Pulmonary Arterial Hypertension Therapy Research Articles

Removing the FDA's Boxed Hepatotoxicity Warning and Liver Function Testing Requirement for Ambrisentan.

Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed. To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS. This serial cross-sectional study used data from 3 longitudinal health care insurance claims databases-Medicaid, Optum's deidentified Clinformatics Data Mart, and Merative Marketscan-to perform an interrupted time series analysis of prescription fills and LFTs for patients taking ambrisentan and bosentan. Participants were patients filling prescriptions for ambrisentan and bosentan from July 1, 2007, to December 31, 2018. Data analysis was performed from April 2021 to August 2023. Removal of the boxed warning for hepatotoxicity and the REMS LFT monitoring requirements on ambrisentan in March 2011. The primary outcomes were use of ambrisentan (ie, individuals with at least 1 dispensing per 1 000 000 individuals enrolled in the 3 datasets) vs bosentan and LFT monitoring (ie, proportion of initiators with at least 1 ordered test) before initiation and before the first refill. A total of 10 261 patients received a prescription for ambrisentan during the study period (7442 women [72.5%]; mean [SD] age, 52.6 [17.6] years), and 11 159 patients received a prescription for bosentan (7931 women [71.1%]; mean [SD] age, 47.7 [23.7] years). Removal of the ambrisentan boxed hepatotoxicity warning and LFT monitoring requirement was associated with an immediate increase in the use of ambrisentan (1.50 patients per million enrollees; 95% CI, 1.08 to 1.92 patients per million enrollees) but no significant change in the use of bosentan. There were reductions in recorded LFTs before drug initiation (13.1% absolute decrease; 95% CI, -18.2% to -8.0%) and before the first refill (26.4% absolute decrease; 95% CI, -34.4% to -18.5%) of ambrisentan but not bosentan. In this serial cross-sectional study of ambrisentan, labeling changes and removal of the REMS-related LFT requirement were associated with shifts in prescribing and testing behavior for ambrisentan but not bosentan. Further clinician education may be needed to maximize the benefits of REMS programs and labeling warnings designed to ensure the safe administration of high-risk medications.

US commercial health plan coverage dynamics in pulmonary arterial hypertension therapies.

Health plan coverage is central to patient access to care, especially for rare, chronic diseases. For specialty drugs, coverage varies, resulting in barriers to access. Pulmonary arterial hypertension (PAH) is a rare, progressive, and fatal disease. Guidelines suggest starting or rapidly escalating to combination therapy with drugs of differing classes (phosphodiesterase 5 inhibitors [PDE5is], soluble guanylate cyclase stimulators [sGC stimulators], endothelin receptor antagonists [ERAs], and prostacyclin pathway agents [PPAs]). To assess the variation in commercial health plan coverage for PAH treatments and how coverage has evolved. To examine the frequency of coverage updates and evidence cited in plan policies. We used the Tufts Medical Center Specialty Drug Evidence and Coverage database, which includes publicly available specialty drug coverage policies. Overall, and at the drug and treatment class level, we identified plan-imposed coverage restrictions beyond the drug's US Food and Drug Administration label, including step therapy protocols, clinical restrictions (eg, disease severity), and prescriber specialty requirements. We analyzed variation in coverage restrictiveness and how coverage has changed over time. We determined how often plans update their policies. Finally, we categorized the cited evidence into 6 different types. Results reflected plan coverage policies for 13 PAH drugs active between August 2017 and August 2022 and issued by 17 large US commercial health plans, representing 70% of covered lives. Coverage restrictions varied mainly by step therapy protocols and prescriber restrictions. Seven plans had step therapy protocols for most drugs, 9 for at least one drug, and 1 had none. Ten plans required specialist (cardiologist or pulmonologist) prescribing for at least one drug, and 7 did not. Coverage restrictions increased over time: the proportion of policies with at least 1 restriction increased from 38% to 73%, and the proportion with step therapy protocols increased from 29% to 46%, with generics as the most common step. The proportion of policies with step therapy protocols increased for every therapy class with generic availability: 18% to 59% for ERAs, 33% to 77% for PDE5is, and 33% to 43% for PPAs. The proportion of policies with prescriber requirements increased from 24% to 48%. Plans updated their policies 58% of the time annually and most often cited the 2019 CHEST clinical guidelines, followed by randomized controlled trials. Plan use of coverage restrictions for PAH therapies increased over time and varied across both drugs and plans. Inconsistency among health plans may complicate patient access and reduce the proportion who can persist on PAH treatments.

Comparative Effectiveness of Sotatercept and Approved Add-On Pulmonary Arterial Hypertension Therapies: A Systematic Review and Network Meta-Analysis.

There are no direct comparisons of sotatercept to add-on therapies approved for PAH. This study aimed to compare the efficacy and safety of add-on sotatercept versus other add-on therapies using a network meta-analysis. We searched MEDLINE, Embase, the Cochrane CENTRAL, and Clinicaltrials.gov until April 15, 2023, for randomized trials involving PAH patients treated with add-on sotatercept or add-on other PAH therapies. Data extraction and risk of bias assessments were performed independently and in duplicate using the Cochrane RoB 2.0 tool. We performed frequentist random-effects network meta-analysis using the restricted maximum likelihood (REML) estimator and assessed the certainty of evidence using the GRADE approach. Our search found 18 trials (5777 patients) eligible for analysis. Sotatercept reduces clinical worsening as compared to placebo (RR 0.21 [95% CI 0.11 to 0.41]; high certainty). Sotatercept probably reduces clinical worsening more compared to add-on ERA (RR 0.28 [95% CI 0.14 to 0.55]), prostanoid (Inh) (RR 0.21 [95% CI 0.07 to 0.67]), and prostanoid (PO) (RR 0.32 [95% CI 0.16 to 0.67]) (all moderate certainty). Sotatercept probably improves 6MWD as compared to placebo (MD 36.89m [95% CI 25.26 to 48.51]). Although sotatercept probably improves 6MWD more than add-on ERA (MD 18.38m [95% CI 5.92 to 30.84]) and prostanoid (PO) (MD 25.66m [95% CI 13.71 to 37.61]), it did not exceed the MCID of 33m (both moderate certainty). Sotatercept is an effective add-on therapy for PAH, likely superior to many approved add-on PAH therapies in reducing clinical worsening.

Evaluating the Impact of Pulmonary Arterial Hypertension Therapies on Pericardial Effusion and Patient Survival.

To evaluate the impact of Pulmonary Arterial Hypertension (PAH) therapies on the incidence of pericardial effusion and its prognostic implications for patient survival. This retrospective cohort study included 60 patients diagnosed with PAH at a high-volume tertiary care center, treated with intravenous or subcutaneous prostanoids. Data were collected from 2015 to 2019, including echocardiographic assessments, right heart catheterization, World Health Organization functional class evaluations, six-minute walk distance tests, and biomarkers such as brain natriuretic peptide and N-terminal prohormone of brain natriuretic peptide. Follow-up was conducted at least 90 days post-treatment initiation. Pericardial effusion was observed in 31.7% of patients before therapy. Patients with moderate to large effusions had a significantly higher mortality risk (HR = 1.92; 95% CI 1.1-44.78; p =0.0044), while small effusions appeared protective (HR = 0.27; 95% CI 0.15-0.48; p =0.006). Survival rates declined from 89% at one year to 71% at three years post-therapy, with effusion presence correlating with more severe PAH manifestations. Initial pericardial effusion severity is a critical predictor of mortality in PAH patients. Early assessment and stratified management of pericardial effusion are essential for optimizing therapeutic outcomes in PAH management. Future research should explore targeted interventions for managing pericardial effusion to improve patient prognosis.

Recovery of optimal vitamin D improves responsiveness to phosphodiesterase-5 inhibitors therapy in pulmonary arterial hypertension

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): R.A. has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie-Curie grant agreement Nº 847635. Introduction Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We demonstrated that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH. Also, recent evidence suggests that vitD deficiency may cause insufficient response to phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, in some patients with PAH. Thus, in this study, we hypothesize that the recovery of optimal vitD levels in experimental PAH might help to improve responsiveness to PDE5i therapy. Methods Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and divided into two groups: (a) daily tadalafil therapy (oral;10mg/kg) + continued vitD-free diet (n=9) or (b) daily tadalafil therapy (oral;10mg/kg) + single oral dose of 50,000 IU/Kg of vitD plus standard diet (n=9) for four weeks. Animals were then used for exercise capacity evaluation, invasive haemodynamic, pulmonary vascular analysis, and sample collection. Evolution of cardiac (dys)function was assessed by echocardiography. Results Recovering optimal vitD levels improved pulmonary endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the vasodilator response to sildenafil. Moreover, pulmonary small artery (<55 µm) remodeling was decreased in vitD-restored group, as measured by a decline in mean lumen/total ratio and mean medial thickness. In a morphometric analysis, vitD treatment attenuated increases in both right ventricle (RV) and right atrial hypertrophy, as well as the fulton index. VitD supplementation also improved the exercise capacity with increases seen in distance run, evaluated by endurance tests in a treadmill set. RV catheterization showed that vitD did not decreased the RV dysfunction, evaluated by end-systolic and end-diastolic pressure. Similar to the RV, no alterations were observed in pulmonary artery pressures. However, echocardiographic analysis revealed an improved pulmonary flow in the vitD-restored group, where pulmonary artery acceleration time normalized to ejection time ratio and pulmonary artery velocity-time integral were increased. It also improved tricuspid annular plane systolic excursion (TAPSE). Conclusion Altogether, these data suggest that in animals with PAH treated with tadalafil, restoring vitD levels to an optimal range improves some pathophysiological features of PAH. Therefore, in addition to recovery of optimal vitD status being indicated to restore calcium homeostasis in those PAH patients with severe deficiency, it might help to improve responsiveness to PDE5i.

Selexipag Dosing Strategies for Pediatric Patients with Pulmonary Arterial Hypertension.

This retrospective chart review of patients less than 18years old with pulmonary arterial hypertension (PAH) receiving selexipag was conducted to describe selexipag dosing practices, impact on concomitant PAH therapies, and the safety and efficacy of selexipag. Twenty-seven patients aged 1-17years started a median dose of oral selexipag 100µg twice daily. Therapy was increased by a median of 100µg twice daily every 6days to a maximally tolerated median dose of 800µg twice daily. All 24 patients on another prostacyclin derivative were able to discontinue therapy at their maximum tolerated selexipag dose; other concomitant PAH therapies did not change. Changes in echocardiogram data and 6-MWT results were variable. No patients discontinued selexipag; four patients received decreased doses due to flushing (n = 1), drug interactions (n = 2), or increased frequency of nose bleeds (n = 1).

Pulmonary Arterial Hypertension (PAH) Group 1: Overview, Workup, Risk Stratification, and Current (and Future) Treatment Approaches

Abstract: Risk assessment (or risk stratification) and both current and future therapies for pulmonary arterial hypertension (PAH) will be discussed in part B. Risk assessment is key in the initial evaluation and follow-up of persons with PAH. Risk assessment provides information on disease severity and mortality, which, over time, have been incorporated into the application of PAH therapies. After the initial risk assessment, a 4-strata approach is recommended at subsequent follow- up evaluations by the 2022 ERS/ESC pulmonary hypertension (PH) guidelines as described initially in COMPERA 2.0. This method appears to have increased sensitivity to changes in risk from baseline to follow-up and to changes in long-term mortality risk. Current PAH therapies target the prostacyclin, endothelin, and nitric oxide pathways. A sequential approach to therapy has been recommended since publication of the 2009 guidelines and, in the most recent iteration incorporates the 4-strata approach at follow-up. Additional therapy is recommended when intermediate- high or high-risk status is present. New therapies are under active investigation that include targeting novel pathways. Sotatercept, a fusion protein that binds to and sequesters select transforming growth factor β superfamily ligands, is the most promising novel therapy at this time. A recent phase 3, randomized, double-blind, placebo-controlled study in group 1 PAH patients showed a statistically significant improvement in 6-minute walk distance and additional studies of this drug in PH populations are ongoing. Progress in phenotyping this heterogeneous disease is being made, and as PAH therapies continue to evolve, the use of personalized treatment regimens may be possible in the care of this complex, and highly morbid and mortal disease.

Pharmacological Agents and Potential New Therapies in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an imbalance between vasoactive mediators, which causes vascular remodeling, increased pulmonary vascular resistance, and right ventricular overload, ultimately leading to heart failure and death. A metabolic theory has been suggested to explain the pathophysiology of PAH whereby abnormalities in mitochondrial biogenesis can trigger a hyperproliferative and apoptosis-resistant phenotype in cardiopulmonary and malignant cells, leading to mitochondrial dysfunction, which in turn causes the Warburg effect. This can culminate in the mitophagy of pulmonary vessels and cardiomyocytes. The present narrative review focuses on the pathophysiology of PAH, the pharmacological agents currently available for its treatment, and promising and challenging areas of therapeutic investigation.

Management of pulmonary vascular disease associated with congenital left-to-right shunts: A single-center experience

ObjectiveThe study objective was to describe the course and outcomes of children under 18 years of age, with left-to-right shunts and pulmonary arterial hypertension undergoing 1 of 2 management approaches: pulmonary arterial hypertension treatment before left-to-right shunt repair (Treat First) and left-to-right shunt repair first with or without subsequent pulmonary arterial hypertension treatment (Repair First). MethodsWe performed a retrospective single-center study, conducted from September 2015 to September 2021, of children with left-to-right shunts and pulmonary arterial hypertension (defined as indexed pulmonary vascular resistance ≥ 4 Wood units [WU]∗m2) but without Eisenmenger physiology. Patient characteristics, longitudinal hemodynamics data, pulmonary arterial hypertension management, left-to-right shunt repair, and outcomes were reviewed. ResultsOf 768 patients evaluated for left-to-right shunt closure, 51 (6.8%) had left-to-right shunts associated with pulmonary arterial hypertension (median age 1.1 [0.37-5] years, median indexed pulmonary vascular resistance 6 [5.2-8.7] WU∗m2). In the "Treat First" group (n = 33, 65%), 27 patients (82%) underwent left-to-right shunt closure and 6 patients (18%) did not respond to pulmonary arterial hypertension therapy and did not undergo left-to-right shunt closure. In the "Repair First" group (n = 18, 35%), 12 patients (67%) received pulmonary arterial hypertension therapy and 6 patients (33%) did not. Mortality rates were 6% in the "Treat First" group and 11% in "Repair First" group with follow-ups of 3.4 and 2.5 years, respectively. After left-to-right shunt closure, there was no significant change in indexed pulmonary vascular resistance over a median follow-up of 2 years after surgery (P = .77). ConclusionsIn children with left-to-right shunts and associated pulmonary arterial hypertension, treatment with pulmonary arterial hypertension–targeted therapy before defect repair does not appear to endanger the subjects and may have some benefit. The response to pulmonary arterial hypertension–targeted therapy before shunt closure persists 2 to 3 years postclosure, providing valuable insights into the long-term management of these patients.

Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial

Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. Gossamer Bio.

The impact of cardiovascular and lung comorbidities in patients with pulmonary arterial hypertension: A systematic review and meta-analysis

BackgroundContemporary patients with pulmonary arterial hypertension (PAH) are older and exhibit cardiovascular and/or lung comorbidities. Such patients have typically been excluded from major PAH drug trials. This systematic review compares baseline characteristics, hemodynamic parameters, and mortality rate between PAH patients with significant number of comorbidities compared to those with fewer or no comorbidities. ΜethodsA systematic literature search in PubMed and Cochrane databases was conducted searching for studies comparing PAH patients with more than two cardiovascular comorbidities and/or at least a lung comorbidity against those with fewer comorbidities. ResultsSeven observational studies were included. PAH patients with comorbidities were older, with an almost equal female-to-male ratio, shorter 6-minute walk distance, higher NT-proBNP levels, and lower lung diffusion for carbon monoxide. In terms of hemodynamics, they had higher mean right atrial pressure and pulmonary artery wedge pressure, lower mean pulmonary arterial pressure, pulmonary vascular resistance and mixed venous oxygen saturation. Pooled analysis of six studies demonstrated a higher mortality risk for PAH patients with comorbidities compared to those without (HR 1.86, 95% CI 1.20 to 2.89, p<0.001, I²=92%), with the subgroup of PAH patients with lung comorbidities having an even higher mortality risk (test for subgroup differences: p<0.001). Combination drug therapy for PAH was less frequently used in patients with comorbidities. ConclusionsCardiovascular and lung comorbidities impact the clinical characteristics and outcomes of PAH patients, highlighting the need for optimal phenotyping and tailored management for this high-risk population.

Frequency, characteristics and risk assessment of pulmonary arterial hypertension with a left heart disease phenotype.

To obtain real-world evidence about the features and risk stratification of pulmonary arterial hypertension (PAH) with a left heart disease (LHD) phenotype (PAH-LHD). By reviewing the records of consecutive incident PAH patients at 7 tertiary centers from 2001 to 2021, we selected 286 subjects with all parameters needed to determine risk of death at baseline and at first follow-up with COMPERA and COMPERA 2.0 scores. Fifty seven (20%) had PAH-LHD according to the AMBITION definition. Compared with no-LHD ones, they were older, had higher BMI, more cardiovascular comorbidities, higher E/e' ratio and left atrial area, but lower BNP concentrations and better right ventricular function and pulmonary hemodynamics. Survival was comparable between PAH-LHD and no-LHD patients, although the former were less commonly treated with dual PAH therapy. Both COMPERA and COMPERA 2.0 discriminated all-cause mortality risk of PAH-LHD at follow-up, but not at baseline. Risk profile significantly improved during follow-up only when assessed by COMPERA 2.0. At multivariable analysis with low-risk status as reference, intermediate-high and high-risk, but not LHD phenotype, were associated with higher hazard of all-cause mortality. Results were comparable in secondary analyses including patients in the last 10years and atrial fibrillation and echocardiographic abnormalities as additional criteria for PAH-LHD. In real life, PAH-LHD patients are frequent, have less severe disease and are less likely treated with PAH drug combinations than no-LHD. TheCOMPERA 2.0 model may be more appropriate to evaluate their mortality risk during follow-up and how it is modulated by therapy.

Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

Non-canonical IKB kinases regulate YAP/TAZ and pathological vascular remodeling behaviors in pulmonary artery smooth muscle cells.

Pulmonary arterial hypertension (PAH) causes pulmonary vascular remodeling, increasing pulmonary vascular resistance (PVR) and leading to right heart failure and death. Matrix stiffening early in the disease promotes remodeling in pulmonary artery smooth muscle cells (PASMCs), contributing to PAH pathogenesis. Our research identified YAP and TAZ as key drivers of the mechanobiological feedback loop in PASMCs, suggesting targeting them could mitigate remodeling. However, YAP/TAZ are ubiquitously expressed and carry out diverse functions, necessitating a cell-specific approach. Our previous work demonstrated that targeting non-canonical IKB kinase TBK1 reduced YAP/TAZ activation in human lung fibroblasts. Here, we investigate non-canonical IKB kinases TBK1 and IKKε in pulmonary hypertension (PH) and their potential to modulate PASMC pathogenic remodeling by regulating YAP/TAZ. We show that TBK1 and IKKε are activated in PASMCs in a rat PH model. Inflammatory cytokines, elevated in PAH, activate these kinases in human PASMCs. Inhibiting TBK1/IKKε expression/activity significantly reduces PAH-associated PASMC remodeling, with longer-lasting effects on YAP/TAZ than treprostinil, an approved PAH therapy. These results show that non-canonical IKB kinases regulate YAP/TAZ in PASMCs and may offer a novel approach for reducing vascular remodeling in PAH.

Fixed-dose combination therapy in pulmonary arterial hypertension: Pros & cons

Quality of life of patients suffering from chronic diseases is inevitably conditioned by the number of pills taken during the day. To improve patients' tolerability, compliance and quality of life and reduce healthcare costs, pharmaceutical companies are focusing on the commercialization of fixed-dose combination (FDC) therapies.The last ESC/ERS guidelines for the treatment of pulmonary arterial hypertension (PAH) recommend initial dual combination therapy for newly diagnosed patients at low or intermediate mortality risk. In this regard, polypills including an endothelin receptor antagonist (ERA) and a phosphodiesterase 5 inhibitor (PDE5-i) could represent an useful therapeutic strategy, although with some limitations. To date, evidence about the use of FDCs in PAH is limited but future studies evaluating their safety and efficacy are welcome.

Pulmonary Hypertension in Systemic Sclerosis.

Systemic sclerosis is a multisystem connective tissue disease that is associated with substantial morbidity and mortality. Visceral organ involvement is common in patients with systemic sclerosis and occurs independently of skin manifestations. Pulmonary hypertension (PH) is an important and prevalent complication of systemic sclerosis. The clinical classification of PH cohorts conditions with similar pathophysiological mechanisms into one of five groups. While patients with systemic sclerosis can manifest with a spectrum of pulmonary vascular disease, notable clinical groups include group 1 pulmonary arterial hypertension (PAH) associated with connective tissues disease, PAH with features of capillary/venous involvement, group 2 PH associated with left heart disease, and group 3 PH associated with interstitial lung disease. Considerable efforts have been made to advance screening methods for PH in systemic sclerosis including the DETECT and ASIG (Australian Scleroderma Interest Group) composite algorithms. Current guidelines recommend annual assessment of the risk of PAH as early recognition may result in attenuated hemodynamic impairment and improved survival. The treatment of PAH associated with systemic sclerosis requires a multidisciplinary team including a PH specialist and a rheumatologist to optimize immunomodulatory and PAH-specific therapies. Several potential biomarkers have been identified and there are several promising PAH therapies on the horizon such as the novel fusion protein sotatercept. This chapter provides an overview of PH in systemic sclerosis, with a specific focus on group 1 PAH.

Use of pulmonary arterial hypertension therapies in patient swith sarcoidosis-associated pulmonary hypertension.

Use of pulmonary arterial hypertension therapies in patient swith sarcoidosis-associated pulmonary hypertension.

Survival and response to pulmonary vasodilator therapies in patients with chronic obstructive pulmonary disease and pulmonary vascular phenotype

BackgroundThe aim of the study was to describe and investigate the effect of pulmonary arterial hypertension (PAH) therapies in a cohort of patients with severe precapillary pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD; PH-COPD), and to assess factors predictive of treatment response and mortality. Material and methodsWe retrospectively included patients with severe incident PH-COPD who received PAH therapy and underwent RHC at diagnosis and on treatment. ResultsFrom 2015 to 2022, 35 severe PH-COPD patients, with clinical features of pulmonary vascular phenotype, were included. Seventeen (48.5%) patients were treated with combined PAH therapy. PAH therapy led to a significant improvement in hemodynamics (PVR -3.5 Wood Units (−39.3%); p < 0.0001), and in the simplified four-strata risk-assessment score, which improved by at least one category in 21 (60%) patients. This effect was more pronounced in patients on dual therapy. Kaplan-Meier estimated survival rates at 1, 3 and 5 years were 94%, 65% and 42% respectively. Univariate analysis showed a significant reduction in survival in patients with a higher simplified risk score at follow-up (Hazard ratio (HR) 2.88 [1.16–7.15]; p = 0.02). Hypoxemia <50 mmHg was correlated to mortality in multivariate analysis (HR 4.33 [1.08–17.42]; p = 0.04). ConclusionsOur study confirms the poor prognosis of patients with COPD and a pulmonary vascular phenotype and the potential interest of combined PAH therapy in this population, with good tolerability and greater clinical and hemodynamic improvement than monotherapy. Using the simplified risk score during follow-up could be of interest in this population.

Future Perspectives of Pulmonary Arterial Hypertension: A Review of Novel Pipeline Treatments and Indications.

Pulmonary arterial hypertension is characterized by elevated blood pressure and pathological changes in the pulmonary arterioles, leading to the development of right-heart failure and potentially fatal outcomes if left untreated. This review aims to provide an overview of novel drugs or formulations and new drug indications for pulmonary arterial hypertension that are currently in phases II-III of randomized controlled trials, and describe the rationale for the use of these targeted therapies, as well as their efficacy, safety profile, and impact on quality of life and survival. The literature research was conducted using data from ClinicalTrials.gov for the period between 1 January 2016 up to 31 December 2022. The population of interest includes individuals aged ≥ 18years who have been diagnosed with pulmonary arterial hypertension. The review selection criteria included trials with recruiting, enrolling by invitation, active, terminated or completed status in 2022 and 2023. A total of 24 studies were selected for evaluation based on the inclusion and exclusion criteria. This review summarizes the updated information from randomized clinical trials involving novel therapies for pulmonary arterial hypertension. However, larger clinical trials are required to validate their clinical safety and effects. In the future, clinicians should choose therapies based on the patient's individual situation and requirements when developing treatment strategies.

Cluster analysis identifies novel real-world lung disease-pulmonary hypertension subphenotypes: implications for treatment response.

Clinical trials repurposing pulmonary arterial hypertension (PAH) therapies to patients with lung disease- or hypoxia-pulmonary hypertension (PH) (classified as World Health Organization Group 3 PH) have failed to show a consistent benefit. However, Group 3 PH clinical heterogeneity suggests robust phenotyping may inform detection of treatment-responsive subgroups. We hypothesised that cluster analysis would identify subphenotypes with differential responses to oral PAH therapy. Two k-means analyses were performed on a national cohort of US veterans with Group 3 PH; an inclusive model (I) of all treated patients (n=196) and a haemodynamic model (H) limited to patients with right heart catheterisations (n=112). The primary outcome was organ failure or all-cause mortality by cluster. An exploratory analysis evaluated within-cluster treatment effects. Three distinct clusters of Group 3 PH patients were identified. In the inclusive model (C1I n=43, 21.9%; C2I n=102, 52.0%; C3I n=51, 26.0%), lung disease and spirometry drove cluster assignment. By contrast, in the haemodynamic model (C1H n=44, 39.3%; C2H n=43, 38.4%; C3H n=25, 22.3%), right heart catheterisation data surpassed the importance of lung disease and spirometry. In the haemodynamic model, compared to C3H, C1H experienced the greatest hazard for respiratory failure or death (HR 6.1, 95% CI 3.2-11.8). In an exploratory analysis, cluster determined treatment response (p=0.006). Conclusions regarding within-cluster treatment responses were limited by significant differences between select variables in the treated and untreated groups. Cluster analysis identifies novel real-world subphenotypes of Group 3 PH patients with distinct clinical trajectories. Future studies may consider this methodological approach to identify subgroups of heterogeneous patients that may be responsive to existing pulmonary vasodilatory therapies.