Pulmonary Arterial Hypertension Therapy Research Articles

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).

Efficacy of specific drug class therapy in pulmonary arterial hypertension associated with HIV, portal hypertension or both: a single Center experience

Abstract Background Pulmonary arterial hypertension (PAH) is a rare complication of both HIV infection (HIV-PAH) and portal hypertension (Po-PAH); it can occur in patients with both diseases (HIV/Po-PAH). The use of the PAH-specific drug classes (prostanoids, endothelin-1 receptor antagonists [ERA] and phosphodiesterase-5 inhibitors [PDE5-i]) is largely justified by retrospective and observational case reports since, to date, there are no randomized clinical trials except for the PORTICO trial which demonstrated the efficacy of macitentan in Po-PAH. Purpose the aim of the study was to evaluate the efficacy of PAH-specific drugs, both monotherapy and dual oral upfront therapy (ERA + PDE5i started within 1 month apart), in patients with Po-PAH, HIV/Po-PAH and HIV-PAH. Methods Between 1998 and 2023 we enrolled patients with Po-PAH, HIV-PAH and HIV/Po-PAH referred to our Center and undergoing monotherapy with prostanoid, ERA and PDE5-I or dual upfront oral therapy. The efficacy of the drugs was assessed by comparing clinical parameters (NYHA functional class), exercise capacity (six-minute walking test) and hemodynamic parameters at baseline and after a treatment period of 3-6 months. The data are expressed as mean and standard deviation and were compared with Student's t-test for paired data. Results 128 patients were enrolled (83 Po-PAH, 23 HIV/Po-PAH and 22 HIV-PAH). 20 were treated with ERA monotherapy, 90 with PDE5-I, 13 with prostanoids and 5 treated with dual oral upfront therapy. Conclusions Prostanoids, ERAs and PDE5-Is, both in monotherapy and as dual upfront oral therapy, are associated with a significant improvement in functional class, exercise capacity and hemodynamic parameters. The effect of such drugs is similar to patients suffering from other forms of PAH.

Efficacy and tolerability of triple sequential combination therapies with selexipag in patients with pulmonary arterial hypertension: insights from a single-centre study

Abstract Background and aims In this single-centre study we aimed to evaluate the efficacy and tolerability of prostacyclin receptor agonist selexipag in patients with pulmonary arterial hypertension (PAH). Methods The study included 110 out of the 1071 patients enrolled in the Evaluation of Pulmonary Hypertension Risk factors Associated with Survival study (EUPHRATES) and treated with selexipag added on background dual PAH therapies. The ESC/ERS 2022, SPAHR, French Registry, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Results Age (mean+SD) was 43.4+16.5 years and 84.5 % of patients were female. The PAH was idiopatic, and was associated with congenital heart disease (CHD), connective tissue disease (CTD) and drug in 47.2 %, 46.4 %, 5.5 % and 1 %, respectively. Background dual therapies, functional class (FC) was II, III and IV in 20 %, 65 %, and 15 % of patients. Six-minute walk distance (6MWD) was 314 + 134 m and serum N-terminal-pro-brain natriuretic peptide (NT-proBNP) level was 882+1732 ng/l. Tricuspid annular planary excursion (TAPSE) and tissue velocity (St), right atrial area and pulmonary arterial diameter were 2.02+0.48 cm,12.4+2.8 cm/sec,21.4+7.2 cm2 and 3.54+0.77 cm, respectively. Invasively evaluated pulmonary arterial mean pressure was 60.2±19.9 mm Hg, and pulmonary vascular resistance was 12.3±10.8 Wood units. COMPERA 2.0 1st, 2nd, 3rd and 4th risk strata were noted in 15.5 %, 31.8 %, 2.7 % and 10 %, and French Registry strata 0,1,2 and 3 were documented in 70 %, 14.5 %, 11 %, and 4.5 %, respectively. The SPAHR and REVEAL Lite 2 scores were 1.9+0.5 and 5.9+2.6, respectively. Background combinations were as follows; macitentan+tadalafil in 46.6 %, macitentan+sildenafil in13.6 %, macitentan+ riociguat in 6.8 %, bosentan +tadalafil in 8.7 %, bosentan+sildenafil in 16.5 %, bosentan+riociguat in 1 %, ambrisentan +tadalafil in 1.9 %, and ambrisentan+sildenafil in 2.9 % of patients. Maximally tolerable selexipag doses (ug)were 1600 bid in 21%, 1400 bid in 5 %, 1200 bid in 11%, 1000 bid in 17%, 800 bid in 12%, 600 bid in 9%, 400 bid in 14%, and 200 bid in 11%.Median follow-up period was 527( 278-831) days, and discontiuation rates of selexipag was 13.6 %. Headache, jaw-pain, diarrhoea, nausea, vomiting and flushing were main side effects. The changes in FC, 6MWD, Nt-pro-BNP and echocardiographic measures were not significant. French Registry score (p<0.001) and COMPERA 2.0 score (p<0.001) showed improvements, but SPAHR and REVEAL lite 2 did not. However, other PAH cohort compared with IPAH showed more pronounced improvements in REVEAL lite 2 and SPAHR scores. Clinical worsening and mortality rates were 23.6 % and 10.9 %, respectively. Survival for 1, 3 and 5 years were 95.8 %, 95.8 and 83.7 % in IPAH, and 92.6 %, 84.1 % and 78.8 % in other PAH patients. Conclusion Our results seem to be consistent with efficacy and tolerability of selexipag-included combinations in patients with PAH.

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

The pregnant patient with pulmonary arterial hypertensionand her offspring in the current era. Time to take into account the vasoreactive profile

Abstract Background and aims Pregnancy impose physiological changes that may be difficult to accomplish for women with pulmonary arterial hypertension (PAH). This study evaluates the impact that pregnancy carries in a PAH population managed in a timely manner and whether patients responders to calcium channel blockers (CCB) deserve specific recommendations because of a different prognosis. Methods A retrospective, longitudinal cohort study. All PAH pregnant patients managed at our institution between February 2010 and December 2023 were included. Clinical characteristics at baseline were recorded. Mortality, major complications (maternal death and cardiogenic shock requiring mechanical circulatory support -MCS- or inotropes) and minor complications (hospital admissions for cardiac reason, PAH therapy uptitration and oxygen prescription) were evaluated over the pregnancy course. Long-term follow-up was also assessed. Gestational age, neonatal weight and complications in the new-born (invasive and non-invasive ventilation, inotropic support and neonatal death) were studied. Data were compared between vasoreactive and non-vasoreactive patients. Results 29 patients were studied (median age 31.5, 27-32.7). 8 underwent early termination of pregnancy and 21 decided to proceed. From the latter group, 7 were responders to CCB and none presented complications over the pregnancy course. From the remaining 14 non-respo nders who completed their pregnancy, 13 (92.9%) presented minor complications: 11 (79%) were started on the prostacyclin pathway, 5 (35.7%) required inotropic support, 5 (35.7%) oxygen prescription; and 5 (35.7%) experienced major complications: 2 (14.3%) required MCS, 5 (35.7%) inotropic support, and one patient died (7%). Over a median follow-up period of 5 years (1.2-8.5), 2 patients died from the non-responder cohort (1.4%); while no patient responder to CCB experienced complications; moreover, none lost her vasoreactive response. All the new-borns from non-vasoreactive patients were delivered prematurely; while those from vasoreactive patients reached week 37 in the 85,7% of the cases. One of the new-borns from the non-vasoreactive cohort died, and there was a non-significant trend towards a fewer rate of complications in the vasoreactive offspring (42.9 Vs. 84.6, p = 0.054). Conclusions In spite of the continuous advances in PAH management, pregnancy still associates high maternal and neonatal morbidity. Nevertheless, vasoreactive PAH patients presented a completely different maternal and neonatal prognosis which may prompt specific recommendations for this particular subgroupOutcomes by vasoreactivity profilePregnancy course for the 21 PAH patients

Pulmonary arterial hypertension: updates and perspective with newer therapies.

Pulmonary arterial hypertension (PAH) is a rare condition for which a remarkable change has been witnessed in the epidemiology, assessment and treatment landscape over the last three decades. Well-established registries from the Western world have not only highlighted the shift in the epidemiology to an older, more comorbid cohort but have also identified markers of prognosis that have been validated as part of risk stratification scores in multiple cohorts. The emphasis on early identification through a systematic assessment pathway and the option of upfront combination therapy with serial risk stratification assessment has laid the foundation for the standard of care and improved prognosis. This review provides an update on the assessment and newer therapies for PAH.

Macitentan and Tadalafil Combination Therapy in Incident and Prevalent Pulmonary Arterial Hypertension: Real-World Evidence from the OPUS/OrPHeUS Studies.

Historically, patients recently (≤6months) diagnosed with pulmonary arterial hypertension (PAH; incident) have had poorer survival than those with a longer (>6months) time from PAH diagnosis (prevalent). Despite guideline recommendations for initial combination therapy for most patients with PAH, many are initiated and maintained on monotherapy. Real-world evidence to evaluate the benefit of early combination treatment in newly-diagnosed patients is lacking. Patients with PAH initiating combination therapy with the endothelin receptor antagonist macitentan and the phosphodiesterase-5 inhibitor tadalafil (M+T) were identified from the combined dataset of the US, multicenter OPUS (prospective, observational drug registry; NCT02126943) and OrPHeUS (retrospective, medical chart review; NCT03197688) studies (2013-2020). Descriptive analyses were performed for the incident and prevalent cohorts, as well as the subcohort of incident patients who received M+T as first-line combination therapy (incident initial combination). In OPUS/OrPHeUS, 1336 patients with PAH received M+T during the observation period. For the incident [n=453 (33.9%)], incident initial combination [n=272 (20.4%)], and prevalent [n=837 (62.6%)] cohorts: median (Q1, Q3) M+T exposure was 14.2 (4.2, 27.5), 12.2 (3.2, 25.5), and 14.7 (4.5, 28.0) months. 12-month Kaplan-Meier estimates (95% confidence limits) for survival were 91.2% (87.7, 93.7), 88.5% (83.2, 92.2), and 92.9% (90.6, 94.6), for patients free from hospitalization were 59.4% (54.1, 64.4), 56.3% (49.1, 62.9), and 62.3% (58.5, 65.9), and for patients persisting on combination therapy were 68.6% (63.9, 72.8), 65.0% (58.8, 70.6) and 66.9% (63.5, 70.0). Adverse events (OPUS only) were reported in 77.8%, 80.2%, and 80.3% of patients, respectively, with no unexpected adverse events observed. Despite a historically worse prognosis, incident patients receiving M+T, including as initial combination therapy, had similar survival and hospitalization as prevalent patients. Safety profiles were similar across cohorts. Together, these data support the use of early combination therapy with macitentan and tadalafil.

Early Addition of Selexipag to Double Therapy for Pulmonary Arterial Hypertension

A subgroup analysis of a randomized clinical trial established the efficacy of selexipag plus background therapy (monotherapy or double oral therapy [DOT]) vs placebo plus background therapy and found that the addition of selexipag within 6 months had an added benefit. However, the timing of selexipag addition to DOT and the incremental benefit in clinical practice is not well studied. To compare triple oral therapy (TOT) consisting of selexipag, endothelin receptor antagonist (ERA), and phosphodiesterase type 5 inhibitor (PDE5i) vs DOT consisting of ERA and PDE5i. This comparative effectiveness study was conducted using data from the US Komodo claims database to emulate a randomized trial. Patients aged 18 years or older with pulmonary arterial hypertension (PAH) treated with ERA plus PDE5i with records from July 2015 through June 2022 were duplicated to TOT and DOT and artificially censored when observed treatment deviated from assigned treatment. Hypothetical randomization was emulated using inverse probability of treatment weighting, and the study accounted for censoring-induced selection bias using inverse probability of censoring weighting. A pooled logistic model estimated the per-protocol difference between treatment groups. Data were analyzed from November 2022 through July 2023. TOT (addition of selexipag within 3, 6, and 12 months of initiating DOT) vs DOT. Adjusted risk of all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression over a 2-year follow-up. A total of 2966 patients with PAH (mean [SD] age, 54.3 [14.0] years; 2125 female [71.6%]) met eligibility criteria. Adding selexipag within 6 months of ongoing DOT was associated with a reduction in risk for all-cause hospitalization (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94), PAH-related hospitalization (aHR, 0.81; 95% CI, 0.70-0.95), and PAH-related progression (aHR, 0.82; 95% CI, 0.70-0.95) vs DOT alone. There were no associations if selexipag was initiated within 12 months for all-cause hospitalization, PAH-related hospitalization, or PAH-related disease progression. The association remained with a greater decrease in risk for disease progression vs DOT for selexipag initiation within 3 months (aHR, 0.74; 95% CI, 0.61-0.90). This study found that early selexipag addition to ERA plus PDE5i was associated with a reduction in risk of hospitalization and disease progression. These findings suggest that delays in selexipag initiation likely contribute to suboptimal patient and health system outcomes.

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.

Long-term swimming exercise attenuates right ventricular hypertrophy via modulating meta-inflammation in monocrotaline-induced pulmonary hypertensive rats

Pulmonary arterial hypertension (PAH) is a complex disease characterized by elevated pulmonary vascular resistance, resulting in right ventricular (RV) hypertrophy and, eventually, failure, which remains the primary cause of mortality in PAH patients. While current PAH therapies primarily target vascular abnormalities, most fail to address RV dysfunction. Therefore, improving RV function is a critical treatment goal. Exercise has emerged as an effective intervention for PAH, but the specific impact of swimming exercise on this disease and its associated pathological changes has been less extensively studied. In this study, we investigated the effects of swimming training (60 min/day, 5 days/week for 4 weeks) on monocrotaline (MCT; 60 mg/kg, i. p.)-induced PAH in rats. Our findings demonstrate that swimming significantly attenuates RV hypertrophy and reduces mean pulmonary arterial pressure (MPAP), mitigating the detrimental effects of PAH. Furthermore, we observed structural remodeling in the right ventricle, including increased myocardial necrosis, collagen deposition, and fibrosis-related protein expression. Swimming exercise training was found to reduce these pathological changes, suggesting a protective effect on the right ventricle. Mechanistically, our study revealed the crucial role of meta-inflammation in PAH and the anti-PAH effects of exercise. Swimming training attenuated macrophage accumulation, reduced serum inflammatory cytokines, and improved systemic and RV insulin sensitivity, highlighting its potential to modulate meta-inflammatory processes. In summary, our study suggests that swimming training exerts a beneficial effect on RV function and hypertrophy in MCT-induced PAH rats by targeting meta-inflammation. These results underscore the potential value of exercise-based rehabilitation as a complementary therapy for PAH patients.

The spectrum of systemic sclerosis-associated pulmonary hypertension: Insights from the ASPIRE registry

There are limited data assessing the spectrum of systemic sclerosis-associated pulmonary hypertension (PH). Data for 912 systemic sclerosis patients assessed between 2000and 2020 were retrieved from the Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre (ASPIRE) registry and classified based on 2022 European Society of Cardiology/European Respiratory Society(ESC/ERS) guidelines and multimodality investigations. Reduction in pulmonary vascular resistance (PVR) diagnostic threshold to >2WU resulted in a 19% increase in precapillary PH diagnoses. Patients with PVR ≤2WU had superior survival to PVR >2-3WU which was similar to PVR >3-4WU. Survival in pulmonary arterial hypertension (PAH) was superior to PH associated with lung disease. However, patients with mild parenchymal disease on CT had similar characteristics and outcomes to patients without lung disease. Combined pre- and postcapillary PH had significantly poorer survival than isolated postcapillary PH. Patients with mean pulmonary arterial wedge pressure (PAWP) 13-15mmHg had similar haemodynamics and left atrial volumes to those with PAWP>15mmHg. Unclassified-PH had more frequently dilated left atria and higher PAWP than PAH. Although Unclassified-PH had a similar survival to No-PH, 36% were subsequently diagnosed with PAH or PH associated with left heart disease. The presence of 2-3 radiological signs of pulmonary veno-occlusive disease was noted in 7% of PAH patients and was associated with worse survival. Improvement in incremental shuttle walking distance of ≥30m following initiation of PAH therapy was associated with superior survival. PAH patients diagnosed after 2011 had greater use of combination therapy and superior survival. A number of systemic sclerosis PH phenotypes can be recognized and characterized using haemodynamics, lung function and multimodality imaging.

Clinical trial design, end-points, and emerging therapies in pulmonary arterial hypertension.

Clinical trials in pulmonary arterial hypertension (PAH) have led to the approval of several effective treatments that improve symptoms, exercise capacity and clinical outcomes. In phase 3 clinical trials, primary end-points must reflect how a patient "feels, functions or survives". In a rare disease like PAH, with an ever-growing number of treatment options and numerous candidate therapies being studied, future clinical trials are now faced with challenges related to sample size requirements, efficiency and demonstration of incremental benefit on traditional end-points in patients receiving background therapy with multiple drugs. Novel clinical trial end-points, innovative trial designs and statistical approaches and new technologies may be potential solutions to tackle the challenges facing future PAH trials, but these must be acceptable to patients and regulatory bodies while preserving methodological rigour. In this World Symposium on Pulmonary Hypertension task force article, we address emerging trial end-points and designs, biomarkers and surrogate end-point validation, the concept of disease modification, challenges and opportunities to address diversity and representativeness, and the use of new technologies such as artificial intelligence in PAH clinical trials.

MiR-30d Attenuates Pulmonary Arterial Hypertension via Targeting MTDH and PDE5A and Modulates the Beneficial Effect of Sildenafil.

Pulmonary arterial hypertension (PAH) is associated with aberrant pulmonary vascular smooth muscle cell (PASMC) function and vascular remodeling. MiR-30d plays an important role in the pathogenesis of several cardiovascular disorders. However, the function of miR-30d in PAH progression remained unknown. Our study shows that circulating miR-30d level is significantly reduced in the plasma from PAH patients. In miR-30d transgenic (TG) rats, overexpressing miR-30d attenuates monocrotaline (MCT)-induced pulmonary hypertension (PH) and pulmonary vascular remodeling. Increasing miR-30d also inhibits platelet-derived growth factor-bb (PDGF-bb)-induced proliferation and migration of human PASMC. Metadherin (MTDH) and phosphodiesterase 5A (PDE5A) are identified as direct target genes of miR-30d. Meanwhile, nuclear respiratory factor 1 (NRF1) acts as a positive upstream regulator of miR-30d. Using miR-30d knockout (KO) rats treated with sildenafil, a PDE5A inhibitor that is used in clinical PAH therapies, it is further found that suppressing miR-30d partially attenuates the beneficial effect of sildenafil against MCT-induced PH and vascular remodeling. The present study shows a protective effect of miR-30d against PAH and pulmonary vascular remodeling through targeting MTDH and PDE5A and reveals that miR-30d modulates the beneficial effect of sildenafil in treating PAH. MiR-30d should be a prospective target to treat PAH and pulmonary vascular remodeling.

Risk stratification and treatment goals in pulmonary arterial hypertension.

Risk stratification has gained an increasing role in predicting outcomes and guiding the treatment of patients with pulmonary arterial hypertension (PAH). The most predictive prognostic factors are three noninvasive parameters (World Health Organization functional class, 6-min walk distance and natriuretic peptides) that are included in all currently validated risk stratification tools. However, suffering from limitations mainly related to reduced specificity of PAH severity, these variables may not always be adequate in isolation for guiding individualised treatment decisions. Moreover, with effective combination treatment regimens and emerging PAH therapies, markers associated with pulmonary vascular remodelling are expected to become of increasing relevance in guiding the treatment of patients with PAH. While reaching a low mortality risk, assessed with a validated risk tool, remains an important treatment goal, preliminary data suggest that invasive haemodynamics and cardiac imaging may add incremental value in guiding treatment decisions.

Pulmonary hypertension associated with left heart disease.

Left heart disease (LHD) is the most common cause of pulmonary hypertension (PH), which may be classified further as isolated post-capillary (ipcPH) or combined post- and pre-capillary PH (cpcPH). The 7th World Symposium on Pulmonary Hypertension PH-LHD task force reviewed newly reported randomised clinical trials and contemplated novel opportunities for improving outcome. Results from major randomised clinical trials reinforced prior recommendations against the use of pulmonary arterial hypertension therapy in PH-LHD outside of clinical trials, and suggested possible harm. Greater focus on phenotyping was viewed as one general strategy by which to ultimately improve clinical outcomes. This is potentially achievable by individualising ipcPH versus cpcPH diagnosis for patients with pulmonary arterial wedge pressure within a diagnostic grey zone (12-18 mmHg), and through a newly developed PH-LHD staging system. In this model, PH accompanies LHD across four stages (A=at risk, B=structural heart disease, C=symptomatic heart disease, D=advanced), with each stage characterised by progression in clinical characteristics, haemodynamics and potential therapeutic strategies. Along these lines, the task force proposed disaggregating PH-LHD to emphasise specific subtypes for which PH prevalence, pathophysiology and treatment are unique. This includes re-interpreting mitral and aortic valve stenosis through a contemporary lens, and focusing on PH within the hypertrophic cardiomyopathy and amyloid cardiomyopathy clinical spectra. Furthermore, appreciating LHD in the profile of PH patients with chronic lung disease and chronic thromboembolic pulmonary disease is essential. However, engaging LHD patients in clinical research more broadly is likely to require novel methodologies such as pragmatic trials and may benefit from next-generation analytics to interpret results.

Influence of estrogen on right ventricular mitochondrial function in pulmonary hypertension

There is a female predominance in pulmonary arterial hypertension (PAH) with a ~4:1 female-to-male ratio. However, female PAH patients exhibit better right ventricular (RV) function and thus better survival than the males. The majority of the current PAH therapies target pulmonary vascular remodeling and/or vasoconstriction in the pulmonary vasculature. However, no therapies directly target the RV, partially because the underlying mechanisms of RV failure in PAH are not fully understood. Since the RV serves as the main determinant of mortality, clarifying the mechanism of RV failure and the associated sex differences in PAH may promote the development of novel therapeutic strategies. Numerous molecular abnormalities have been detected in RV in PAH, particularly due to the suppression of mitochondrial function, including the inhibition of glucose oxidation and a shift to uncoupled aerobic glycolysis (Warburg metabolism) and excessive mitochondrial fission. The mitochondrial suppression is associated with hypocontractility and increased apoptosis in RV cardiomyocytes, and the hyperproliferative, pro-fibrotic, and apoptosis-resistant phenotypes in RV fibroblasts in PAH. Mitochondria also serve as the site for sex steroid synthesis, and in turn, the sex steroids, particularly estradiol (E2), influence the mitochondria both indirectly and directly. It is not well understood how E2 affects mitochondrial function in RV in PAH. Hence, this review focuses on the key mitochondrial genes and proteins that are influenced by PAH, E2, and sex.

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.

Group 5 Pulmonary Hypertension: Multiple Systemic Diseases, Multiple Mechanisms of Pulmonary Hypertension, and Multiple Management Challenges

: Group 5 pulmonary hypertension (PH) with unclear and/or multifactorial mechanisms includes a wide variety of conditions associated with PH, and the mechanisms by which PH develops vary dramatically depending on the underlying condition. Indeed, in many group 5 conditions, such as sarcoidosis, multiple distinct drivers of PH are present concurrently in a single patient, with the predominant factor depending on the predisposing disease phenotype. For this reason, thorough diagnostic evaluation to most accurately phenotype every patient with group 5 PH is essential. Treatment of these patients should begin by fully characterizing and optimizing the management of their underlying disease, often in conjunction with disease experts. Initial targets of PH treatment include identifying and correcting factors that worsen PH, such as volume overload and hypoxemia, as well as a complete PH evaluation, searching for other undiagnosed causes of PH (e.g., congenital heart disease or chronic thromboembolic disease). Data to guide treatment with therapies specific to pulmonary arterial hypertension (PAH) are inadequate for any specific recommendations, and adverse effects in group 5 patients are common. If these therapies are considered, evaluation by a multidisciplinary team that includes a PH specialist is recommended. Factors in the selection of PAH therapies should include consideration of the dominant physiologic features of the underlying disease, the severity of hemodynamic and right ventricular abnormalities, the risk of adverse drug effects, and any known contraindications to PAH-specific medications based on the underlying condition. Vigilant monitoring following initiation of PAH-specific therapy is critical, as the clinical effects are hard to predict, and untoward events, such as uncovering pulmonary veno-occlusive disease, may occur. Collaborative care by a multidisciplinary team of experts is key to the management of this challenging patient population.

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.