Pulmonary Arterial Hypertension Therapy Research Articles

Recent Controversies in Initiation of Drug Therapy for Pulmonary Arterial Hypertension

Current guidelines recommend the early use of combination therapy for pulmonary arterial hypertension (PAH). However, it remains unclear whether initial combination therapy is associated with improved survival. Furthermore, the optimal combination of initial PAH therapy (including the early use of prostacyclins) is a subject of debate. With the definition of pulmonary hypertension lowered to a mean PAP of 20 mmHg, an evidence gap exists regarding approach to treating a new group with only mildly abnormal hemodynamics. The talk will highlight some of the controversies in the treatment of PAH. Current guidelines recommend the early use of combination therapy for pulmonary arterial hypertension (PAH). However, it remains unclear whether initial combination therapy is associated with improved survival. Furthermore, the optimal combination of initial PAH therapy (including the early use of prostacyclins) is a subject of debate. With the definition of pulmonary hypertension lowered to a mean PAP of 20 mmHg, an evidence gap exists regarding approach to treating a new group with only mildly abnormal hemodynamics. The talk will highlight some of the controversies in the treatment of PAH.

A Review of Pulmonary Arterial Hypertension Treatment in Extracorporeal Membrane Oxygenation: A Case Series of Adult Patients.

Little data is published describing the use of medications prescribed for pulmonary arterial hypertension (PAH) in patients receiving extracorporeal membrane oxygenation (ECMO). Even though many patients with PAH may require ECMO as a bridge to transplant or recovery, little is reported regarding the use of PAH medications in this setting. This retrospective case series summarizes the clinical experience of 8 patients with PAH receiving ECMO and reviews medication management in the setting of ECMO. Eight PAH patients, 5 of whom were female, ranging in age from 21 to 61 years old, were initiated on ECMO. Veno-arterial (VA) ECMO was used in 4 patients, veno-venous (VV) ECMO and hybrid ECMO configurations in 2 patients respectively. Common indications for ECMO included cardiogenic shock, bridge to transplant, and cardiac arrest. All patients were on intravenous (IV) prostacyclin therapy at baseline. Refractory hypotension was noted in 7 patients of whom 5 patients required downtitration or discontinuation of baseline PAH therapies. Three patients had continuous inhaled epoprostenol added during their time on ECMO. In patients who were decannulated from ECMO, PAH therapies were typically resumed or titrated back to baseline dosages. One patient required no adjustment in PAH therapy while on ECMO. Two patients were not able to be decannulated from ECMO. The treatment of critically ill PAH patients is challenging given a variety of factors that could affect PAH drug concentrations. In particular, PAH patients on prostacyclin analogues placed on VA ECMO appear to have pronounced systemic vasodilation requiring vasopressors which is alleviated by temporarily reducing the intravenous prostacyclin dose. Patients should be closely monitored for potential need for rapid titrations in prostacyclin therapy to maintain hemodynamic stability.

Intra-Airway Gene Delivery for Pulmonary Hypertension in Rodent Models.

Pulmonary arterial hypertension (PAH) is a severe and progressive cardiopulmonary disease characterized by pathological remodeling of the resistance pulmonary arteries (PA), ultimately leading to right ventricular (RV) failure and death. Animal models have been particularly useful for unraveling the pathogenesis of PAH by providing incisive experimental strategies that were impossible in human studies. Over the past decade, gene therapy has been making considerable progress as an alternative strategy for treating PAH disease. Animal models mimicking PAH disease are essential at preclinical stages for assessing the therapeutic potential of gene therapy and determining genome viral vectors transduction, safety, dosage, and localization of transgene expression. The most commonly used PAH rat models in gene therapy studies are the monocrotaline (MCT), the chronic hypoxia-Sugen 5416, and the pneumonectomy (PNT)-MCT models. Here, we provide detailed protocols for creating these preclinical rodent models of PAH commonly used to assess the efficiency of lung gene therapy in PAH.

Inhaled Nitric Oxide Therapy for Pulmonary Arterial Hypertension of Newborn

Background: Inhaled nitric oxide (iNO) has been in use for several decades now in neonates with hypoxic respiratory failure (HRF) associated with pulmonary hypertension (PH). Its requirement is uncommon, and is considered as an advanced form of support that is not widely available. Analysis of outcomes in specific settings, notably from low-middle income countries, is crucial. Objectives: To evaluate the patient profile and outcomes of neonates treated with iNO in our Level IIIB unit. Methods: This retrospective observational study describes the clinical diagnosis, management strategies and short-term outcomes of all neonates who received iNO in the years between 2013 and 2021. Details were retrieved from Electronic Medical Records and systematically analysed. Observation: Of 35 infants who received iNO during the study period, 31 (88.6%) were >34 weeks. The median and interquartile range (IQR) of oxygenation index at which iNO was started was 28 (20,33). The median (IQR) duration of iNO therapy was 48 (23,95) hours. Overall, 18 neonates (51.4%) survived till hospital discharge. Therapeutic response was best observed in infants with HRF secondary to meconium aspiration syndrome or congenital pneumonia (100% survival). Though the benefits of iNO use in congenital diaphragmatic hernia and bronchopulmonary dysplasia associated with PH are debatable, its use continues as a rescue measure. Conclusion: iNO is used in severe HRF associated with PH in neonates and can improve survival rates in select patient profiles without any major adverse outcomes.

Right ventricular reverse remodeling assessed by echocardiography as a new goal-oriented treatment strategy in PAH patients

While in heart failure with reduced ejection fraction, left ventricular reverse remodeling is associated with better prognosis, right ventricular reverse remodeling (RVRR) was less investigated in pulmonary arterial hypertension (PAH). To investigate whether RVVR assessed by echocardiography could help to stratify PAH patient's prognosis. Between 2002 and 2019, consecutive PAH patients were included, treated and followed in a single PAH center in accordance with the guidelines. In addition to regular risk stratification parameters, we measured several RV systolic function and size parameters at baseline, 1-year of follow-up as well as their change (i.e., delta) under treatment. Primary composite outcome was 3-year transplant-free survival and death from all cause from the 1-year evaluation. Conditional inference trees were used to determine which echocardiographic parameters and cutoffs values were associated with primary outcome from hierarchy of multiple covariates in multivariable Cox regression analysis. In total, 126 incident patients were included (63% female, mean age 59 ± 18 yo), mainly due to connectivite-tissue disease and idiopathic PAH (26%, 22% respectively). At 1-y follow-up under PAH therapy, NYHA ( P < 0.01), NTproBNP ( P < 0.01), mPAP ( P < 0.01) were significantly improved. Conditional inference trees showed that 1-year tricuspid annular plane systolic excursion gain > 1 mm and right ventricular end-diastolic area decreased > 2 cm 2 were associated with 3-year transplant-free survival in multivariable Cox regression analysis (HR = 0.23, 95% CI [0.08–0.61] P = 0.0035, HR = 0.34, 95% CI [0.12–0.94], P = 0.038). Simple score from 0 (absence of RVRR), 1 (partial RVRR) and 2 (complete RVRR), describing the number of echocardiographic parameters reach at 1-year was investigated: complete RVRR depicted better prognosis (log-rank P < 0.001) ( Fig. 1 ). Complete RVRR represent a new goal-oriented treatment strategy in PAH patients.

MMP-10 from M1 macrophages promotes pulmonary vascular remodeling and pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by muscularized pulmonary blood vessels, leading to right heart hypertrophy and cardiac failure. However, state-of-the-art therapeutics fail to target the ongoing remodeling process. Here, this study shows that matrix metalloproteinases (MMP)-1 and MMP-10 levels are increased in the medial layer of vessel wall, serum, and M1-polarized macrophages from patients with PAH and the lungs of monocrotaline- and hypoxia-induced PAH rodent models. MMP-10 regulates the malignant phenotype of pulmonary artery smooth muscle cells (PASMCs). The overexpression of active MMP-10 promotes PASMC proliferation and migration via upregulation of cyclin D1 and proliferating cell nuclear antigen, suggesting that MMP-10 produced by infiltrating macrophages contributes to vascular remodeling. Furthermore, inhibition of STAT1 inhibits hypoxia-induced MMP-10 but not MMP-1 expression in M1-polarized macrophages from patients with PAH. In conclusion, circulating MMP-10 could be used as a potential targeted therapy for PAH.

An open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of GSK2586881 in participants with pulmonary arterial hypertension.

Preclinical and early clinical studies suggest that angiotensin‐converting enzyme type 2 activity may be impaired in patients with pulmonary arterial hypertension (PAH); therefore, administration of exogenous angiotensin‐converting enzyme type 2 (ACE2) may be beneficial. This Phase IIa, multi‐center, open‐label, exploratory, single‐dose, dose‐escalation study (NCT03177603) assessed the potential vasodilatory effects of single doses of GSK2586881 (a recombinant human ACE2) on acute cardiopulmonary hemodynamics in hemodynamically stable adults with documented PAH who were receiving background PAH therapy. Successive cohorts of participants were administered a single intravenous dose of GSK2586881 of 0.1, 0.2, 0.4, or 0.8 mg/kg. Dose escalation occurred after four or more participants per cohort were dosed and a review of safety, tolerability, pharmacokinetics, and hemodynamic data up to 24 h postdose was undertaken. The primary endpoint was a change in cardiopulmonary hemodynamics (pulmonary vascular resistance, cardiac index, and mean pulmonary artery pressure) from baseline. Secondary/exploratory objectives included safety and tolerability, effect on renin‐angiotensin system peptides, and pharmacokinetics. GSK2586881 demonstrated no consistent or sustained effect on acute cardiopulmonary hemodynamics in participants with PAH receiving background PAH therapy (N = 23). All doses of GSK2586881 were well tolerated. GSK2586881 was quantifiable in plasma for up to 4 h poststart of infusion in all participants and caused a consistent and sustained reduction in angiotensin II and a corresponding increase in angiotensin (1–7) and angiotensin (1–5). While there does not appear to be a consistent acute vasodilatory response to single doses of GSK2586881 in participants with PAH, the potential benefits in terms of chronic vascular remodeling remain to be determined.

Secular and Regional Trends among Pulmonary Arterial Hypertension Clinical Trial Participants.

Rationale: The population of patients with pulmonary arterial hypertension (PAH) has evolved over time from predominantly young White women to an older, more racially diverse and obese population. Whether these changes are reflected in clinical trials is not known. Objectives: To determine secular and regional trends among PAH trial participants. Methods: We performed a pooled cohort analysis using harmonized data from phase III clinical trials of PAH therapies submitted to the U.S. Food and Drug Administration. We used mixed-effects linear and logistic regression to assess regional differences in participant age, sex, body habitus, and hemodynamics over time. Results: A total of 6,599 participants were enrolled in 18 trials between 1998 and 2013; 78% were female. The mean age of participants in North America, Europe, and Latin America at the time of study start increased by 2.09 (95% confidence interval [CI], 0.67-3.51), 1.62 (95% CI, 0.24-3.00), and 4.75 (95% CI, 2.29-7.21) years per 5 years, respectively (P = 0.01). Body mass index at the time of study start increased by 0.72 kg/m2 per 5 years (95% CI, 0.44-0.99; P < 0.001) across all regions. Eighty-five percent of participants in early studies were non-Hispanic White, but this decreased over time to 70%. Ninety-seven percent of Asians and 74% of Hispanics in the sample were recruited from Asia and Latin America. Conclusions: Patients enrolled in more recent PAH therapy trials are older and more obese, mirroring the changing epidemiology of observational cohorts. However, these trends varied by geographic region. PAH cohorts remain predominantly female, presenting challenges for generalizability to male patients. Although the proportion of non-White participants increased over time, this was primarily through recruitment in Asia and Latin America.

Use of Pulmonary Arterial Hypertension Therapies in Patients with a Fontan Circulation: Current Practice Across the United Kingdom.

BackgroundThe Fontan circulation is a successful operative strategy for abolishing cyanosis and chronic volume overload in patients with congenital heart disease with single ventricle physiology. “Fontan failure” is a major cause of poor quality of life and mortality in these patients. We assessed the number and clinical characteristics of adult patients with Fontan physiology receiving pulmonary arterial hypertension (PAH) therapies across specialist centers in the United Kingdom.Methods and ResultsWe identified all adult patients with a Fontan‐type circulation under active follow‐up in 10 specialist congenital heart disease centers in England and Scotland between 2009 and 2019. Patients taking PAH therapies were matched to untreated patients. A survey of experts was also performed. Of 1538 patients with Fontan followed in specialist centers, only 76 (4.9%) received PAH therapies during follow‐up. The vast majority (90.8%) were treated with a phosphodiesterase‐5 inhibitor. In 33% of patients, PAH therapies were started after surgery or during hospital admission. In the matched cohort, treated patients were more likely to be significantly limited, have ascites, have a history of protein‐losing enteropathy, or receive loop diuretics (P<0.0001 for all), also reflecting survey responses indicating that failing Fontan is an important treatment target. After a median of 12 months (11–15 months), functional class was more likely to improve in the treated group (P=0.01), with no other changes in clinical parameters or safety issues.ConclusionsPAH therapies are used in adult patients with Fontan circulation followed in specialist centers, targeting individuals with advanced disease or complications. Follow‐up suggests stabilization of the clinical status after 12 months of therapy.

Aggressive Afterload Lowering to Improve the Right Ventricle: A New Target for Medical Therapy in Pulmonary Arterial Hypertension?

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

121 Imaging of improved right ventricular function and risk status in pulmonary arterial hypertension

Abstract Aims Right ventricular function adaptation to afterload as assessed by the ratio of tricuspid annular plane excursion (TAPSE) to systolic pulmonary artery pressure (PASP) has been shown to be of prognostic relevance in pulmonary arterial hypertension (PAH). To test the hypothesis that improvement in TAPSE/PASP under targeted therapies is associated with the likelihood to achieve a better prognostic low-risk status in PAH. Methods and results The study retrospectively enrolled 677 PAH patients (55% idiopathic) with follow-up clinical, right heart catheterization, and echocardiographic evaluations within 12 months [interquartile range (IQR): 180–344 days] after initiation of targeted therapies from 2005 to 2017 in 11 Italian centres. European guidelines-derived and United States Registry to Evaluate Early and Long-Term PAH Disease Management registry REVEAL 2.0 risk scores were assessed at baseline and follow-up. The patients improved their functional class and 6-min walk distance, but a minority of them achieved or maintained the low risk status as assessed either with the European or the REVEAL 2.0 score (30% and 27%, respectively). The TAPSE/PASP ratio increased curvilinearly in proportion to decreased pulmonary vascular resistance (PVR) by more than 50%. Patients at low risk were, respectively, 4.93 and 3.37 times more likely to have TAPSE/PASP ≥0.35 mm/mmHg than those at intermediate or high risk, according to the ESC/ERS [odds ratio: (OR) 4.93, confidence interval (CI): 3.40–7.14; P = 0.0001] and the REVEAL 2.0 score (OR: 3.37, CI: 2.32–4.90; P = 0.0001). Conclusions Improvement of TAPSE/PASP under targeted therapies in PAH is associated with a low risk status, marked reduction in PVR, and improved outcome.

Clinical Relevance of Right Atrial Functional Response to Treatment in Pulmonary Arterial Hypertension

Background: Right atrial (RA) function has emerged as an important determinant of outcome in pulmonary arterial hypertension (PAH). However, studies exploring RA function after initiation of specific pulmonary vascular treatment and its association with outcome in patients with incident PAH are lacking.Methods: RA peak longitudinal strain (PLS), passive strain (PS), and peak active contraction strain (PACS) were retrospectively assessed in 56 treatment-naïve patients with PAH at baseline and during follow-up after initiation of specific monotherapy or combination therapy. Patients were grouped according to their individual RA functional response to treatment, based on change from baseline (Δ): worsened (first Δ-tertile), stable (second Δ-tertile), and improved (third Δ-tertile). The Spearman's rho correlation and linear regression analysis were used to determine associations. Time to clinical worsening (defined as deterioration of functional class or 6-min walking distance, disease-related hospital admission, or death) was measured from the follow-up assessment. The association of RA functional treatment response with time to clinical worsening was assessed using the Kaplan–Meier and the Cox regression analyses.Results: Median (interquartile range) time to echocardiographic follow-up was 11 (9–12) months. Of the 56 patients, 37 patients (66%) received specific dual or triple combination therapy. Δ RA PLS during follow-up was significantly associated with changes in key hemodynamic and echocardiographic parameters. The change of pulmonary vascular resistance, right ventricular (RV) end-systolic area, and global longitudinal strain were independently associated with Δ RA PLS. The median time to clinical worsening after echocardiographic follow-up was 6 (2–14) months [17 events (30%)]. In the multivariate Cox regression analysis, worsening of RA PLS was significantly associated with clinical deterioration (hazard ratio: 4.87; 95% CI: 1.26–18.76; p = 0.022). Patients with worsened RA PLS had a significantly poorer prognosis than those with stable or improved RA PLS (log-rank p = 0.012). By contrast, PS and PACS did not yield significant prognostic information.Conclusion: Treatment-naïve patients with PAH may show different RA functional response patterns to PAH therapy. These functional patterns are significantly associated with clinically relevant outcome measures. Improvements of RA function are driven by reductions of afterload, RV remodeling, and RV dysfunction.

PH Roundtable: Genetics and Pulmonary Hypertension

PH Roundtable: Genetics and Pulmonary Hypertension

Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies are not curative, and therapeutic approaches mostly target endothelial dysfunction, while PASMC dysfunction is under investigation. In PAH, modifications in intracellular Ca2+ homoeostasis could partly explain PASMC dysfunction. One of the most crucial actors regulating Ca2+ homeostasis is store-operated Ca2+ channels, which mediate store-operated Ca2+ entry (SOCE). This review focuses on the main actors of SOCE in human and experimental PASMC, their contribution to PAH pathogenesis, and their therapeutic potential in PAH.

Abstract 13798: Pulmonary Arterial Hypertension Associated With Repaired Congenital Heart Disease in Children: Comparable Survival to Eisenmenger Syndrome

Introduction: Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD). Advances in management have altered the demographics of PAH-CHD, with fewer cases of Eisenmenger syndrome (ES) and more patients with PAH after CHD repair, who have worse outcomes than ES patients and an idiopathic PAH (IPAH)-like phenotype. However, pediatric data are limited. Methods: Patients under active follow-up in the National Paediatric Pulmonary Hypertension service UK between 2001 and 2021 were identified. Incident patients were included in survival analysis. Results: Overall, 164 patients with repaired PAH-CHD were included (57.9% female, 53.7% trisomy 21, 3.7[0.1-16.8] years at diagnosis), along with 95 patients with ES and 146 with IPAH. Most repaired PAH-CHD patients had an isolated post-tricuspid (59%), followed by a combined pre/post-tricuspid (28%) and isolated pre-tricuspid shunt (13.4%). Median age at repair was 13.6[5.6-51] months. PAH was diagnosed prior to repair in 24.5%. Symptoms were present in 53.7%, whereas 46.3% were identified during surveillance. PAH therapy was started in 86%; at last follow-up, repaired PAH-CHD patients were less likely to be on combination therapy than IPAH patients (32.9% vs 70.5%, p&lt;0.0001). Resolution of PH occurred in 8.5% patients at 6.4[3.1-9.4] months from diagnosis. Transplant-free survival in repaired PAH-CHD was 91.9% (95%CI: 87.6-96.4%) at 1 year, 86.1% (80.4-92.2%) at 5 years, and 77% (68.2-86.9%) at 10 years. Repaired PAH-CHD diagnosed in infancy had a significantly worse survival ( Fig 1A ). There was no difference in survival between repaired PAH-CHD and ES (p=0.68). IPAH had a worse survival than both groups (HR vs repaired 1.97, 95%CI:1.22-3.2, p=0.006, Fig 1B ). Conclusions: In this national paediatric cohort, patients with PAH after CHD repair had a better prognosis than patients with IPAH and similar to ES, albeit with a 23% mortality at 10 years, worse in patients diagnosed as infants.

Therapy for Pulmonary Arterial Hypertension: Glance on Nitric Oxide Pathway.

Pulmonary arterial hypertension (PAH) is a severe disease with a resultant increase of the mean pulmonary arterial pressure, right ventricular hypertrophy and eventual death. Research in recent years has produced various therapeutic options for its clinical management but the high mortality even under treatment remains a big challenge attributed to the complex pathophysiology. Studies from clinical and non-clinical experiments have revealed that the nitric oxide (NO) pathway is one of the key pathways underlying the pathophysiology of PAH. Many of the essential drugs used in the management of PAH act on this pathway highlighting its significant role in PAH. Meanwhile, several novel compounds targeting on NO pathway exhibits great potential to become future therapy medications. Furthermore, the NO pathway is found to interact with other crucial pathways. Understanding such interactions could be helpful in the discovery of new drug that provide better clinical outcomes.

β-Arrestin–Mediated Angiotensin II Type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a disease of abnormal pulmonary vascular remodeling whose medical therapies are thought to primarily act as vasodilators but also may have effects on pulmonary vascular remodeling. The angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that promotes vasoconstriction through heterotrimeric G proteins but also signals via β-arrestins, which promote cardioprotective effects and vasodilation through promoting cell survival. We found that an AT1R β-arrestin-biased agonist promoted vascular remodeling and worsened PAH, suggesting that the primary benefit of current PAH therapies is through pulmonary vascular reverse remodeling in addition to their vasodilation.

Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension

IntroductionIn the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag. MethodsPatients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019.ResultsOverall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan–Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively.ConclusionsThese results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen.Trial RegistrationClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01898-1.

Real-World Analysis of Treatment Patterns Among Hospitalized Patients with Pulmonary Arterial Hypertension.

IntroductionHospitalization is an important clinical factor associated with survival and rehospitalization in patients with pulmonary arterial hypertension (PAH). Thus, this study examined treatment patterns before and after hospitalization in the US-specific population.MethodsAdult PAH patients in the United States were identified using the Optum® Clinformatics® database from January 1, 2014, to June 30, 2019, and were required to have continuous health plan enrollment for at least 6 months prior to the first (index) hospitalization through at least 90 days post-discharge. Baseline patient characteristics were evaluated from 6 months prior to through the index hospitalization. PAH treatment patterns were examined from 30 days pre-index admission (pre-hospitalization) and 90 days post-index hospital discharge (post-hospitalization), and stratified by therapy type: monotherapy, double- or triple-combination therapy, or no PAH therapy.ResultsA total of 3116 hospitalized patients with PAH met selection criteria. The mean age and Charlson comorbidity index score were 68.1 years and 5.1, respectively. In the pre- and post-hospitalization periods (all-cause), respectively, patients prescribed monotherapy were most common (from 64.8% pre- to 51.9% post-hospitalization), followed by patients with no evidence of PAH therapy (from 14.6 to 28.5%). Among PAH-related hospitalizations, patients with monotherapy were also most common (from 60.8% pre- to 49.1% post-hospitalization), followed by patients with no evidence of PAH therapy (from 10.0 to 22.8%). The majority of patients with all-cause hospitalizations (72.8%) had no therapy modification; 20.0% de-escalated therapy (including 15.0% from monotherapy to no therapy) and 6.1% escalated therapy (including 2.2% from no therapy to monotherapy and 3.2% from monotherapy to double or triple therapy).ConclusionInpatient admissions did not appear to drive changes in PAH therapy management, as monotherapy predominated, and most patients had no therapy modification within 90 days of a hospitalization. These results warrant future research to understand the reasons behind the limited treatment intensification observed and the impact of post-hospitalization optimization on clinical and economic outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41030-021-00173-6.

Magnolol Attenuates Right Ventricular Hypertrophy and Fibrosis in Hypoxia-Induced Pulmonary Arterial Hypertensive Rats Through Inhibition of the JAK2/STAT3 Signaling Pathway.

Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol (6, 6′, 7, 12-tetramethoxy-2,2′-dimethyl-1-β-berbaman, C18H18O2) is a compound isolated from Magnolia Officinalis. It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. In vivo, male Sprague Dawley rats were exposed to 10% O2 for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of Fulton index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3; these changes were attenuated by treating with magnolol. In vitro, the cultured H9c2 cells or cardiac fibroblasts were exposed to 3% O2 for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagen Ⅰ, collagen Ⅲ, and α-SMA). Administration of magnolol and TG-101348 or JSI-124 (both JAK2 selective inhibitors) could prevent myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. Based on these observations, we conclude that magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway. Magnolol may possess the potential clinical value for PAH therapy.