±2, 70±9, and 44±5 (mean±SD) mmHg, respectively; the pulmonary vascular resistance indices of the groups were 0.6±0.3, 3.2±0.7, and 1.7±0.5, respectively; and the Fulton indices [-RV/(LV + Septum)] were 0.22±0.01, 0.44±0.07, and 0.23±0.02, respectively. The VEGFNP/SDFNP delivery delayed the thickening of distal pulmonary vessels: the number of nearly occluded vessels in a whole lung section from the MCT and MCT + VEGFNP/SDFNP groups were 46±12 and 2±3, respectively. Gene expression analysis of the endothelial cell markers, VE-cadherin, KDR, BMPR2, and eNOS, and smooth cell markers, SM-MHC and α-SMA, indicated significant loss of distal pulmonary vessels in the MCT- treated rats. VEGFNP/SDFNP delivery did not recover the loss, but significantly increased eNOS and decreased α-SMA expression in the MCT-treated lungs. Thus, the therapeutic effect of VEGFNP/SDFNP may be mediated by improving/repairing endothelial function in the PAH lungs.

A Single Center Experience of Pulmonary Arterial Hypertension Management in Korea: A 25-Year Comparative Analysis Following the Introduction of Targeted Therapy.

The transformation of pulmonary arterial hypertension (PAH) treatment in Korea, ushered by targeted therapy's advent, prompted our analysis of baseline attributes, treatment trends, and survival shifts within our single-center registry. We examined 230 patients (72.6% female, mean age 40.6±17.4 years) diagnosed and/or treated between 1980 and 2021 in our PAH clinic. Given targeted therapy's introduction and active use since 2007, we compared diagnostic classification, demographics, and treatment patterns at that juncture. Survival analysis encompassed PAH types and the overall population. For historical survival comparison, 50 non-registry patients were retrospectively added, and age-sex matching enabled pooled analysis. Congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH) constituted the largest subset (43.0%), trailed by connective tissue disease-associated PAH (CTD-PAH, 29.6%) and idiopathic PAH (IPAH, 19.1%). Post-2007, CTD-PAH proportions surged, notably with an elevated initiation rate of targeted therapy (95.4%). Overall survival rates at 1, 5, and 10 years stood at 91.3%, 77.4%, and 65.8%, respectively, with CHD-PAH exhibiting superior survival to idiopathic or CTD-PAH. Age-sex matching analysis indicated survival disparities between those starting immediate targeted therapy vs. conservative treatment upon diagnosis, especially driven by IPAH. In the post-introduction of the targeted therapy era, patients with PAH promptly started treatment right away, and higher survival rates of patients who started initial PAH-targeted therapy were demonstrated. The transition towards early treatment initiation might have likely contributed to the elevated survival rates observed in Korea's PAH patient cohort.

Current Overview of the Biology and Pharmacology in Sugen/Hypoxia-Induced Pulmonary Hypertension in Rats.

The Sugen 5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) demonstrates most of the distinguishing features of PAH in humans, including increased wall thickness and obstruction of the small pulmonary arteries along with plexiform lesion formation. Recently, significant advancement has been made describing the epidemiology, genomics, biochemistry, physiology, and pharmacology in Su/Hx challenge in rats. For example, there are differences in the overall reactivity to Su/Hx challenge in different rat strains and only female rats respond to estrogen treatments. These conditions are also encountered in human subjects with PAH. Also, there is a good translation in both the biochemical and metabolic pathways in the pulmonary vasculature and right heart between Su/Hx rats and humans, particularly during the transition from the adaptive to the nonadaptive phase of right heart failure. Noninvasive techniques such as echocardiography and magnetic resonance imaging have recently been used to evaluate the progression of the pulmonary vascular and cardiac hemodynamics, which are important parameters to monitor the efficacy of drug treatment over time. From a pharmacological perspective, most of the compounds approved clinically for the treatment of PAH are efficacious in Su/Hx rats. Several compounds that show efficacy in Su/Hx rats have advanced into phase II/phase III studies in humans with positive results. Results from these drug trials, if successful, will provide additional treatment options for patients with PAH and will also further validate the excellent translation that currently exists between Su/Hx rats and the human PAH condition.