Pulmonary Arterial Hypertension Population Research Articles

Long-term efficacies of selective vasodilators in pulmonary arterial hypertension: a comprehensive comparison using a spontaneous reporting database.

There is no clinical evidence of differences in drugs associated with long-term survival in patients with pulmonary arterial hypertension (PAH) due to the small population and lack of information on death in Japanese medical database systems. This study evaluated whether patient data from a spontaneous reporting database could be used for comparing the effects of pulmonary vasodilators on long-term survival in PAH patients. PAH patient data reported in the Japanese Adverse Drug Event Report (JADER) database from April 2004 to July 2022 were extracted. Kaplan-Meier curves were used to compare survival times. Adjusted hazard ratios (aHRs) for all-cause mortality were determined using Cox proportional hazards models. Of 1969 PAH patients reported in the JADER database, 1208 were included in the survival analyses. The patient demographics were similar to those of the PAH population reported in the Japan Pulmonary Hypertension Registry. Among drugs targeting the prostacyclin pathway, epoprostenol was most associated with long-term survival (aHR, 0.38; 95% confidence interval (CI), 0.23-0.64). The PAH patients treated with endothelin receptor antagonists had improved survival, especially among the macitentan users (aHR, 0.30; 95% CI, 0.22-0.42). Sildenafil was associated with a poor prognosis in the PAH patients (aHR, 1.56; 95% CI, 1.19-2.04). Although our results must be interpreted with caution due to several limitations inherent to spontaneous reporting databases, our approach using the JADER database for survival analysis may provide useful information in limited situations such as the treatment of rare diseases including PAH.

The Association Between Non-Clinically Apparent Liver Fibrosis and Pulmonary Arterial Hypertension in Hispanic Patients.

Pulmonary arterial hypertension (PAH) is a deadly cardiopulmonary disease with multi-organ involvement including impaired liver function. Liver dysfunction in PAH is poorly understood but significantly associated with morbidity and mortality. Hispanics have a significantly higher prevalence of non-alcoholic fatty liver disease (NAFLD) and evidence of more advanced disease in comparison to other ethnic groups. The clinical impact of NAFLD in Hispanic PAH patients is unknown. We aimed to investigate the impact of a validated scoring system, non-alcoholic fatty liver disease fibrosis score (NFS), to predict the degree of liver fibrosis in a Hispanic PAH population and its relationship to hemodynamics, functional class, and outcomes. A retrospective review of all treatment-naive Hispanic patients with group I World Health Organization (WHO) pulmonary hypertension (PH) at a single academic center between February 2016 and March 2021 was performed. Patients with history of substance or alcohol abuse, non-group I WHO PH, pre-existent liver disease, chronic kidney disease, atrial fibrillation, thyroid disease, and warfarin use were excluded from the study. The diagnosis of group I WHO PH was determined by cardiac catheterization after the exclusion of other etiologies. NFS was calculated for each patient and correlated with functional capacity, hemodynamics, N-terminal-pro-B-type natriuretic peptide (NT-proBNP), and survival. A total of 96 Hispanic patients were included in our study. The median age of patients in our cohort was 49 years (interquartile range: 15) and 69% of our cohort were females. Higher NFSs indicating advanced hepatic fibrosis (F3-F4) were found to correlate with elevated right-sided cardiac filling pressures (r = 0.27, P = 0.03), elevated levels of NT-proBNP (r = 0.32, P = 0.01), lower 6-minute walk distance (6MWD) (r = -0.49, P = 0.001), lower functional capacity (World Health Organization functional class, WHO-FC, r = -0.35, P = 0.051), a higher prevalence of diabetes (21.1% versus 51.9%, P = 0.001), a higher prevalence of risk factors for metabolic syndrome (81.5% versus 65.0%, P = 0.035), and worse 5-year survival rates. In Hispanic patients with PAH, NFSs correlate with the degree of right-sided pressure overload. In addition, advanced NFSs were independently associated with lower 5-year survival rates and added prognostic information to other established risk parameters in PAH. This study suggests that screening for liver disease in this vulnerable patient population can aid in earlier detection leading to discussion of lifestyle modifications and possible escalation of PAH-targeted therapies, thus leading to potential improvement in survival rates.

Pulmonary Arterial Hypertension in Hyperthyroidism: Age, Ethnic, and Gender Disparities

Objective: Pulmonary arterial hypertension (PAH) affects 2.6% of adults and 36% of people with chronic obstructive pulmonary disease (COPD). Several case reports and small case series suggested a hyperthyroidism-PAH association.
 Design: Retrospective chart review.
 Methods: We undertook a retrospective chart review (1982–2018) to assess PAH prevalence in a multi-ethnic convenience sample of hyperthyroid adults with multiple etiologies. We calculated associations of pulmonary artery maximum systolic pressure (PSAPmax) with subject age, and maximum serum triiodothyronine (T3) and thyroxine (T4), free T3, and T4, minimum serum thyroid-stimulating hormone (TSH), and thyroid antibody titers, comparing PAH prevalence and the odds of being undiagnosed as to hyperthyroidism etiology by gender and ethnicity/race.
 Results: We found a high prevalence of PAH in hyperthyroid people, like that reported for people with COPD. We found no significant association between PSAPmax and any thyroid function test or thyroid antibody titer. As reported more recently in the general population, PSAPmax significantly correlated with age in hyperthyroid people. There was no significant disparity in the prevalence of PAH among White, non-Hispanic Black, and Latinx hyperthyroid people or between genders. The percentage of patients whose hyperthyroidism etiology was undiagnosed was high with significant disparity only between non-Hispanic Black and White people and between men and women. PAH was common in hyperthyroid subjects with any hyperthyroidism etiology.
 Conclusions: 2D-echocardiography should be performed in all hyperthyroid people because PAH is common, especially in older people because of their co-morbidities and poorer prognoses. Further research is needed regarding demographic disparities in being undiagnosed as to hyperthyroidism etiology.
 Principal Verdicts/Significance Statement: We reconfirmed the high PAH incidence in hyperthyroidism, previously reported, but profoundly under-recognized by physicians, to patients’ detriment. Further, we found that the shift in the general PAH population from younger to older individuals is mirrored in hyperthyroid people with PAH. This is concerning because older people have more co-morbidities and worse prognoses, necessitating early, effective intervention. PAH was present with diverse hyperthyroidism etiologies, suggesting that it is multicausal, resulting from autoimmunity, thyroid hormone excess, and goitrous upper airway obstruction and should be considered, regardless of etiology. Our observations that many subjects had no established hyperthyroidism etiology and that males and Blacks were likelier to be undiagnosed are concerning, warranting further study.

SATISFY-JP, a phase II multicenter open-label study on Satralizumab, an anti-IL-6 receptor antibody, use for the treatment of pulmonary arterial hypertension in patients with an immune-responsive-phenotype: Study protocol.

Pulmonary arterial hypertension (PAH), an intractable disease with a poor prognosis, is commonly treated using pulmonary vasodilators modulating the endothelin, cGMP, and prostacyclin pathway. Since the 2010s, drugs for treating pulmonary hypertension based on mechanisms other than pulmonary vasodilation have been actively developed. However, precision medicine is based on tailoring disease treatment to particular phenotypes by molecular-targeted drugs. Since interleukin-6 (IL-6) is involved in the development of PAH in animal models, and some patients with PAH have elevated IL-6 levels, the cytokine is expected to obtain potentials for therapeutic targeting. Accordingly, we identified a phenotype with elevated cytokine activity of the IL-6 family in the PAH population by combining case data extracted from the Japan Pulmonary Hypertension Registry with a comprehensive analysis of 48 cytokines using artificial intelligence clustering techniques. Including an IL-6 threshold ≥2.73 pg/mL as inclusion criteria for reducing the risk of insufficient efficacy, an investigator-initiated clinical study using satralizumab, a recycling anti-IL6 receptor monoclonal antibody, for patients with an immune-responsive phenotype is underway. This study is intended to test whether use of patient biomarker profile can identify a phenotype responsive to anti-IL6 therapy.

Novel Loss of Function KCNA5 Variants in Pulmonary Arterial Hypertension.

Reduced expression and/or activity of Kv1.5 channels (encoded by KCNA5) is a common hallmark in human or experimental pulmonary arterial hypertension (PAH). Likewise, genetic variants in KCNA5 have been found in PAH patients, but their functional consequences and potential impact on the disease are largely unknown. Herein, we aimed to characterize the functional consequences of 7 KCNA5 variants found in a cohort of PAH patients. Potassium currents were recorded by patch-clamp technique in HEK293 cells transfected with WT or mutant Kv1.5 cDNA. Flow cytometry, western blot and confocal microscopy techniques were used for measuring protein expression and cell apoptosis in HEK293 and human pulmonary artery smooth muscle cells (hPASMC). KCNA5 variants found in PAH patients (namely, p.Arg184Pro and p.Gly384Arg) resulted in a clear loss of potassium channel function as assessed by electrophysiological and molecular modelling analyses. The p.Arg184Pro variant also resulted in a pronounced reduction of Kv1.5 expression. Transfection with p.Arg184Pro or p.Gly384Arg variants decreased apoptosis of hPASMCs compared with the WT, demonstrating that KCNA5 dysfunction in both variants affects cell viability. Thus, in addition to affecting channel activity, both variants were associated with impaired apoptosis, a crucial process linked to the disease. The estimated prevalence of dysfunctional KCNA5 variants in the PAH population analyzed was around 1 %. Our data indicate that some KCNA5 variants found PAH patients have critical consequences for channel function supporting the idea that KCNA5 pathogenic variants may be a causative or contributing factor for PAH.

Exhaled Air Metabolome Analysis for Pulmonary Arterial Hypertension Fingerprints Identification—The Preliminary Study

Pulmonary arterial hypertension (PAH) is a rare disease with a serious prognosis. The aim of this study was to identify biomarkers for PAH in the breath phase and to prepare an automatic classification method to determine the changing metabolome trends and molecular mapping. A group of 37 patients (F/M: 8/29 women, mean age 60.4 ± 10.9 years, BMI 27.6 ± 6.0 kg/m2) with diagnosed PAH were enrolled in the study. The breath phase of all the patients was collected on a highly porous septic material using a special patented holder PL230578, OHIM 002890789-0001. The collected air was then examined with gas chromatography coupled with mass spectrometry (GC/MS). The algorithms of Spectral Clustering, KMeans, DBSCAN, and hierarchical clustering methods were used to perform the cluster analysis. The identification of the changes in the ratio of the whole spectra of biomarkers allowed us to obtain a multidimensional pathway for PAH characteristics and showed the metabolome differences in the four subgroups divided by the cluster analysis. The use of GC/MS, supported with novel porous polymeric materials, for the breath phase analysis seems to be a useful tool in selecting bio-fingerprints in patients with PAH. The four metabolome classes which were obtained constitute novel data in the PAH population.

Influence of Iron Deficiency on Clinical and Haemodynamic Parameters in Pulmonary Arterial Hypertension Cohorts.

Iron deficiency (Fedef) has been shown to be common in patients with group 1 or pulmonary arterial hypertension (PAH). Several studies have shown a negative impact of Fedef on clinical and haemodynamic parameters of the disease, but data from individual studies have not been strong enough to lead to incorporation of the finding of Fedef into prognostic or therapeutic algorithms. The goal of this meta-analysis was to combine data from available studies to better define any associations between Fedef and established variables of prognostic importance in PAH. A literature search identified nine studies with extractable data relevant to the study questions. The impact of Fedef upon the following parameters was evaluated: 6-minute walk distance (6MWD), WHO-functional class, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, echocardiography, and findings from right heart catheterisation (RHC). Pooled results were reported as mean difference or risk difference with 95% confidence intervals utilising a random effects modeling approach. Fedef in the PAH population was common (47% of cases) and was associated with cardiovascular dysfunction (lower tricuspid annular plane systolic excursion [TAPSE], elevated NT-proBNP, and lower mixed venous oxygen saturation) and with reduction in functional capacity (lower 6MWD and higher functional class). This meta-analysis strengthens the relationships between Fedef and several markers of poor outcome in PAH. Fedef in patients with PAH warrants further scrutiny and merits consideration as a cause of clinical deterioration. Even though causation and longitudinal relationships between Fedef and PAH could not be identified, effect of Fedef on factors that affect disease prognosis is noteworthy and worthy of more focussed studies.

Genetic background of pediatric PAH in Spain and its clinical implications: data from the REHIPED Spanish Registry

Abstract Background The genetic background of pulmonary arterial hypertension (PAH) in the Spanish pediatric population could be different from the genetic background described in other countries. Besides, clinical implications of a positive genetic result in the PAH pediatric population are not fully understood yet, and could result in the “reclassification” of patients from one PAH group to another type among the current pediatric classification. Material and methods Patients under 19 years at diagnosis included in the REHIPED registry from January 2011 to December 2021 were included. Clinical variables and genetical results were recorded. Succesive NGS panels involving up to 35 genes were used. After the results of the genetic testing, we analyzed differences in survival, and if patients “moved” to another category in the current Nice classification. Results In the selected cohort of 98 patients (56.1% female), median age at diagnosis was 7.1 years (IQr 1.5–14.7), and ethnicity as follows: Caucasian (81.6%), Romani (8.2%), others (10.2%) (Table 1). Before the genetic testing, patients had been classified as Idiopathic (53.1%), Congenital Heart Disease-PAH (30.6%), Heritable (5.1%), Pulmonary veno-oclusive disease (PVOD) 6.1%, and Multisystemic disorder associated with PAH (5.1%). Pathogenic or likely pathogenic variants were found in 44 of the screened patients (44.9%): BMPR2 (12 cases), EIF2AK4 (9), TBX4 (n=4), MECP2 (n=3), KCNK3 (n=2), FOXF1 (n=2), NFU1 (N=4), ACVRL1 (n=1), BMPR1B (n=1), CLBCI (n=1), GBE1 (n=1), GDF2 (n=1), SOX17 (n=1), VHL (n=1), and digenic pathogenic variant in ABCC8/SMAD1 (n=1). After genetic analysis, 28 patients (28.6%) were “reclassified” (Fig. 1, panel A), with HPAH, PVOD and multisystemic disorders increasing up to 18.4%, 8.2%, and 12.2%, respectively. Worse Survival from death or lung transplantation was observed in heritable PVOD and multisystemic disorders (Fig. 1, panel B). Conclusions The Spanish pediatric PAH population showed higher prevalence of EIF2AK4 than other pediatric registries. Genetic testing resulted in the “reclassification” of a significant number of patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Rio Hortega grant from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III).

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

Social determinants of health in pulmonary arterial hypertension patients in the United States: Clinician perspective and health policy implications.

Social determinants of health (SDoH) can impact the vulnerable pulmonary arterial hypertension (PAH) population, especially during the COVID‐19 pandemic. Providers' understanding of SDoH at the point of care and their impact is unknown. We conducted semi‐structured virtual interviews with US clinicians at 17 pulmonary hypertension (PH) centers and one patient advocate from the Pulmonary Hypertension Association. We sought participants' perspective on SDoH in PAH and their impact. Transcripts were developed and analyzed for key themes to assess potential policy implications. Participants served a large PAH population and demonstrated high awareness of SDoH and its impact on treatment and outcomes. They reported that patients' SDoH, including socioeconomic status, health insurance, access to health care, education levels, health literacy, employment status, and insecurities associated with housing, food, transportation, and family support, impacted health and well‐being. COVID‐19‐related social isolation, mental health, and substance abuse contributed to significant inequities in care provision and outcomes. While telemedicine helped clinicians manage patients remotely during the pandemic, there was a concern for patients with limited access to this medium. Participants reported no formal screening for SDoH at the point of care. With the recognition and the desire to act upon health inequities associated with SDoH, participants felt that it was vital for their centers to have a dedicated PH social worker and support staff to optimize care and outcomes. An approach that integrates SDoH in PAH care management, streamlined through institutional policy, could address health disparities leading to improved healthcare access, outcomes, and quality of care.

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

The Association of N-Terminal Pro-Brain Natriuretic Peptide With Time to Clinical Worsening in Hispanic Patients With Pulmonary Arterial Hypertension.

BackgroundMeasurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) level is an important parameter in the risk assessment of patients with pulmonary arterial hypertension (PAH). Data about the prognostic value of NT-proBNP in the Hispanic PAH population are lacking. Historically, clinical trials in PAH have only included a minority of Hispanic patients. It has been reported that baseline NT-proBNP levels differ between different ethnicities. Furthermore, NT-proBNP levels can be impacted by declining renal function, making its interpretation difficult regarding clinical decision making.MethodsIn a retrospective single-center cohort analysis, Hispanic patients with PAH had a baseline outpatient NT-proBNP level drawn during a period of clinical stability and were followed for 1 year to monitor for time to clinical worsening (TTCW). The association of baseline NT-proBNP and TTCW was assessed in patients with normal and abnormal renal function.ResultsA total of 26 patients (22%) met the clinical endpoint of clinical worsening. Twenty-seven patients (24%) had chronic kidney disease (CKD). At baseline NT-proBNP levels showed a significant inverse correlation with 6-min walk test (6MWD, r = -0.382, P = 0.02), and a significant positive correlation with renal function (r = 0.273, P = 0.05). NT-proBNP levels did not correlate with age (r = 0.19, P = 0.11) or body mass index (BMI) (r = -0.292, P = 0.061). NT-proBNP levels of > 1,415 ng/L were significantly associated with shorter TTCW (P < 0.01) in all patients and in patients with CKD (P = 0.03). A stepwise increase in NT-proBNP levels by 100 ng/L was associated with a higher risk of meeting the clinical endpoint of TTCW in patients with normal renal function (hazard ratio (HR) = 1.8, P < 0.01) and CKD (HR = 1.5, P < 0.01).ConclusionsIn Hispanic patients with PAH, NT-proBNP is a valuable tool to predict 1-year TTCW, independent of renal function.

Treatment effect of selexipag on time to disease progression when initiated early in pulmonary arterial hypertension (PAH) patients: GRIPHON and TRITON pooled analysis

Abstract Background In PAH clinical practice, drugs targeting the prostacyclin pathway, including the oral prostacyclin receptor agonist selexipag, are often initiated years after diagnosis. The GRIPHON (NCT01106014) and TRITON (NCT02558231) randomised controlled trials examined the impact of selexipag on disease progression, primary and secondary endpoints, respectively. In GRIPHON, selexipag significantly reduced the risk of disease progression (composite primary endpoint) in a PAH population (N=1156) with a mean time from diagnosis of 2.4 years, as part of an oral triple, double or monotherapy regimen versus placebo. In TRITON, a potential signal for reduced risk of disease progression was observed with initial triple oral therapy (selexipag, macitentan, tadalafil) versus initial double oral therapy (placebo, macitentan, tadalafil) in a population of 247 newly diagnosed, treatment naïve patients. Purpose To investigate the impact of initiating selexipag within 6 months of diagnosis on disease progression in a large PAH population. Methods We selected patients from GRIPHON and TRITON diagnosed within 6 months of randomization and compared those on active therapy with selexipag (selexipag group) versus those on control therapy with placebo (control group). Disease progression endpoints were defined as in the GRIPHON and TRITON studies, respectively. Hazard ratios (HR) and 95% CI for time to first disease progression event up to end of double-blind treatment (selexipag/placebo) + 7 days were estimated using a Cox regression model which included treatment as a factor, and baseline prognostic factors and study as covariates. Results Overall, 649 patients met the criteria (diagnosis ≤6 months) for these analyses: 329 in the selexipag group (207 from GRIPHON and 122 from TRITON) and 320 in the control group (197 from GRIPHON and 123 from TRITON). Patient characteristics at baseline and treatment regimens were balanced between the treatment groups. With respect to treatment regimen, selexipag/placebo was given as part of triple therapy in 44%, double therapy in 32% and monotherapy in 24% of patients. The median (range) exposure to study treatment was 510 (4–1280) and 409 (3–1318) days in the selexipag and control groups, respectively. There were 67 (20%) and 116 (36%) patients who experienced a disease progression event in the selexipag and control groups, respectively. Selexipag reduced the risk of disease progression (first event) by 52% compared to control (HR 0.48 [95% CI 0.35, 0.66]) (Figure). Conclusions This post-hoc pooled analysis of GRIPHON and TRITON patients diagnosed within 6 months suggests that targeting the prostacylin pathway with selexipag within a short time after diagnosis may reduce the risk of disease progression in a broad PAH population. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson &amp; Johnson

TRANSITIONING FROM PARENTERAL PROSTACYCLIN THERAPY TO ORAL SELEXIPAG IN PULMONARY ARTERIAL HYPERTENSION

TOPIC: Pulmonary Vascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary arterial hypertension (PAH) is a serious condition that confers a poor prognosis if not promptly diagnosed and treated. Although parenteral medications targeting the prostacyclin pathway are often prescribed for high-risk patients, the transition to a more convenient and tolerable medication acting on the same pathophysiologic pathway may provide significant benefit in patients with stable disease who are burdened by the multiple complications inherent to parenteral therapy. CASE PRESENTATION: Three patients were successfully transitioned from parenteral prostacyclin therapy to selexipag at a single tertiary-care, expert pulmonary hypertension centre. Prior to transition, two patients were prescribed subcutaneous treprostinil and one intravenous epoprostenol. Reasons for transition included severe site pain with subcutaneous therapy, recurrent line infections, and patient preference. All patients were functional class II at time of transition. Right heart catheterization pre-transition demonstrated pre-capillary pulmonary hypertension in two patients (mPAP of 33mmHg with PVR of 5.2WU in the first, and mPAP of 32mmHg with PVR of 6.3WU in the second), with normal hemodynamics in the third. Transitions were performed in the outpatient setting over the course of 4-8 weeks. All patients achieved maximum daily dosing of selexipag (3200mcg) at the end of transition, with each patient experiencing temporary side effects during transition, e.g. headache, jaw pain, diarrhea, nausea, myalgias, limb pain, and peri-orbital edema. Following transition, there was no incidence of mortality (PAH or otherwise), PAH-related hospitalizations, re-initiation of parenteral therapy, or worsening of functional class or 6-minute walk distance in any of the three patients within 36 months of follow-up (in 6-, 12-, 24-, and 36- months intervals). Echocardiographic and right heart catheterization parameters were stable post-transition. DISCUSSION: All three patients were successfully transitioned from parenteral prostacyclin therapies to selexipag as evidenced by a lack of death, hospitalizations, and/or failure of oral therapy, as well as stability in various functional, echocardiographic, and hemodynamic outcomes with up to 36-months of follow-up. While parental prostacyclin analogues are still required for patients with high-risk or refractory disease, the patients in this study were those who were clinically and hemodynamically stable pre-transition with infusion-related morbidity. This may reflect the phenotype of patient where transition could be considered. CONCLUSIONS: In a carefully selected patient population with PAH on parenteral prostacyclin therapy, transition to selexipag may be a safe and viable option. Further studies are required to better delineate baseline predictors of long-term therapeutic efficacy and safety in a real-world PAH population. REFERENCE #1: Chin KM, McLaughlin V, Kim NH, et al. Clinical Course of Patients Transitioned from Another Prostacyclin Pathway Agent (PPA) to Selexipag in SPHERE. J Hear Lung Transplant. 2019;38(4, Supplement):S486. doi:https://doi.org/10.1016/j.healun.2019.01.1236 REFERENCE #2: Parikh KS, Doerfler S, Shelburne N, et al. Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol. 2020;75(4):299-304. doi:10.1097/FJC.0000000000000800 REFERENCE #3: Sargent T, Hansen L, Hohsfield R. Transitions between infused and oral prostacyclin pathway agents in pulmonary arterial hypertension: key considerations. Pulm Circ. 2020;10(3):2045894020931324. doi:10.1177/2045894020931324 DISCLOSURES: No relevant relationships by Brandon Budhram, source=Web Response No relevant relationships by Andrea Gardner, source=Web Response Speaker/Speaker's Bureau relationship with Janssen Please note: 2016-2021 Added 05/01/2021 by Nathan Hambly, source=Web Response, value=Honoraria Advisory Committee Member relationship with Janssen Please note: 2016-2021 Added 05/01/2021 by Nathan Hambly, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: 2016-2021 Added 04/30/2021 by Nathan Hambly, source=Web Response, value=Honoraria Advisory Committee Member relationship with Boehringer Ingelheim Please note: 2016-2021 Added 04/30/2021 by Nathan Hambly, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Roche Please note: 2016-2021 Added 04/30/2021 by Nathan Hambly, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Roche Please note: 2016-2021 Added 04/30/2021 by Nathan Hambly, source=Web Response, value=Honoraria

Long-Term Outcomes in Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension in the Modern Treatment Era: Meta-Analyses of Randomized, Controlled Trials and Observational Registries.

ObjectiveData on the magnitude of benefit of modern therapies for pulmonary arterial hypertension (PAH) in connective tissue disease (CTD)–associated PAH are limited. In this study, we performed meta‐analyses of randomized, controlled trials (RCTs) and registries to quantify the benefit of these modern therapies in patients with CTD‐PAH.MethodsThe PubMed and Embase databases were searched for articles reporting data from RCTs or registries published between January 1, 2000 and November 25, 2019. Eligibility criteria included multicenter studies with ≥30 CTD‐PAH patients. For an RCT to be included, the trial had to evaluate an approved PAH therapy, and long‐term risks of clinical morbidity and mortality or 6‐minute walk distance had to be reported. For a registry to be included, survival rates had to be reported. Random‐effects models were used to pool the data.ResultsEleven RCTs (total of 4,329 patients; 1,267 with CTD‐PAH) and 19 registries (total of 9,739 patients; 4,008 with CTD‐PAH) were included. Investigational therapy resulted in a 36% reduction in the risk of clinical morbidity/mortality events both in the overall PAH population (hazard ratio [HR] 0.64, 95% confidence interval [95% CI] 0.54, 0.75; P < 0.001) and in CTD‐PAH patients (HR 0.64, 95% CI 0.51, 0.81; P < 0.001) as compared to control subjects. The survival rate was lower in CTD‐PAH patients compared to all PAH patients (survival rate 62%, 95% CI 57, 67% versus 72%, 95% CI 69, 75% at 3 years). The survival rate in CTD‐PAH patients treated primarily after 2010 was higher than that in CTD‐PAH patients treated before 2010 (survival rate 73%, 95% CI 62, 81% versus 65%, 95% CI 59, 71% at 3 years).ConclusionModern therapy provides a similar reduction in morbidity/mortality risk in patients with CTD‐PAH when compared to the PAH population overall. Risk of death is higher in CTD‐PAH patients than in those with PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and up‐front intensive treatment are warranted.

Prediction Models and Scores in Pulmonary Hypertension: A Review.

Pulmonary arterial hypertension (PAH) is a serious disease with increased morbidity and mortality. The need for an individualized patient treatment approach necessitates the use of risk assessment in PAH patients. That may include a range of hemodynamic, clinical, imaging and biochemical parameters derived from clinical studies and registry data. In the current systematic review, we summarize the available data on risk prognostic models and scores in PAH and we explore the possible concordance amongst different risk stratification tools in PAH. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines aided the performance of this systematic review. Eligible studies were identified through a literature search in the electronic databases PubMed, Science Direct, Google Scholar and Cochrane with the use of various combinations of MeSH and non-MeSH terms, with a focus on PAH. Overall, 25 studies were included in the systematic review; out of them, 9 were studies deriving prognostic equations and risk scores and 16 were validating studies of an existing score. The majority of risk stratification scores use hemodynamic data for the assessment of prognosis, while others also include clinical and demographic variables in their equations. The risk discrimination in the overall PAH population was adequate, especially in differentiating the low versus high-risk patients, but their discrimination ability in the intermediate groups remained lower. Current ESC/ERS proposed risk stratification score utilizes a limited number of parameters with prognostic significance, whose prognostic ability has been validated in European patient populations. Despite improvement in risk estimation of prognostic tools of the disease, PAH morbidity and mortality remain high, necessitating the need for the risk scores to undergo periodic re-evaluation and refinements to incorporate new data into predictors of disease progression and mortality and, thereby, maintain their clinical utility.

PULMONARY ARTERIAL PULSATILITY INDEX AS A PREDICTOR OF MORTALITY IN PULMONARY ARTERIAL HYPERTENSION

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Pulmonary arterial hypertension (PAH) is a condition characterized by an increase in pulmonary artery pressure (PAP) and right ventricular (RV) afterload, leading to RV failure and mortality. Right heart catheterization (RHC) remains the mainstay of diagnosis of pulmonary arterial hypertension and provides important prognostic information. The pulmonary arterial pulsatility index (PAPi), calculated as pulmonary arterial pulse pressure divided by right atrial pressure (RAP), has recently been suggested as a predictor of mortality in PAH. We aimed to determine whether the PAPi at diagnosis is associated with mortality in PAH. METHODS: We conducted a retrospective single-centre cohort study of incident patients ≥ 18 years old diagnosed with PAH by RHC between January 1, 2015 and April 31, 2019. PAPi was calculated as pulmonary arterial pulse pressure (systolic PAP – diastolic PAP) divided by RAP. The primary outcome was all-cause mortality. Cox regression analysis and Kaplan-Meier plots were used to assess the association between PAPi and mortality. RESULTS: There were 98 incident patients identified (mean age 59.6 ± 1.5 at diagnosis, 67% female). Mean PAP was 46 ± 1.2 mmHg, mean RAP was 9.6 ± 0.6 mmHg, and mean pulmonary vascular resistance was 9.1 ± 0.5 Wood Units. Twenty-five (26%) of patients received no initial therapy, 44 (45%) patients received initial oral monotherapy, 25 (26%) received dual oral combination therapy and 4 (4%) received triple therapy. Using the median PAPi value of 5.4, two groups were created. Baseline characteristics across groups (PAPi < 5.4 vs. ≥ 5.4) were primarily female (71% vs. 63%, p = 0.39); mean age 58 ± 2.2 years vs. 61 ± 2.2 years (p=0.31); mean body mass index 31.1 ± 1.4 kg/m2 vs. 28.0 ± 0.9 kg/m2 (p=0.06); and mean initial six minute walk distance 335 ± 20 m vs. 365 ± 20 m (p=0.29). There was no difference in the proportion of patients in New York Heart Association functional class I-II vs. III-IV between groups (p=0.69). Treatment strategy with no PAH therapy, monotherapy, dual therapy and triple therapy did not differ significantly between PAPi < 5.4 and PAPi ≥ 5.4 groups (22% vs. 29%, p=0.49; 51% vs. 38%, p=0.22; 24% vs. 26%, p=0.2; 2% vs. 6%, p = 0.31). There were 21 deaths during the follow-up period. In Cox regression modelling, those with PAPi ≥ 5.4 had a mortality hazard ratio, adjusted for age and sex, of 0.41 (95% CI 0.16-1.08, p=0.07). CONCLUSIONS: In this cohort, baseline PAPi ≥ 5.4 was associated with a trend toward lower all-cause mortality. A Canadian multicentre analysis is planned to help further validate whether PAPi predicts outcomes in a larger PAH population. CLINICAL IMPLICATIONS: PAPi is a useful prognostic variable in left heart failure and could also potentially be useful in PAH. Further studies are needed to compare PAPi with other invasive and non-invasive prognostic variables in PAH. DISCLOSURES: Industry sponsored clinical trial relationship with Johnson and Johnson Please note: $5001 - $20000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Grant/Research Support Industry sponsored clinical trial relationship with United Therapeutics Please note: $5001 - $20000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Grant/Research Support Industry sponsored clinical trial relationship with Bayer Please note: $20001 - $100000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Grant/Research Support industry sponsored clinical trial relationship with Gilead Please note: $5001 - $20000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Grant/Research Support Speaker/Speaker's Bureau relationship with Bayer Please note: $1001 - $5000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Honoraria Investigator relationship with Bayer Pharmaceuticals Please note: $20001 - $100000 Added 06/11/2020 by Naushad Hirani, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Actelion Canada Please note: $1001 - $5000 Added 06/11/2020 by Naushad Hirani, source=Web Response, value=Honoraria No relevant relationships by Jonathan Liu, source=Web Response No relevant relationships by Jordan Sugarman, source=Web Response No relevant relationships by Mitesh Thakrar, source=Web Response No relevant relationships by Rhea Varughese, source=Web Response Speaker/Speaker's Bureau relationship with Actelion Please note: $20001 - $100000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Honoraria Consultant relationship with Actelion/Janssen Please note: $5001 - $20000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Consulting fee Travel support relationship with Actelion/Janssen Please note: $1001 - $5000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Travel Grant/Research relationship with Janssen Please note: $20001 - $100000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Grant/Research Speaker/Speaker's Bureau relationship with Bayer Please note: $1001 - $5000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Honoraria

Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible factor (HIF)2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed, followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from idiopathic PAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH-associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline-exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyperproliferative phenotype and overactive arginase activity in blood outgrowth endothelial cells from idiopathic PAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

The features of rare pathogenic BMPR2 variants in pulmonary arterial hypertension: Comparison between patients and reference population

BackgroundMutations in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2) are the most common genetic risk factors underlying pulmonary arterial hypertension (PAH). However, the features of PAH-related BMPR2 rare variants remain unclear. We propose that the discrepancy of BMPR2 rare variants landscape between patients with PAH and reference population would be important to address the genetic background of PAH-related variants. MethodsWe genotyped BMPR2 rare variants in 670 Chinese patients with pulmonary arterial hypertension. The BMPR2 rare variants were screened in 10,508 reference people from two exome databases. ResultsThe prevalence of rare BMPR2 variants in patients with PAH was significantly higher compared to the reference population (21.5%, 144/670 vs 0.87%, 91/10508, p = 1.3 × 10−118). In patients with PAH, 49% of identified BMPR2 rare variants were loss-of-function or splicing. These BMPR2 rare variants were only observed in 1% of the reference population (p = 9.0 × 10−12). Arg491, which is absent in the reference population, represented as hot-spot site (14.6%, 21/144) in PAH patients. BMPR2 missense mutations in PAH patients were more likely distributed in extracellular ligand-binding domain (ECD, 29.7% vs 11.1%, p < 0.001). Compared with Non-PAH-related variations, PAH-related missense variants tend to alter the amino acid electric status (51.4% vs 23.3%, p < 0.001). ConclusionsBMPR2 variants located in extracellular ligand-binding domain or altered the amino acid electric status are more pathogenic.

Right Atrial Conduit Phase Emptying Predicts Risk of Adverse Events in Pediatric Pulmonary Arterial Hypertension

Idiopathic pulmonary arterial hypertension (PAH) is a severe disease associated with a 20% 5-year mortality, often due to right heart failure. Recent studies suggest that compensatory changes in right atrial (RA) function may precede other clinical and echocardiographic evidence of right ventricular dysfunction. No prior prospective study has evaluated the role of RA emptying pattern as a prognostic marker of adverse clinical events in pediatric PAH. To demonstrate whether RA fractional emptying indices will prospectively predict risk of adverse clinical outcomes in pediatric PAH patients. Single-center, prospective cohort analysis of 41 patients with idiopathic or heritable PAH and 1:1 age and sex-matched controls with normal echo and electrocardiogram. Right atrial area (RAA) was measured just prior to tricuspid valve opening (RAAmax), at electrical p wave (RAAp), and just after tricuspid valve closing (RAAmin). Right atrial conduit fraction percent (RA cF%) was defined as the percentage of total RAA change happening prior to the electrical p wave= (RAAmax - RAAp)/(RAAmax - RAAmin) ∗ 100. Clinical worsening was analyzed with a predefined composite adverse event outcome. RA measurements were technically feasible in all study participants. The PAH patients (median age 11.9years) had decreased RA cF% compared with controls (P<.0001), and PAH subjects with lower RA cF% demonstrated higher right ventricular systolic (R=-0.49, P=.019) and end-diastolic (R=-0.52, P=.012) pressure than those with higher RA cF%. Sixteen subjects had a clinical event. Right atrial cF% (hazard ratio=0.09; P<.001) was highly prognostic for risk of adverse clinical event with area under the curve=0.90 on receiver operating characteristic curve analysis (median 3.2-year follow-up). Right atrial conduit phase emptying is significantly altered in pediatric PAH. Within the PAH population, decreased RA cF% was prognostic for risk of clinical worsening. The combination of accuracy and ease of measurement could make RA cF% a clinically useful, noninvasive biomarker of early right heart failure and risk of disease progression in pediatric PAH.