Pulmonary Arterial Hypertension Therapy Research Articles

Abstract 11565: Improvement in Cardiopulmonary Function in a Rat Model of Pulmonary Arterial Hypertension Observed With RKER-012, a Novel Activin Receptor Type II Ligand Trap, was Associated With Reduced Markers of Inflammation and Fibrosis in the Right Ventricle

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary vascular resistance, impaired cardiac output, and right ventricle (RV) overload. PAH is associated with imbalanced TGF-ß signaling, marked by elevated SMAD2/3 signaling, which is associated with inflammation and fibrosis contributing to heart failure. Initially, the RV can compensate for increased pressure due to its adaptive contractility, but chronic pressure overload leads to maladaptive RV remodeling through inflammatory and fibrotic pathways. Current therapies for PAH are primarily vasodilators which do not treat the underlying pathology. RKER-012 is a research form of KER-012, an investigational modified ActRIIB ligand trap designed to inhibit signaling through SMAD2/3. We investigated RKER-012’s mechanism of prevention of cardiac pathology in a Sugen/Hypoxia (SH) PAH model. Rats received a subcutaneous (SQ) dose of 25 mg/kg Sugen 5416 under hypoxic conditions. For 3 weeks, SH rats received vehicle (SH-VEH) or 10 mg/kg RKER-012 (SH-RKER-012) twice weekly SQ. Control rats received VEH twice weekly in normoxic conditions. Systolic pulmonary arterial pressure (sPAP) and Fulton index (FI) were measured. qPCR of RV tissue was used to evaluate the mechanism of RKER-012 in this model. SH-VEH rats had increased FI and sPAP (both p≤0.0001) compared to NX, consistent with development of cardiac and pulmonary impairment. Relative to SH-VEH, RKER-012 reduced increased FIand prevented increased sPAP (both p≤0.001) in SH rats so that sPAP did not differ from NX. Relative to NX, SH-VEH had increased RV expression of fibrotic markers such as Timp1, Col1a1, Col3a1, Runx2, and LOX (all p≤0.05). In contrast, SH-RKER-012 rats had reduced expression of Timp1, Col1a1, Col3a1, Runx2 and LOX (all p≤0.05) relative to SH-VEH. Inflammation markers CD68 and MCP1 (both p≤0.05) were increased in SH-VEH compared to NX. CD68 expression was reduced in SH-RKER-012 (p≤0.01) compared to NX but MCP1 expression was not affected (p=0.54). These results support that RKER-012 attenuated upregulation of key inflammation and fibrosis markers in a PAH preclinical model and suggest that KER-012 has a distinct mechanism from vasodilation and could be developed as a cardioprotective treatment for PAH.

Profibrotic Effects of Endothelin-1 on Fibroblasts Are Mediated by Aldosterone in Vitro: Relevance to the Pathogenesis and Therapy of Systemic Sclerosis and Pulmonary Arterial Hypertension.

Endothelin-1 (ET-1) is a vasoactive and profibrotic peptide that plays a pivotal role in diseases such as systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH), by inducing fibrosis and vascular remodeling. Such effects may be sustained by the induction of aldosterone production and reactive oxygen species (ROS). We have used fibroblasts obtained from skin of healthy donors and SSc patients and commercial fibroblasts from lung to evaluate whether ET-1 is able to stimulate ROS production directly or indirectly through aldosterone induction. We found that ET-1 receptors are present in all types of fibroblasts analyzed, whereas the expression of mineralocorticoid receptor (MCR) is lower in dermal fibroblasts from healthy donors (HDFs) compared to fibroblasts derived from lung (HPFs) or from skin of SSc patients (SScHDFs). ET-1 induces ROS production in HDFs and SScHDFs after 24 h of incubation involving its receptor B (ETB), whereas aldosterone exerts its effects after 40 min of incubation. Moreover, ROS production was inhibited by the pre-incubation of cells with MCR inhibitor. Our results indicate that ET-1 induces ROS indirectly through aldosterone production suggesting that aldosterone may play a pivotal role in the pathogenesis of SSc and PAH.

Medication use by US patients with pulmonary hypertension associated with chronic obstructive pulmonary disease: a retrospective study of administrative data

BackgroundPulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). While clinical guidelines recommend specific drug therapies for pulmonary arterial hypertension (PAH), these drug therapies are not recommended for PH due to lung disease.MethodsThis was a retrospective cohort study using the Optum® Clinformatics® Data Mart from January 2009–September 2019. An algorithm was designed to identify adults with ≥ 2 ICD-9-CM or ICD-10-CM diagnosis codes for PH and with ≥ 2 diagnosis codes for COPD. Sensitivity analyses were conducted among subgroups of patients with evidence of a right heart catheterization (RHC) or pulmonary function test (PFT). Patient characteristics, medications used, and durations of use of PAH and COPD medications were analyzed.ResultsA total of 25,975 patients met the study inclusion criteria. Their mean age was 73.5 (SD 10.0) years and 63.8% were female. Medications targeting PAH were prescribed to 643 (2.5%) patients, most frequently a phosphodiesterase-5 inhibitor (2.1%) or an endothelin receptor antagonist (0.75%). Medications for COPD were prescribed to 17,765 (68.4%) patients, most frequently an inhaled corticosteroid (57.4%) or short-acting beta agonist (50.4%). The median durations of use ranged from 4.9 to 12.8 months for PAH medications, and from 0.4 to 5.9 months for COPD medications. Of the subgroup of patients with RHC (N = 2325), 257 (11.1%) were prescribed a PAH medication and 1670 (71.8%) used a COPD medication. Of the subgroup with a PFT (N = 2995), 58 (1.9%) were prescribed a PAH medication and 2100 (70.1%) a COPD medication.ConclusionsPatients with PH associated with COPD were identified in a US administrative claims database. Very few of these patients received any of the medications recommended for PAH, and only about two thirds received medications for COPD.

Transitioning Stable Patients with Pulmonary Arterial Hypertension from Parenteral Prostanoids to Oral Selexipag

Introduction: Parenteral prostanoids are the most potent therapies for pulmonary arterial hypertension (PAH) but are associated with complications and lifestyle limitations. Carefully selected stable patients may be considered for a transition from parenteral prostanoids to a more convenient oral regimen. We present our experience transitioning patients on parenteral prostanoids to selexipag on an outpatient basis. Methods: This was a retrospective cohort study of all group 1 PAH patients on parenteral prostanoids who transitioned to selexipag using a standardized outpatient-based protocol. Hospitalization and routine prognostic data were recorded. Results: Fourteen patients were followed for a median of 1,240 (1,052–1,528) days; all were functional class (FC) II (n = 9) or III (n = 5). Thirteen patients completed the transition, including 11 who underwent catheterization 376 (321–735) days after discontinuing parenteral therapy. Three patients had unfavorable transitions requiring reinitiation of parenteral treatment. Overall, pulmonary vascular resistance increased (3.3–4.5 WU, p = 0.01), cardiac index fell (4.0–2.8 L/min/m², p = 0.01), N-terminal pro-hormone of brain natriuretic peptide worsened (111–205 pg/dL, p = 0.03), but PAH-related hospitalizations improved (27–8, p = 0.02). Cardiac imaging, FC, and 6-min walk distance (6MWD) were unchanged. Patients who failed were older (64 vs. 56 years old) with shorter 6MWD (274 vs. 392 m) and higher REVEAL 2.0 scores (11 vs. 3). Conclusions: Transition from parenteral prostanoids to oral selexipag in carefully selected low-risk patients was well-tolerated in many patients, with up to 5 years of follow-up. Overall, the hemodynamic response to transition is unpredictable and close monitoring, particularly in the first year of follow-up, is recommended. Additional evaluation of potential predictors of success is necessary.

UNISUS study design: a phase 3 superiority study comparing the efficacy, safety, and tolerability of macitentan 75 mg vs macitentan 10 mg in patients with pulmonary arterial hypertension (PAH)

Abstract Background While advances in PAH-specific therapies have substantially improved survival, there is still an unmet need to improve long-term outcomes in PAH. Purpose The UNISUS study is the first head-to-head superiority study in PAH, comparing the time to morbidity or mortality (M/M) with macitentan 75 mg vs macitentan 10 mg in PAH patients. Methods UNISUS, an ongoing multicentre, prospective, double-blind (DB), adaptive, event-driven superiority study randomises PAH patients 1:1 to receive macitentan 75 mg or macitentan 10 mg, with a target enrolment of ∼900 patients. Efficacy and safety are continuously assessed by an independent data monitoring committee (IDMC), who advises on pre-specified adaptive changes in study conduct, including expansion of the study population. An independent clinical event committee adjudicates all M/M events. The initial population was restricted to patients in functional class (FC) II/III, aged 18–75 years and excluded those with portopulmonary hypertension (PoPH) and those who were PAH treatment-naïve or receiving a prostanoid analogue. Stable (≥3 months) background PAH-therapy may be maintained, except for endothelin receptor agonists (ERAs), which must be stopped the day before initiating study drug. The study is comprised of a screening period, a 4-week run-in period (if ERA treatment-naïve or on sub-optimal ERA dose), and an event-driven DB treatment period, followed by a 2-year open-label extension with macitentan 75 mg. Initiation of macitentan 75 mg occurs after a 4-week up-titration step with macitentan 37.5 mg (Figure 1). The primary endpoint is time to first on-treatment M/M event, defined as first of: all-cause death, PAH-related hospitalisation, or PAH-related disease progression (confirmed ≥15% decrease in 6-minute walk distance (6MWD) and either FC worsening or addition of PAH therapy). Other endpoints include change from baseline to Week 24 in 6MWD and PAH-SYMPACT symptom scores; time to PAH-related hospitalisation or death; time to all-cause death (may be supplemented with data from an external control arm derived from the CARE PAH study [NCT04955990]); and the safety and tolerability of the study drugs. Figure 2 shows planned assessments and sub-studies. To maximise patient retention, add-on PAH therapies are allowed after a M/M event and, for patients at risk of withdrawing and unable to attend visits, the investigator may consider options for reduced follow-up. Results After 60 patients had been exposed for ≥8 weeks, the IDMC reviewed unblinded safety/tolerability data and recommended to expand recruitment from the restricted population to the target population (i.e., including patients: with PoPH, in FC II–IV, from any PAH therapy background [including naïve], aged ≥18 years). Conclusion UNISUS is the first head-to-head superiority study in PAH; with over 200 patients enrolled, it is currently recruiting the target population. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Actelion Pharmaceuticals Ltd., a Janssen pharmaceutical company of Johnson & Johnson.

Effects of targeted therapy on blood gas analysis in pulmonary arterial hypertension – a retrospective analysis

Abstract Background In pulmonary arterial hypertension (PAH), there is an excessive respiratory drive, which leads to inefficient ventilation with subsequent hypocapnia. Changes in blood gas analysis (BGA) may correlate with symptom severity and outcome. Data on impact of targeted PAH therapy on BGA are scarce and it remains unclear if these values can be used for risk stratification purposes. Purpose To assess capillary BGA in PAH at diagnosis and to evaluate the effect of targeted therapy on classical and calculated BGA parameters. Methods 147 patients (62.3±17.1 years; female/male ratio: 66.7/33.3%) with newly diagnosed PAH were treated with targeted PAH therapy. 12-month follow-up included assessment of capillary blood gases and clinical variables. Patients underwent repeat RHC after 15.9±15.5 months. Results At diagnosis, both pcO2 (66.8±1.3 mmHg) and pcCO2 (32.7±0.5 mmHg) were slightly reduced. At 12-month follow-up, pcCO2 increased significantly to values within normal range (35.3±0.4 mmHg), while pcO2 showed no significant changes. After using the formula to calculate standard pcO2, baseline values were even lower, but there were significant improvements at 12-month follow-up, also reaching normal values. Changes in pcCO2 and standard pcO2 at diagnosis correlated with hemodynamics and survival at follow-up. Repeated RHC demonstrated significant reductions in mean PAP (48.9±1.2 to 39.9±1.0 mmHg; −18.4%), and PVR (11.3±0.7 to 6.2±0.3 WU; −45.1%), and an increase in cardiac index (2.1±0.04 to 2.6±0.1 ml/min/m2; +23.8%) (all p<0.05). Hemodynamic improvements correlated with improved clinical parameters, including 6-minute walking distance (344±9 to 393±9 m), NTproBNP serum levels (2.163±219 to 772±84 ng/l, both p<0.05) and WHO-FC at 12 months, resulting in improved risk status. Conclusions Targeted PAH therapy leads to significantly improved cardiopulmonary hemodynamics with subsequent increase in pcCO2, presumably due to less hyperventilation. Changes in pcCO2 and standard pcO2 (but not pcO2) correlate with hemodynamics and survival, potentially serving as non-invasive parameters for risk assessment and therapeutic response. The discrepancy between pcO2 and standard pcO2 at diagnosis suggests that pcO2 is upregulated by the hyperventilatory state. Standard pcO2 represents an easy-to-calculate parameter that can help more accurately identify PAH patients requiring O2 therapy in addition to targeted therapy. Further studies are needed in this context. Funding Acknowledgement Type of funding sources: None.

The discrepancy between FDG uptake and myocardial fibrosis in patients with pulmonary arterial hypertension – PET/MRI study

Abstract Background Inflammatory processes play an important role in pulmonary arterial hypertension (PAH) pathophysiology. We previously confirmed that in case of right ventricle (RV) failure, changes of cytokines' levels are correlated with myocardial metabolic and hemodynamic alterations observed in PET/MRI hybrid imaging. Presence of late gadolinium enhancement (LGE) in RV insertion points (RVIPs) has been found in majority of PAH patients and is often recognized as evidence of myocardial fibrosis due to RV pressure overload. As qualitative and/or quantitative assessments of LGE may vary due to natural PAH progression or specific therapy, we hypothesized that simple presence of LGE at RVIPs is not unequivocal to fibrotic tissue (without metabolic activity). Purpose To check the relationship between LGE mass and 18F-fluorodexyglucose uptake in RV insertion points in PAH patients using PET/MRI hybrid imaging. Methods Twenty-eight clinically stable PAH patients (49.9±15.9 years) had simultaneous PET/MRI scans during baseline and follow up (FU) visits, Figure. 18F-fluorodexyglucose (FDG) was used as a tracer and its cardiac uptake was presented as a maximum standardized uptake value (SUV) for RV insertion points (SUV in RVIPS). Septal delayed enhancement mass was quantified in RVIPs and presented as LGE mass. Occurrences of clinical end-points (CEP, defined as death or clinical deterioration) were assessed during 24 months observation. Results LGE was found in RVIPs of all PAH patients. Mean LGE mass was 6.32±4.41 g and mean SUV in RVIPS was 7.28±5.36. Follow up values were 8.01±7.75g (p=0.4) and 5.80±3.16 (p=0.16), respectively. We observed significant correlation between baseline SUV in RVIPS and mean pulmonary pressure, mPAP (r=0.49, p=0.04) but no correlation was found between LGE mass and SUV in RVIPS (in both baseline and FU scans). Between baseline and follow up visits, 16 patients had CEP and needed PAH therapy escalation. CEP+ group of PAH patients presented higher baseline LGE mass (7.53±4.75 vs 3.92±2.21, p=0.04) and SUV in RVIPS (7.27±5.42 vs 6.01±4.52, p=0.4). In all CEP patients who initiated prostacycline therapy and survived (n=8, 50%), SUV in RVIPS decreased in FU PET scans together with an increase in LGE mass in MRI. At FU visits we also observed significant improvement of MRI-derived RV ejection fraction (45.1±9.6% to 52.4±12.9%, p=0.01), and mPAP (50.5±18.3 to 42.8±18.6 mmHg, p=0.03). Conclusions Effective PAH therapy have an impact on both LGE mass and FDG uptake in cardiac local tissue changes. Since there was no correlation between LGE mass and FDG uptake RV insertion points, the question arises what the cause of these LGE changes is. Increased fibrosis should cause diminished local glucose metabolism. This phenomenon opens new questions concerning pathophysiology processes in RVIPs and requires confirmation on bigger PAH population. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Center for Science in Poland

Efficacy and dose-response relationship of oral treprostinil in PAH patients on monotherapy or dual background therapy

Abstract Background FREEDOM-C and FREEDOM-C2 were randomized, placebo-controlled, double-blinded international, multicenter studies investigating the use of oral treprostinil (TRE) in subjects on mono or dual background pulmonary arterial hypertension (PAH) therapies. Both had a primary endpoint of change in 6-minute walk distance (6MWD) at Week 16 vs baseline. Previous post-hoc analyses combining mono and dual therapy subjects (PDE-5i and/or ERA) from these studies revealed a TRE dose-dependent increase in 6MWD. (1. White & Rao, 2016) Purpose This post-hoc analysis was performed to determine if subjects from FREEDOM-C and FREEDOM-C2 derive improvements in 6MWD with increasing doses of TRE when stratified by mono or dual background therapy and to determine if PAH background therapies (mono or dual) impacted 6MWD. Methods All active subjects (n=331) from FREEDOM-C and FREEDOM-C2 were grouped into TRE dose tertiles (low-dose: ≤2 mg BID, mid-dose: >2 mg to ≤3.5 mg BID, and high-dose: >3.5 mg BID). Placebo subjects (n=329) were in a separate 0 mg dose group. No data imputation was implemented. Comparisons of 6MWD change at Weeks 4, 8, 12, and 16 between mono and dual therapy subgroups at any dose group were performed using a two-sample t-test or nonparametric Wilcoxon rank-sum test. The nonparametric Kruskal-Wallis test was conducted with subsequent pairwise comparisons of 6MWD change at Week 16 between the four dose groups through Dunn's approach. Additionally, the Jonckheere-Terpstra test was used to assess the linear trend for 6MWD improvement with higher doses of TRE. Results Baseline characteristics of the combined intention to treat (ITT) population and summary of 6MWD for subjects with both baseline and Week 16 data are in Table 1. 6MWD change improved steadily to Week 16 in subjects at higher TRE doses, regardless of the number of PAH background therapies (Figure 1). No statistical differences were found between mono and dual therapy at any time point or for any dose group. At Week 16, there was a significant difference in 6MWD change between the placebo group and high dose group within both mono and dual background therapy subjects. The difference between the low- and high-dose groups was significant for subjects on dual background therapy. There was a significant positive linear trend for TRE doses in 6MWD improvement at Week 16 for both monotherapy subjects (one-sided p-value = 0.0002) and dual therapy subjects (one-sided p-value = 0.0242). Conclusions 6MWD improved in PAH patients regardless of their background therapy (monotherapy or dual background) and derive greater 6MWD improvements with higher doses of TRE. The observed dose-dependent 6MWD increase supports the use of TRE in sequential combination with background therapies (mono or dual). Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): United Therapeutics Corporation

Behavior of right atrial strain in patients with advanced idiopathic pulmonary arterial hypertension after initiation of specific combined therapy

Abstract Background Right atrial (RA) function has emerged as an important determinant of outcome in pulmonary arterial hypertension (PAH). However, studies exploring RA function and assessing its behavior in response to specific PAH combination therapy, independent of RA size in patients with PAH is not adequately investigated. Purpose Assess the behavior of strain based measures of RA in response to combined PAH therapy, independent of RA size in patients with PAH. Methods RA peak longitudinal strain (PLS) and peak active contraction strain (PACS) were retrospectively assessed in 38 patients with advanced idiopathic pulmonary arterial hypertension (IPAH) who were referred to Aswan heart Centre and not receiving proper GDMT; at baseline and during follow-up after initiation of specific PAH combination therapy in the form of either Sildenafil/Bosentan or Sildenafil/Macitentan. Results Most of the patients were females with median (IR) age 34 (27–39) years. All patients presented with dyspnea WHO-FC III. At baseline, all patients were receiving only monotherapy in the form of sildenafil. Median (IR) time to echocardiographic follow-up was 11 (8–18) months. Patients presented with markedly right ventricle (RV) and RA enlargement, depressed RV systolic function, and reduced RA strain parameters compared with values previously reported in healthy controls. Among various baseline associations of the RA PLS, the strongest were with baseline RA area (rho: −0.659; p<0.001) and RVEF by CMR (rho: 0.570; p<0.001). At follow up; RA PLS and PACS significantly increased (16.6 vs 24 and 7.06 vs 11.42, respectively: p<0.001); however, RA area did not show significant decrease. Only RV TDI & FAC showed significant improvement among different RV function parameters measured by echocardiography. During the follow up period, 11 out of 38 patients (28.9%) were hospitalized. RA PLS change was significantly lower in the hospitalized group than the non-hospitalized group (4.40 vs 10.2; p=0.014). RA PLS change was independently associated with hospitalization in the multivariate regression analysis (95% CI: −0.061 to −0.010; p=0.008). Conclusion Initiation of specific PAH combination therapy in undertreated patients with IPAH showed improvement in RA strain parameters despite no change in RA area during follow up. Funding Acknowledgement Type of funding sources: None.

Risk stratification parameters as assessed by continuous long-term cardiac monitoring in pulmonary hypertension – heart rate variability, heart rate, and physical activity

Abstract Background Pulmonary hypertension (PH) is a progressive disease affecting both the pulmonary vasculature and the heart. In the current ESC/ERS guidelines nine variables are used in PH risk assessment, and have been proven to be independent predictors of survival in PH. The risk assessment parameters include clinical symptoms, exercise capacity and imaging. The present study is the first to assess continuous 24/7 heart rate variability (HRV), heart rate (HR) and physical activity monitoring in patients with PH. Purpose To identify risk stratification parameters by continuous cardiac monitoring in PH. Methods Patients diagnosed with PH were included in this prospective single-centre study. Patients had a Reveal LINQ insertable cardiac monitor implanted to continuously monitor heart rate variability (HRV), heart rate at day and night and physical activity. HRV was expressed as the mean HRV in sinus rhythm during each full day (SDANN method). Pearson and Spearman correlations between the loop recorder variables and ESC/ERS risk stratification variables were calculated and compared with the loop recorder data in 30-days intervals. Results A total of 41 patients were prospectively enrolled, 27 patients with pulmonary arterial hypertension (PAH) and 14 patients with chronic thromboembolic pulmonary hypertension (CTPEH). The patients were monitored continuously in a total of 82 patient-years, had a mean age of 58 years and were primarily in a stable disease phase with a mean WHO functional class (FC) of 2.2. HRV and physical activity divided by heart rate at daytime showed the highest correlations respectively with current risk parameters. In particular, high correlations were found between HRV and NT-proBNP (R=−0,69 p≤2.2e-16), WHO FC (R=−0,65 p=2.4e-5), RVEF (R=0,61 p=0,00012) and right atrial pressure (RAP) (R=−0.67 p=0.0023) (Figure 1). Conclusion This study demonstrates the potential of HRV, and physical activity divided by heart rate daytime as risk parameters in pulmonary hypertension. Progression of symptoms in PH are often delayed compared with pathophysiological changes, and continuous monitoring offers a potential to early recognition of disease progression and optimization of PAH therapy. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The study was supported by the Heart Centre Research Council,Rigshospitalet and an investigator initiated study research grant fromJansson Pharmaceuticals.

ORAL TREPROSTINIL AS PART OF A TRIPLE-THERAPY REGIMEN FOR PULMONARY ARTERIAL HYPERTENSION: ANALYSIS FROM THE FREEDOM-EV OPEN-LABEL EXTENSION

ORAL TREPROSTINIL AS PART OF A TRIPLE-THERAPY REGIMEN FOR PULMONARY ARTERIAL HYPERTENSION: ANALYSIS FROM THE FREEDOM-EV OPEN-LABEL EXTENSION

Relevance of comorbidities on initial combination therapy in pulmonary arterial hypertension.

Demographic characteristics of pulmonary arterial hypertension (PAH) patients have changed over time, but the effects of cardiovascular risk factors on risk status and pulmonary vascular resistance (PVR) reduction with initial oral combination therapy are not known. Therefore, we tested the relevance of cardiovascular comorbidities in this setting. The study enrolled 181 treatment-naive PAH patients with a 6-month (IQR 144-363 days) right heart catheterisation and risk assessment after initial oral combination therapy. Group A included 96 (53.0%) patients without cardiac comorbidities; Group B included 54 (29.8%) patients with one cardiac comorbidity; Group C included 31 (17.1%) patients with two cardiac comorbidities or more. Group C patients were older with a balanced sex distribution. There was a significant difference in PVR reduction moving from the absence to one or at least two cardiac comorbidities, respectively: median -45.0%, -30.3%, -24.3%. A European Respiratory Society/European Society of Cardiology low-risk status was present at first follow-up in 50 (52.0%) patients in Group A, 19 (35.1%) in Group B and 9 (29.0%) in Group C; a REVEAL 2.0 low-risk status was present at first follow-up in 41 (42.0%) patients in Group A, 15 (27.7%) in Group B and 7 (22.6%) in Group C. Group A patients were 2.3 times more likely to achieve/maintain a low-risk status compared with Group B and C (OR 2.27, 95% CI 1.15-4.54, p=0.02). No significant difference was observed between patients with non-cardiac comorbidities and those without comorbidities. Initial oral combination therapy seems associated with a less effective response for patients with cardiovascular comorbidities compared with the others, related to the magnitude of treatment-induced decrease in PVR.

Socioeconomically disadvantaged veterans experience treatment delays for pulmonary arterial hypertension.

Prompt initiation of therapy after pulmonary arterial hypertension (PAH) diagnosis is critical to improve outcomes; yet delays in PAH treatment are common. Prior research demonstrates that individuals with PAH belonging to socially disadvantaged groups experience worse clinical outcomes. Whether these poor outcomes are mediated by delays in care or other factors is incompletely understood. We sought to examine the association between race/ethnicity and socioeconomic status and time-to-PAH treatment. We conducted a retrospective cohort study of Veterans diagnosed with incident PAH between 2006 and 2019 and treated with PAH therapy. Our outcome was time-to-PAH treatment. Our primary exposures were race/ethnicity, annual household income, health insurance status, education, and housing insecurity. We calculated time-to-treatment using multivariable mixed-effects Cox proportional hazard models. Of 1827 Veterans with PAH, 27% were Black, 4% were Hispanic, 22.1% had an income < $20,000, 53.3% lacked non-VA insurance, 25.5% had <high school education, and 3.9% had housing insecurity. Median time-to-treatment was 114 days (interquartile range [IQR] 21-336). Our multivariable models demonstrated increased time-to-treatment among patients with lower household income (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.60-0.91 for < $20,000 vs. ≥ $100,000) and those without non-VA insurance (HR 0.90, 95% CI 0.82-1.00). Race/ethnicity, education, and housing insecurity were not associated with time-to-treatment. Veterans with PAH experienced substantial and potentially harmful treatment delays, with median time-to-treatment of 16 weeks after diagnosis. Those with lower income and those without non-VA health insurance experienced even greater treatment delays. Additional research is urgently needed to develop interventions to improve timely PAH treatment and mitigate economic disparities in treatment.

Schistosomiasis-Associated Pulmonary Arterial Hypertension

Schistosomiasis is a major cause of group 1 pulmonary arterial hypertension (PAH) worldwide. Schistosomiasis results from a parasitic infection present in over 200 million individuals worldwide. Schistosomiasis-associated PAH was initially thought to be obstructive due to egg embolization but has a pulmonary vascular pathology like other forms of group 1 PAH and can be treated using conventional PAH therapies. Mechanisms that underlie the development of schistosomiasis-associated PAH include type 2 inflammation which triggers TGF-β signaling; importantly, TGF-β signaling is a pathway shared with other PAH etiologies. However, many things which are unknown about this disease remain, including if the lung vascular pathology results from egg embolization causing localized inflammation and vessel remodeling, or if this is a form of portopulmonary hypertension resulting from schistosomiasis liver disease.

Long-term course of pulmonary arterial hypertension in adults with congenital heart disease under targeted therapy: a retrospective analysis of a single tertiary center.

Pulmonary arterial hypertension (PAH), a common complication in adults with congenital heart disease (CHD), leads to significant morbidity and mortality. Targeted PAH medication is available, but PAH-CHD patient data are limited. Several questions regarding indication, treatment escalation, and combination therapy remain unanswered. The aim of this study was therefore to evaluate PAH-specific treatment in adults with PAH-CHD to better understand PAH-specific therapy management. In this cross-sectional study we retrospectively examined clinical, demographic, and cardiac-catheterization data and medical management for PAH-CHD, and analyzed clinical course and midterm outcome. Over up to 14 years (median, 6.2 years), 103 PAH-CHD patients (66% female) receiving targeted PAH-therapy for pre-tricuspid-shunt (15.5%), post-tricuspid-shunt (32.0%), and complex CHD (52.4%) were followed. Based on modified clinical European Society of Cardiology (ESC) classification, patients were assigned to the following subgroups: Eisenmenger syndrome (ES) (45.6%), severe pulmonary vascular disease (PVD) in complex CHD (20.4%), post-repair patients (19.4%), prevalent systemic-to-pulmonary shunt (3.9%), coincidental/small defects (0%), and Fontan circulation (10.7%). Changes in targeted PAH therapy were observed 249 times, with up to 6 (median, 2) therapy changes over a median period of 1.3 years. Over the study course, the medical treatment strategy changed towards combination therapy (baseline, 13.6%; study-end, 41%), resulting mostly in stabilized functional class or even improvement in cases of prevalent systemic-to-pulmonary shunt, ES, and patients with repaired CHD. Functional class deterioration, however, was seen in patients with severe PVD due to complex CHD, and Fontan patients. Of the 103 patients in the study, 25 died (24.3%). Patients with repaired CHD and patients with systemic-to-pulmonary shunt or ES showed the best survival rates. Mortality was remarkably higher in patients with severe PVD in complex CHD and Fontan patients. Many patients with PAH-CHD benefited from targeted PAH therapy over a median period of 6.2 years. Treatment decisions after targeted PAH-medication initiation were based mainly on clinical assessment. To counteract disease progression, an escalation towards combination therapy was observed during the study course. We consider survival rates under targeted PAH medication to be favorable, particularly in the ES subgroup. Nevertheless, further research is needed to optimize the use of PAH medication, especially in patients with complex CHD.

BURDEN OF ILLNESS IN PATIENTS WITH PULMONARY HYPERTENSION DUE TO COPD IN US ADMINISTRATIVE CLAIMS DATA

BURDEN OF ILLNESS IN PATIENTS WITH PULMONARY HYPERTENSION DUE TO COPD IN US ADMINISTRATIVE CLAIMS DATA

Improved Survival for Patients with Systemic Sclerosis-associated Pulmonary Arterial Hypertension: The Johns Hopkins Registry.

Rationale: To date, it remains unclear whether recent changes in the management of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) have improved survival. Objectives: To describe a cohort of patients with SSc-PH and compare their characteristics and survival between the last two decades. Methods: Patients with SSc-PH prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Center Registry were grouped into two cohorts based on the date of diagnostic right heart catheterization: cohort A included patients whose disease was diagnosed between 1999 and 2010, and cohort B included those whose disease was diagnosed between 2010 and 2021. Patients' characteristics were compared between the two cohorts. Measurements and Main Results: Of 504 patients with SSc-PH distributed almost equally between the two cohorts, 308 (61%) had World Symposium on Pulmonary Hypertension group 1, 43 (9%) had group 2, and 151 (30%) had group 3 disease. Patients with group 1 disease in cohort B had significantly better clinical and hemodynamic characteristics at diagnosis, were more likely to receive upfront combination pulmonary arterial hypertension therapy, and had a nearly 4-year increase in median transplant-free survival in univariable analysis than those in cohort A (P < 0.01). Improved transplant-free survival was still observed after adjusting for patients' baseline characteristics. In contrast, for group 2 or 3 patients with SSc-PH, there were no differences in baseline clinical, hemodynamic, or survival characteristics between the two cohorts. Conclusions: This is the largest single-center study that compares clinical characteristics of patients with SSc-PH between the last two decades. Transplant-free survival has improved significantly for those with group 1 disease over the last decade, possibly secondary to earlier detection and better therapeutic management. Conversely, those with group 2 or 3 disease continue to have dismal prognosis.

Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease with high morbidity and mortality. Deleterious remodeling in the pulmonary arterial system leads to irreversible arterial constriction and elevated pulmonary arterial pressures, right heart failure, and eventually death. The difficulty in treating PAH stems in part from the complex nature of disease pathogenesis, with several signaling compounds known to be involved (e.g., endothelin-1, prostacyclins) which are indeed targets of PAH therapy. Over the last decade, potassium channelopathies were established as novel causes of PAH. More specifically, loss-of-function mutations in the KCNK3 gene that encodes the two-pore-domain potassium channel KCNK3 (or TASK-1) and loss-of-function mutations in the ABCC8 gene that encodes a key subunit, SUR1, of the ATP-sensitive potassium channel (KATP) were established as the first two potassium channelopathies in human cohorts with pulmonary arterial hypertension. Moreover, voltage-gated potassium channels (Kv) represent a third family of potassium channels with genetic changes observed in association with PAH. While other ion channel genes have since been reported in association with PAH, this review focuses on KCNK3, KATP, and Kv potassium channels as promising therapeutic targets in PAH, with recent experimental pharmacologic discoveries significantly advancing the field.

Assessing Daily Life Physical Activity by Actigraphy in Pulmonary Arterial Hypertension: Insights From the Randomized Controlled Study With Selexipag (TRACE)

Reduced daily life physical activity (DLPA) in pulmonary arterial hypertension (PAH) contributes to a poor quality of life. Can actigraphy be used to assess changes in DLPA in patients with PAH receiving selexipag or placebo? Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension (TRACE) was a prospective, multicenter, randomized, placebo-controlled, double-blind, exploratory phase 4 study enrolling patients with PAH in World Health Organization functional class II/III, receiving stable endothelin receptor antagonist with/without phosphodiesterase type 5 inhibitor background therapy. Primary end points were change from baseline to Week 24 in actigraphy-assessed DLPA (recorded by using an accelerometer), including daily time spent in nonsedentary physical activity (NSPA), daily time spent in moderate to vigorous physical activity (MVPA), daily volume of activity, and daily number of steps. At baseline, patients (N= 108) were prevalent, on stable background PAH therapy, and at low risk of disease progression. Patients showed high compliance with wear of the accelerometer throughout the study. From baseline to Week 24, mean daily time spent in NSPA increased by 1.1min and decreased by 16.7min in the selexipag and placebo groups (treatment difference [95%CI], 17.8 [-6.0, 41.6] min); mean time spent in MVPA increased by 0.3min and was reduced by 2.0min in the selexipag and placebo groups (treatment difference [95%CI], 2.3 [-10.8, 15.4] min); and mean number of daily steps decreased by 0.3 and 201.9 in the selexipag and placebo groups (treatment difference [95%CI], 201.6 [-243.0, 646.2]). TRACE enrolled a prevalent population on background therapy and at low risk of disease progression. Changes in DLPA were small and highly variable, with no statistically significant differences between treatment groups. This patient-centric study was the first randomized trial in PAH to capture high-quality actigraphy data and to describe DLPA in terms of mean/median and variability, which may inform the design of future studies. ClinicalTrials.gov; No.: NCT03078907; URL: www. gov.

A Protocol for Fabrication and on-Chip Cell Culture to Recreate PAH-Afflicted Pulmonary Artery on a Microfluidic Device.

Pulmonary arterial hypertension (PAH) is a rare pulmonary vascular disease that affects people of all ethnic origins and age groups including newborns. In PAH, pulmonary arteries and arterioles undergo a series of pathological changes including remodeling of the entire pulmonary vasculatures and extracellular matrices, mis-localized growth of pulmonary arterial cells, and development of glomeruloid-like lesions called plexiform lesions. Traditionally, various animal and cellular models have been used to understand PAH pathophysiology, investigate sex-disparity in PAH and monitor therapeutic efficacy of PAH medications. However, traditional models can only partially capture various pathological features of PAH, and they are not adaptable to combinatorial study design for deciphering intricately intertwined complex cellular processes implicated in PAH pathogenesis. While many microfluidic chip-based models are currently available for major diseases, no such disease-on-a-device model is available for PAH, an under investigated disease. In the absence of any chip-based models of PAH, we recently proposed a five-channel polydimethylsiloxane (PDMS)-based microfluidic device that can emulate major pathological features of PAH. However, our proposed model can make a bigger impact on the PAH field only when the larger scientific community engaged in PAH research can fabricate the device and develop the model in their laboratory settings. With this goal in mind, in this study, we have described the detailed methodologies for fabrication and development of the PAH chip model including a thorough explanation of scientific principles for various steps for chip fabrication, a detailed list of reagents, tools and equipment along with their source and catalogue numbers, description of laboratory setup, and cautionary notes. Finally, we explained the methodologies for on-chip cell seeding and application of this model for studying PAH pathophysiology. We believe investigators with little or no training in microfluidic chip fabrication can fabricate this eminently novel PAH-on-a-chip model. As such, this study will have a far-reaching impact on understanding PAH pathophysiology, unravelling the biological mystery associated with sexual dimorphism in PAH, and developing PAH therapy based on patient sex and age.