Outcomes In Pulmonary Arterial Hypertension Research Articles

Association of risk assessment at diagnosis with healthcare resource utilization and health-related quality of life outcomes in pulmonary arterial hypertension.

We aimed to describe the clinical characteristics, healthcare resource utilization (HCRU) and costs, health-related quality of life (HRQoL), and survival for patients with pulmonary arterial hypertension (PAH), stratified by 1-year mortality risk at diagnosis. Adults diagnosed with PAH at the Sheffield Pulmonary Vascular Disease Unit between 2012 and 2019 were included. Patients were categorized as low, intermediate, or high risk for 1-year mortality at diagnosis. Demographics, clinical characteristics, comorbidities, HCRU, costs, HRQoL, and survival were analyzed. Overall, 1717 patients were included: 72 (5%) at low risk, 941 (62%) at intermediate risk, and 496 (33%) at high risk. Low-risk patients had lower HCRU prediagnosis and 1-year postdiagnosis than intermediate- or high-risk patients. Postdiagnosis, there were significant changes in HCRU, particularly inpatient hospitalizations and accident and emergency (A&E) visits among high-risk patients. At 3 years postdiagnosis, HCRU for all measures was similar across risk groups. Low-risk patients had lower EmPHasis-10 scores (indicating better HRQoL) at diagnosis and at 1-year follow-up compared with intermediate- and high-risk patients; only the score in the high-risk group improved. Median overall survival decreased as risk category increased in analyzed subgroups. Low-risk status was associated with better 1-year survival and HRQoL compared with intermediate- and high-risk patients. HCRU decreased in high-risk patients postdiagnosis, with the most marked reduction in A&E admissions. The pattern of decreased per-patient inpatient hospitalizations and A&E visits at 3 years postdiagnosis suggests that a diagnosis of PAH helps to decrease HCRU in areas that are key drivers of costs.

Impact of different sequential triple oral combination therapies based selexipag on outcomes in pulmonary arterial hypertension.

While the GRIPHON study and others have confirmed the efficacy and safety of selexipag with single, dual, and initial triple combination therapy for patients with pulmonary arterial hypertension (PAH), multicenters studies concerning diverse triple oral combination therapies based on selexipag are limited. This study was conducted to evaluate the effects of various sequential triple oral combination therapies on PAH outcomes. A retrospective study was carried out involving 192 patients from 10 centers, who were receiving sequential triple oral combination therapy consisting of an endothelin receptor antagonist (ERA), a phosphodiesterase 5 inhibitor (PDE5i)/riociguat and selexipag. Clinical parameters, event-free survival, and all-cause survival were assessed and analyzed at baseline and posttreatment. Among the 192 patients, 37 were treated with ERA + riociguat + selexipag, and 155 patients received ERA + PDE5i + selexipag. Both sequential triple oral combination therapies improved the World Health Organization functional class and raised the count of low-risk parameters. As a result of the larger patients' population in the ERA + PDE5i + selexipag group, these individuals exhibited significant increases in 6-minutewalking distance(6MWD), pulmonary arterial systolic pressure,pulmonary arterial pressure, right ventricle, andeccentricity index, and significant decreases in N-terminal probrain natriuretic peptide after 6 months of treatment. Nevertheless, both sequential triple oral combination therapy groups demonstrated similar shifts in these clinical parameters between baseline and 6 months. Baseline 6MWD and mean pulmonary arterial pressure were independent predictors of survival in patients undergoing ERA + PDE5i + selexipag therapy. Importantly, no significant differences were found in 6-month event-free survival and all-cause survival between two groups. Different oral sequential triple combination therapies based on selexipag could comparably improve outcomes in patients with PAH.

Premorbid weight in pulmonary arterial hypertension.

Relationships between obesity and outcomes in pulmonary arterial hypertension (PAH) are complex. Previous work suggested obesity, occurring alongside PAH, may be associated with better survival. In our work, we suggest obesity prior to PAH development is associated with worse survival. This may add a novel temporal element to the "obesity-paradox."

Predictors of the response to phosphodiesterase-5 inhibitors in pulmonary arterial hypertension: an analysis of the Spanish registry

BackgroundAchieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients.ObjectiveTo Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH.MethodsWe carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response.ResultsTwo hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response.ConclusionMale sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.

Use of the index of pulmonary vascular disease for predicting long-term outcome of pulmonary arterial hypertension associated with congenital heart disease.

Limited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH. This retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death. The 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 (P = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45-13.73; P = .009). The IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered.

Prognostic value of the right ventricular ejection fraction using three-dimensional echocardiography: Systematic review and meta-analysis.

Three-dimensional echocardiography (3DE) is a robust method for measuring the right ventricular (RV) ejection fraction (EF), which is closely associated with outcomes. We performed a systematic review and meta-analysis (1) to examine the prognostic value of RVEF and (2) to compare its prognostic value with that of left ventricular (LV) EF and LV global longitudinal strain (GLS). We also performed individual patient data analysis to validate the results. We searched articles reporting the prognostic value of RVEF. Hazard ratios (HR) were re-scaled using the within-study standard deviation (SD). To compare predictive values of RVEF and LVEF or LVGLS, the ratio of HR related to a 1-SD reduction of RVEF versus LVEF or LVGLS was calculated. Pooled HR of RVEF and pooled ratio of HR were analyzed in a random-effects model. Fifteen articles with 3,228 subjects were included. Pooled HR of a 1-SD reduction of RVEF was 2.54 (95% confidence interval (CI): 2.15-3.00). In subgroup analysis, RVEF was significantly associated with outcome in pulmonary arterial hypertension (PAH) (HR: 2.79, 95% CI: 2.04-3.82) and cardiovascular (CV) diseases (HR: 2.23, 95%CI: 1.76-2.83). In studies reporting HRs for both RVEF and LVEF or RVEF and LVGLS in the same cohort, RVEF had 1.8-fold greater prognostic power per 1-SD reduction than LVEF (ratio of HR: 1.81, 95%CI: 1.20-2.71), but had predictive value similar to that of LVGLS (ratio of HR: 1.10, 95%CI: 0.91-1.31) and to LVEF in patients with reduced LVEF (ratio of HR: 1.34, 95%CI: 0.94-1.91). In individual patient data analysis (n = 1,142), RVEF < 45% was significantly associated with worse CV outcome (HR: 4.95, 95% CI: 3.66-6.70), even in patients with reduced or preserved LVEF. The findings of this meta-analysis highlight and support the use of RVEF assessed by 3DE to predict CV outcomes in routine clinical practice in patients with CV diseases and in those with PAH.

Is low-risk status a surrogate outcome in pulmonary arterial hypertension? An analysis of three randomised trials

Targeting short-term improvements in multicomponent risk scores for mortality in patients with pulmonary arterial hypertension (PAH) could result in improved long-term outcomes. We aimed to determine whether PAH risk scores were adequate surrogates for clinical worsening or mortality outcomes in PAH randomised clinical trials (RCTs). We performed an individual participant data meta-analysis of RCTs selected from PAH trials provided by the US Food and Drug Administration (FDA). We calculated predicted risk using the COMPERA, COMPERA 2.0, non-invasive FPHR, REVEAL 2.0, and REVEAL Lite 2 risk scores. The primary outcome of interest was time to clinical worsening, a composite endpoint composed of any of the following events: all-cause death, hospitalisation for worsening PAH, lung transplantation, atrial septostomy, discontinuation of study treatment (or study withdrawal) for worsening PAH, initiation of parenteral prostacyclin analogue therapy, or decrease of at least 15% in 6-min walk distance from baseline, combined with either worsening of WHO functional class from baseline or the addition of an approved PAH treatment. The secondary outcome of interest was time to all-cause mortality. We assessed the surrogacy of these risk scores, parameterised as attainment of low-risk status by 16 weeks, for improvement in long-term clinical worsening and survival using mediation and meta-analysis frameworks. Of 28 trials received from the FDA, three RCTs (AMBITION, GRIPHON, and SERAPHIN; n=2508) had the data necessary to assess long-term surrogacy. The mean age was 49 years (SD 16), 1956 (78%) participants were women, 1704 (68%) were classified as White, and 280 (11%) were Hispanic or Latino. 1388 (55%) of 2503 participants with available data had idiopathic PAH and 776 (31%) of 2503 had PAH associated with connective tissue disease. In a mediation analysis, the proportions of treatment effects explained by attainment of low-risk status ranged only from 7% to 13%. In a meta-analysis of trial-regions, the treatment effects on low-risk status were not predictive of the treatment effects on time to clinical worsening (R2 values 0·01-0·19) nor the treatment effects on time to all-cause mortality (R2 values 0-0·2). A leave-one-out analysis suggested that the use of these risk scores as surrogates might lead to biased inferences regarding the effect of therapies on clinical outcomes in PAH RCTs. Results were similar when using absolute risk scores at 16 weeks as the potential surrogates. Multicomponent risk scores have utility for the prediction of outcomes in patients with PAH. Clinical surrogacy for long-term outcomes cannot be inferred from observational studies of outcomes. Our analyses of three PAH trials with long-term follow-up suggest that further study is necessary before using these or other scores as surrogate outcomes in PAH RCTs or clinical care. Cardiovascular Medical Research and Education Fund, US National Institutes of Health.

Surrogate endpoints in pulmonary arterial hypertension trials

Why don't you just look at the pulmonary artery pressure? This question is frequently asked when we discuss endpoints in pulmonary arterial hypertension (PAH) trials with colleagues from other disease areas. Trials of antihypertensive drugs simply look at blood pressure changes, whereas pivotal trials in PAH use change in 6-min walk distance or time to clinical worsening as primary outcome measures. Why the difference? It is not just the invasiveness of right heart catheterisation but much more a question of validated surrogate endpoints. The US Food and Drug Administration (FDA) and other regulatory agencies approve drugs when they improve how patients feel, function, or survive. 1 Temple R Are surrogate markers adequate to assess cardiovascular disease drugs?. JAMA. 1999; 282: 790-795 Crossref PubMed Scopus (298) Google Scholar In systemic hypertension, lowering blood pressure predicts reductions in major adverse cardiovascular events including stroke, myocardial infarction, and cardiovascular death, and so authorities accept blood pressure reduction as a surrogate endpoint—ie, a substitute for a clinically meaningful endpoint that is expected to predict the effect of a therapy. 1 Temple R Are surrogate markers adequate to assess cardiovascular disease drugs?. JAMA. 1999; 282: 790-795 Crossref PubMed Scopus (298) Google Scholar In PAH, there is no convincing evidence that reductions in pulmonary artery pressure or pulmonary vascular resistance are directly linked to improved exercise capacity or better survival. Hence, change in 6-min walk distance is being frequently used as a primary endpoint assessing the function part of the FDA paradigm. Time to clinical worsening has been applied as well, a composite endpoint based on death, PAH-related worsening, and prespecified reductions in exercise capacity. However, these endpoints have limitations. Improvement in 6-min walk distance reflects better exercise capacity but is no surrogate of better outcomes. 2 Gabler NB French B Strom BL et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012; 126: 349-356 Crossref PubMed Scopus (185) Google Scholar Time to clinical worsening does not capture clinical improvement, and reducing clinical worsening events does not necessarily lead to better survival. 3 Sitbon O Channick R Chin KM et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015; 373: 2522-2533 Crossref PubMed Scopus (607) Google Scholar , 4 Galiè N Barberà JA Frost AE et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015; 373: 834-844 Crossref PubMed Scopus (750) Google Scholar , 5 Pulido T Adzerikho I Channick RN et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369: 809-818 Crossref PubMed Scopus (981) Google Scholar In addition, studies designed to show improvement in time to clinical worsening require large sample sizes, a challenge in a rare disease like PAH. Hence, there is an ongoing search for surrogate endpoints. Is low-risk status a surrogate outcome in pulmonary arterial hypertension? An analysis of three randomised trialsMulticomponent risk scores have utility for the prediction of outcomes in patients with PAH. Clinical surrogacy for long-term outcomes cannot be inferred from observational studies of outcomes. Our analyses of three PAH trials with long-term follow-up suggest that further study is necessary before using these or other scores as surrogate outcomes in PAH RCTs or clinical care. Full-Text PDF

Metabolic profiling of in vivo right ventricular function and exercise performance in pulmonary arterial hypertension

Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary arterial hypertension (PAH), however, RV function is challenging to assess. RV responses to hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in PAH. Consecutive subjects with PAH (n = 23) underwent rest and exercise right heart catheterization with multibeat pressure volume loop analysis. Pulmonary arterial blood was collected at rest and during exercise. Mass spectrometry-based targeted metabolomics were performed, and metabolic associations with hemodynamics and comprehensive measures of RV function were determined using sparse partial least squares regression. Metabolite profiles were compared with N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) measurements for accuracy in modeling ventriculo-arterial parameters. Thirteen metabolites changed in abundance with exercise, including metabolites reflecting increased arginine bioavailability, precursors of catecholamine and nucleotide synthesis, and branched-chain amino acids. Higher resting arginine bioavailability predicted more favorable exercise hemodynamics and pressure-flow relationships. Subjects with more severe PAH augmented arginine bioavailability with exercise to a greater extent than subjects with less severe PAH. We identified relationships between kynurenine pathway metabolism and impaired ventriculo-arterial coupling, worse RV diastolic function, lower RV contractility, diminished RV contractility with exercise, and RV dilation with exercise. Metabolite profiles outperformed NT-proBNP in modeling RV contractility, diastolic function, and exercise performance. Specific metabolite profiles correspond to RV functional measurements only obtainable via invasive pressure-volume loop analysis and predict RV responses to exercise. Metabolic profiling may inform discovery of RV functional biomarkers.NEW & NOTEWORTHY In this cohort of patients with pulmonary arterial hypertension (PAH), we investigate metabolomic associations with comprehensive right ventricular (RV) functional measurements derived from multibeat RV pressure-volume loop analysis. Our results show that tryptophan metabolism, particularly the kynurenine pathway, is linked to intrinsic RV function and PAH pathobiology. Findings also highlight the importance of arginine bioavailability in the cardiopulmonary system's response to exercise stress. Metabolite profiles selected via unbiased analysis outperformed N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) in predicting load-independent measures of RV function at rest and cardiopulmonary system performance under stress. Overall, this work suggests the potential for select metabolites to function as disease-specific biomarkers, offers insights into PAH pathobiology, and informs discovery of potentially targetable RV-centric pathways.

Acute Vasoreactivity Testing and Outcomes in Pulmonary Arterial Hypertension: A Call for Increased Testing.

Pulmonary arterial hypertension (PAH) has a progressive, unremitting clinical course. Vasoreactivity testing (VdT) during right heart catheterisation (RHC) identifies a subgroup with excellent long-term response to calcium channel blockade (CCB). Reporting on these patients is limited. Established in 2011, the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry offers the opportunity to assess the frequency of VdT during RHC, treatment and follow up of PAH patients. Registry data from 3,972 PAH patients with index RHC revealed 1,194 VdT appropriate patients. Data was analysed in three groups: 1) VdT+CCB+: VdT positive, CCB treated; 2) VdT+CCB-: VdT positive, no CCB prescribed, 3) VdT-/noVdT: VdT negative, or VdT not tested. Data was reviewed for adherence to guidelines, clinical response (World Health Organization functional class [WHO FC], 6-minute-walk-distance [6MWD], RHC), and outcomes (survival or lung transplantation). Patients included had idiopathic (IPAH=1,087), heritable (HPAH=67) and drug or toxin-induced PAH (DPAH=40). A VdT was performed in 22% (268/1,194), with incomplete data in 26% (70/268); 28% (55/198) were VdT+. Analysis group allocation was: VdT+CCB+ (33/55), VdT+CCB- (22/55), VdT- (143)/noVdT (996). From patients with 1-year data VdT+CCB+ and VdT-/noVdT patients improved WHO FC, 6MWD and cardiac index (CI); VdT+CCB- data remained similar. Within the VdT+CCB+ group, 30% (10/33) were long-term CCB responders with a 100% 5-year survival; non-responders had a 61% survival at 5.4 years. Long-term responders were younger at diagnosis (40 yrs vs 54 yrs). Use of VdT testing and documentation is poor in this contemporary patient cohort. Nonetheless, survival inVdT+CCB+ patients from the PHSANZ registry is excellent, supporting guidelines promoting VdT testing. Strategies to promote the use of VdT are warranted.

Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes.

Pulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets. We collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes. A total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance. Distinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.

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&amp;lt;0.001) and RVEF by CMR (rho: 0.570; p&amp;lt;0.001). At follow up; RA PLS and PACS significantly increased (16.6 vs 24 and 7.06 vs 11.42, respectively: p&amp;lt;0.001); however, RA area did not show significant decrease. Only RV TDI &amp; 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.

The feasibility and value of assessing patient-reported outcomes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease that negatively impacts health‐related quality of life (HRQOL). The PAH‐symptoms and impact (PAH‐SYMPACT) questionnaire is a validated disease‐specific patient‐reported outcome (PRO) instrument that assesses a patient's symptoms and the impact of PAH and its treatment on well‐being. We performed a single‐center prospective cohort study of patients with PAH to determine the feasibility of assessing PROs in clinical practice and to determine the association between PAH‐SYMPACT domains and clinical characteristics and outcomes. One hundred and ten patients completed the 1‐day version of the PAH‐SYMPACT questionnaire which consists of 22 Likert‐scale questions that assess HRQOL across four domains: cardiopulmonary (CP) symptoms, cardiovascular (CV) symptoms, physical impact (PI), and cognitive and emotional (CE) impact. Higher scores indicate worse HRQOL. Patients were predominantly female (n = 86, 78%) with a mean age of 57.8 ± 16.2 years. While several patient characteristics were associated with CP and PI domains, few were associated with CV and CE domains. PI and CE impact scores were associated with recent hospitalizations and mortality and CE impact score was independently associated with an increased risk of death after adjustment for disease severity (hazard ratio: 3.29, 95% confidence interval: 1.56–6.91, p = 0.002). In conclusion, the assessment of PROs in clinical practice using the PAH‐SYMPACT questionnaire is both feasible and valuable. PAH‐SYMPACT scores have independent prognostic value and are not adequately reflected by traditional measures of disease severity. These findings underscore the importance of assessing HRQOL in clinical practice.

Perinatal changes of right ventricle-pulmonary artery coupling and its value in predicting persistent pulmonary hypertension of the newborn.

Right ventricle-pulmonary artery (RV-PA) coupling is an independent predictor of outcome in pulmonary arterial hypertensionin adults. Here, we aimed to investigate the changes in RV-PA coupling during the perinatal period, and to evaluate its performance on predicting persistent pulmonary hypertension of the newborn (PPHN). A total of 1196 fetuses underwent a dedicated echocardiography screening for foetal heart defects during second trimester (24-27 weeks' gestation), third trimester (34-37 weeks' gestation) and neonatal period (within 14 days after delivery) with the measurement of tricuspid annular plane systolic excursion (TAPSE) and mean pulmonary artery pressure (MPAP). The RV-PA coupling (TAPSE/MPAP ratio) was calculated. Six fetuses were diagnosed as persistent pulmonary hypertension of the newborn(PPHN). In normal fetuses, RV-PA coupling had been increasing from the second trimester to the third trimester and then to the neonatal period (0.12 ± 0.02 vs. 0.18 ± 0.05 vs. 0.23 ± 0.08 mm/mmHg, p < 0.05), while it had been decreasing during the same period of time in abnormal fetuses (0.18 ± 0.02 vs. 0.17 ± 0.02 vs. 0.17 ± 0.01 mm/mmHg, p < 0.05). There was a strong positive correlation between RV-PA coupling and gestational age (GA) in normal fetuses (r = 0.71, p < 0.0001). The area under receiver operating characteristic curve (AUC) of 0.989 for RV-PA coupling during second trimester was superior to that for RV-PA coupling during third trimester (AUC: 0.536) in predicting PPHN. The optimal cutoff value was 0.16 mm/mmHg, with a sensitivity of 100.00%, a specificity of 96.36%and an accuracy of 97.73%. RV-PA coupling had close relation with GA in normal fetuses. It was a strong predictor of PPHN.

Heart rate recovery in 1 minute after the 6-minute walk test predicts adverse outcomes in pulmonary arterial hypertension.

Heart rate recovery in 1 minute (HRR1) after the end of the 6-minute walk test (6MWT) is a non-invasive method of determining autonomic dysfunction. This parameter remains largely unexplored in pulmonary arterial hypertension (PAH) registries. We aimed to define the cut-off value and accuracy for abnormal HRR1 after the 6MWT and to investigate the association between HRR1 and clinical worsening in patients with PAH. This composite outcome was defined as first occurrence of all-cause death OR hospitalization from any cause OR disease progression characterized by decreased ≥ 15% in six-minute walking distance from baseline AND start of new specific PAH treatment or persistent worsening of World Health Organization functional class (WHO-FC). We performed a prospective cohort study that included 102 consecutive patients with PAH confirmed by right heart catheterization that underwent an 6MWT upon the diagnosis, recruited from September 2004 to April 2020 and followed up until April 2021 or death. The median HRR1 was 18 beats (IQR: 10-22), 50 and 52 PAH patients with <18 beats and ≥18 beats, respectively. The best cut-off for HRR1 to discriminate clinical worsening was 17 beats, with area under the curve (AUC) of 0.704 (95%CI: 0.584-0.824). The internal validation model by bootstrap showed an AUC of 0.676 (95%CI: 0.566-0.786) and the most accurate value was obtained in the seventh year of follow-up (AUC = 0.711; 95%CI: 0.596-0.844). Patients with an HRR1 <18 beats at baseline had a median event-free time of 2.17 years (95%CI: 1.82 to 2.52) versus 4.75 years (95%CI: 1.43 to 8.07) from those with ≥18 beats. In conclusion, a HRR1 value of less than 18 beats may be a reliable indicator of poor prognosis in patients with PAH.

Atrioventricular plane displacement and regional function to predict outcome in pulmonary arterial hypertension

To investigate if left and right atrioventricular plane displacement (AVPD) or regional contributions to SV are prognostic for outcome in patients with pulmonary arterial hypertension (PAH). Seventy-one patients with PAH and 20 sex- and age-matched healthy controls underwent CMR. Myocardial borders and RV insertion points were defined at end diastole and end systole in cine short-axis stacks to compute biventricular volumes, lateral (SVlat%) and septal (SVsept%) contribution to stroke volume. Eight atrioventricular points were defined at end diastole and end systole in 2-, 3- and 4-chamber cine long-axis views for computation of AVPD and longitudinal contribution to stroke volume (SVlong%). Cut-off values for survival analysis were defined as two standard deviations above or below the mean of the controls. Outcome was defined as death or lung transplantation. Median follow-up time was 3.6 [IQR 3.7] years. Patients were 57 ± 19 years (65% women) and controls 58 ± 15 years (70% women). Biventricular AVPD, SVlong% and ejection fraction (EF) were lower and SVlat% was higher, while SVsept% was lower in PAH compared with controls. In PAH, transplantation-free survival was lower below cut-off for LV-AVPD (hazard ratio [HR] = 2.1, 95%CI 1.2–3.9, p = 0.02) and RV-AVPD (HR = 9.8, 95%CI 4.6–21.1, p = 0.005). In Cox regression analysis, lower LV-AVPD and RV-AVPD inferred lower transplantation-free survival (LV: HR = 1.16, p = 0.007; RV: HR = 1.11, p = 0.01; per mm decrease). LV-SVlong%, RV-SVlong%, LV-SVlat%, RV-SVlat%, SVsept% and LV- and RVEF did not affect outcome. Low left and right AVPD were associated with outcome in PAH, but regional contributions to stroke volume and EF were not.

Impact of Initial Therapeutic Strategy on Long-Term Outcomes in Pulmonary Arterial Hypertension: An Analysis of the PHSANZ Registry

<h3>Purpose</h3> The relationship between initial treatment strategy and survival in pulmonary arterial hypertension (PAH) is uncertain, although early combination therapy is proposed by current guidelines for majority of patients. <h3>Methods</h3> Data were extracted from the Pulmonary Hypertension Society of Australia and New Zealand registry for all patients with a diagnosis with idiopathic/heritable/toxin-induced (I/H/D-PAH) with survival, treatment response and medication data. Patients were divided into prevalent (diagnosed < 2011), early incident (diagnosed 2011-2015) and recent incident (diagnosed 2016-2019) cohort. Early combination therapy was defined as the use of 2 or more drugs within 3 months of treatment initiation. <h3>Results</h3> A total of 489 patients diagnosed between 2006 and 2019 were included with 318 (65%) started on monotherapy, 156 (32%) on early double combination therapy and 13 (3%) on early triple therapy. All patients on triple therapy were on parenteral prostacyclin, as well as 20 (13%) patients of double therapy and 2 (0.6%) receiving monotherapy. Rates of early combination therapy (double or triple) were 20%, 28% and 59% across the 3 treatment eras. In the entire population, there was no significant differences in transplant-free survival according to upfront treatment strategy (log rank test p=0.66). After adjustment for baseline risk according to REVEAL 2.0 score, HR for monotherapy compared to early combination therapy (2 or 3 agents) was 1.11 [0.79-1.62]. With analysis restricted to incident cases only, the adjusted HRs for monotherapy compared to early combination were 1.57 [0.86-2.84] for the period 2011-2015, and 0.78 [0.25-2.40] for period 2016-2019. Change in 6MWD was higher in the early combination group versus monotherapy group (51±86m vs 74±113m, p=0.017). <h3>Conclusion</h3> In a real-world registry where early combination therapy consisted mainly of dual oral agents, a survival benefit over monotherapy was not observed. Further studies are needed to determine impact of specific drug combinations (such as inclusion of parenteral prostacyclin) on long term outcomes.

"Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension." Catherine E. Simpson, Jenny Y. Chen, Rachel L. Damico, et al. Eur Respir J 2020; 55: 1901761.

"Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension." Catherine E. Simpson, Jenny Y. Chen, Rachel L. Damico, et al. Eur Respir J 2020; 55: 1901761.

Treatment with neurohormonal inhibitors and prognostic outcome in pulmonary arterial hypertension with risk factors for left heart disease.

BACKGROUNDDespite major advances in pharmacologic treatment, patients with pulmonary arterial hypertension (PAH) still have a considerably reduced life expectancy. In this context, chronic hyperactivity of the neurohormonal axis has been shown to be detrimental in PAH, thus providing novel insights on the role of neurohormonal blockade as a potential therapeutic target.AIMTo evaluate the application and prognostic effect of neurohormonal inhibitors (NEUi) in a single-center sample of patients with idiopathic PAH and risk factors for left heart disease.METHODSWe analyzed data retrospectively collected from our register of right heart catheterizations performed consecutively from January 1, 2005 to October 31, 2018. Patients on beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker or mineralocorticoid receptor antagonist at the time of right heart catheterization were classified as NEUi users and compared to NEUi non-recipients.RESULTSComplete data were available for 57 PAH subjects: 27 of those (47.4%) were taking at least one NEUi at the time of right heart catheterization and were compared with the remaining 36 NEUi non-recipients. NEUi users were older and had a higher cardiovascular risk profile compared to non-recipients. Additionally, NEUi non-users had a higher probability of dying during the course of follow-up than NEUi recipients (56.7% vs 25.9%, log-rank P = 0.020).CONCLUSIONThe above data highlighted a subgroup of patients with PAH and comorbidities for left heart disease in which NEUi use has shown to be associated with improved survival. Future prospective studies are needed to identify the most appropriate therapeutic strategies in this subset population.

Impact of Initial Therapeutic Strategy on Long-Term Outcomes in Pulmonary Arterial Hypertension: An Analysis of the PHSANZ Registry

The relationship between initial treatment strategy and survival in pulmonary arterial hypertension (PAH) is uncertain, although early combination therapy is proposed by current guidelines for majority of patients.