Survival In Pulmonary Arterial Hypertension Research Articles

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension.

Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance has emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen crosslinking enzyme lysyl oxidase like 2 (LOXL2) in this study. Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from pulmonary arteries of the rat Sugen5416 + hypoxia (SuHx) model of severe PH. Similarly, LOXL2 protein and mRNA levels were increased in pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loops in-vivo with PAT-1251. Importantly PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival. Hypoxia induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH, as well as pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 could be a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH.

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension

Background: Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance has emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen crosslinking enzyme lysyl oxidase like 2 (LOXL2) in this study. Methods and Results: Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from pulmonary arteries of the rat Sugen 5416 + hypoxia (SuHx) model of severe PH. Similarly, LOXL2 protein and mRNA levels were increased in pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loops in-vivo with PAT-1251. Importantly PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival. Conclusion: Hypoxia induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH, as well as pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 is a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH. This work was supported by a NHLBI grant R01HL105296 (to D.E.B.), a NHLBI grant R01HL148112 01 (to L.S.), two Stimulating and Advancing ACCM Research (StAAR) grants from the Department of Anesthesiology and Critical Care Medicine, JHU (to L.S. and J.S.), NHLBI grants R01HL073859 and R01HL126514 (to L.A.S) and a NHLBI K08 grant K08HL145132 (to J.S.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

(157) - Survival in Pulmonary Arterial Hypertension (PAH) for 669 Patients Treated with Selexipag in Clinical Practice: Insights from EXPOSURE

(157) - Survival in Pulmonary Arterial Hypertension (PAH) for 669 Patients Treated with Selexipag in Clinical Practice: Insights from EXPOSURE

Identifying consistent echocardiographic thresholds for risk stratification in pulmonary arterial hypertension.

Several indices of right heart remodeling and function have been associated with survival in pulmonary arterial hypertension (PAH). Outcome analysis and physiological relationships between variables may help develop a consistent grading system. Patients with Group 1 PAH followed at Stanford Hospital who underwent right heart catheterization and echocardiography within 2 weeks were considered for inclusion. Echocardiographic variables included tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) fractional area change (RVFAC), free wall strain (RVFWS), RV dimensions, and right atrial volumes. The main outcome consisted of death or lung transplantation at 5 years. Mathematical relationships between variables were determined using weighted linear regression and severity thresholds for were calibrated to a 20% 1-year mortality risk. PAH patients (n = 223) had mean (SD) age of 48.1 (14.1) years, most were female (78%), with a mean pulmonary arterial pressure of 51.6 (13.8) mmHg and pulmonary vascular resistance index of 22.5(6.3) WU/m2. Measures of right heart size and function were strongly related to each other particularly RVFWS and RVFAC (R 2 = 0.82, p < 0.001), whereas the relationship between TAPSE and RVFWS was weaker (R 2 = 0.28, p < 0.001). Death or lung transplantation at 5 years occurred in 78 patients (35%). Guided by outcome analysis, we ascertained a uniform set of parameter thresholds for grading the severity of right heart adaptation in PAH. Using these quantitative thresholds, we, then, validated the recently reported REVEAL-echo score (AUC 0.68, p < 0.001). This study proposes a consistent echocardiographic grading system for right heart adaptation in PAH guided by outcome analysis.

Abstract 13857: Slit2/ROBO4 Ligand-Receptor Pair as Novel Biomarkers for Survival in Pulmonary Arterial Hypertension

Background: Slit ligand guidance 2 (Slit2) is a ligand of the Roundabout guidance receptor (ROBO4), a transmembrane endothelial-specific receptor expressed in lung tissue. Pulmonary vascular remodeling contributes to PAH development and ROBO4 has been shown to play a role in inhibiting VEGF related angiogenesis. No studies have evaluated ROBO4 and Slit2 levels in PAH. Research Question: This study sought to assess if ROBO4 and/or Slit2 levels are detectable, altered in and associated with survival outcomes and hemodynamic measurements in patients with PAH. Methods: Serum ROBO4 levels were measured in 139 adults with PAH and 90 controls. Serum Slit2 levels were measured in 210 adults with PAH and 40 controls. Mann-Whitney U tests were used to compare biomarker levels in PAH and controls. Biomarker levels in the PAH cohort were compared to hemodynamic measurements and survival analyses were conducted for a composite outcome (death or transplant) using Cox proportional hazard models, and Kaplan Meier analysis with biomarkers dichotomized at the median. Results: ROBO4 and Slit2 levels were higher in PAH vs control patients (p=0.0005, p=0.002). In Kaplan-Meier analysis, ROBO4 and Slit2 levels above the median were associated with time to death or transplant (Logrank test p=0.016, p=0.03). ROBO4 and Slit2 levels were positively associated with death or transplant using Cox proportional regression, adjusted for age with a hazard ratio of 1.8 (95% CI 1.07-2.97, p=0.003) and 1.49 (95% CI 1.11-1.99, p=0.008), respectively. There were no statistically significant associations between ROBO4 and Slit2 levels and hemodynamic data such as mPAP, mRAP and PVR. Conclusions: This pilot data demonstrates that the angiogenic protein Slit2 and its receptor ROBO4 levels are both associated with survival outcomes in PAH. Future studies should evaluate in vitro studies to localize Slit2/ROBO4 in lung tissue using immunohistochemistry.

Plasma TRAIL and ANXA1 in diagnosis and prognostication of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare vasculopathy, with high morbidity and mortality. The sensitivity of the current european society of cardiology/european respiratory society (ESC/ERS) risk assessment strategy may be improved by the addition of biomarkers related to PAH pathophysiology. Such plasma-borne biomarkers may also reduce time to diagnosis, if used as diagnostic tools in patients with unclear dyspnea, and in guiding treatment decisions. Plasma levels of proteins related to tumor necrosis factor (TNF), inflammation, and immunomodulation were analyzed with proximity extension assays in patients with PAH (n = 48), chronic thromboembolic pulmonary hypertension (PH; CTEPH, n = 20), PH due to left heart failure (HF) with preserved (HFpEF-PH, n = 33), or reduced (HFrEF-PH, n = 36) ejection fraction, HF without PH (n = 15), and healthy controls (n = 20). TNF-related apoptosis-inducing ligand (TRAIL) were lower in PAH versus the other disease groups and controls (p < 0.0082). In receiver operating characteristics analysis, TRAIL levels identified PAH from the other disease groups with a sensitivity of 0.81 and a specificity of 0.53 [area under the curve: 0.70; (95% confidence interval, CI: 0.61-0.79; p < 0.0001)]. In both single (p < 0.05) and multivariable Cox regression models Annexin A1 (ANXA1) [hazard ratio, HR: 1.0367; (95% CI: 1.0059-1.0684; p = 0.044)] and carcinoembryonic antigen-related cell adhesion molecule 8 [HR: 1.0603; (95% CI: 1.0004-1.1237; p = 0.0483)] were significant predictors of survival, adjusted for age, female sex and ESC/ERS-initial risk score. Low plasma TRAIL predicted PAH among patients with dyspnea and differentiated PAH from those with CTEPH, HF with and without PH; and healthy controls. Higher plasma ANXA1 was associated with worse survival in PAH. Larger multicenter studies are encouraged to validate our findings.

Cardiohepatic syndrome and its prognostic predictive ability in patients with pulmonary arterial hypertension

With the development of progressive right ventricular dysfunction, pulmonary arterial hypertension (PAH) is one of the causes of type 2 cardiohepatic syndrome (CHS). Risk assessment, timely and effective management are crucial to improve survival in PAH. Thus, we aimed to evaluate the presence of CHS at diagnosis and its association with prognosis in patients with PAH. One hundred and eighteen consecutive incident patients with PAH between January 2013 and June 2021 were retrospectively included. The presence of CHS was assessed from blood tests taken during diagnostic evaluation and was defined as elevation of at least two of three cholestatic liver parameters; total bilirubin, alkaline phosphatase and gamma-glutamyl transferase. The primary endpoint was all-cause mortality. Patients were followed for a median period of 58 (32–96) months. 23.7% of the patients had CHS at diagnosis. Significantly more patients in CHS (+) group were in intermediate and high-risk categories according to 2015 ESC/ERS guideline, REVEAL 2.0 and REVEAL Lite 2 risk assessment methods (p = .02, .03 and <.001, respectively). The presence of CHS was identified as an independent predictor of mortality (HR: 2.17, 95% CI: 1.03–4.65, p = .03) along with older age (HR: 2.89, 95% CI: 1.50–5.56, p = .001) and higher WHO functional class (HR: 2.57, 95% CI: 1.07–6.22, p = .03). To conclude, presence of CHS at diagnosis in patients with PAH was associated with severe disease and poor prognosis independent of other well known risk factors. As a simple and easy parameter to assess from routinely taken blood tests, CHS should be evaluated in patients with PAH.

Clinical characteristics and survival of pulmonary arterial hypertension with or without interstitial lung disease in systemic sclerosis

ObjectivesTo describe the clinical phenotype and prognosis of people in the Australian Scleroderma (SSc) Cohort Study with pulmonary arterial hypertension (PAH) with or without interstitial lung disease (ILD).MethodsParticipants meeting ACR/EULAR criteria for SSc were divided into four mutually exclusive groups: those meeting criteria for PAH (PAH-only), ILD (ILD-only), concurrent PAH and ILD (PAH-ILD) or neither PAH nor ILD (SSc-only). Logistic or linear regression analyses were used for associations between clinical features, health-related quality of life (HRQoL) and physical function. Survival analysis was performed using Kaplan–Meier estimates and Cox-regression modelling.ResultsOf 1561 participants, 7% fulfilled criteria for PAH-only, 24% ILD-only, 7% PAH-ILD and 62% SSc-only. People with PAH-ILD were more frequently male, with diffuse skin involvement, higher inflammatory markers, older age of SSc onset and higher frequency of extensive ILD than the cohort overall (p < 0.001). People of Asian race more frequently developed PAH-ILD (p < 0.001). People with PAH-ILD or PAH-only had worse WHO functional class and 6-min-walk-distance than ILD-only (p < 0.001). HRQoL scores were worst in those with PAH-ILD (p < 0.001).Survival was reduced in the PAH-only and PAH-ILD groups (p < 0.01). Multivariable hazard modelling demonstrated the worst prognosis in extensive ILD and PAH (HR = 5.65 95% CI 3.50–9.12 p < 0.01), followed by PAH-only (HR = 4.21 95% CI 2.89–6.13 p < 0.01) and PAH with limited ILD (HR = 2.46 95% CI 1.52–3.99 p < 0.01).ConclusionsThe prevalence of concurrent PAH-ILD in the ASCS is 7%, with poorer survival in those patients with PAH-ILD compared to ILD or SSc alone. The presence of PAH confers a poorer overall prognosis than even extensive ILD; however, further data are required to better understand the clinical outcomes of this high-risk patient group.

10-year survival of pulmonary arterial hypertension associated with connective tissue disease: insights from a multicenter PAH registry.

To report the 10-year survival rate and prognostic factors of pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) patients, to compare treatment and survival between patients enrolled before and after 2015, and to validate the discrimination of the recommended 4-strata model in predicting 10-year survival at follow-up in Chinese CTD-PAH patients. This study was derived from a Chinese national multicentre prospective registry study from 2009 to 2019. Medical records were collected at baseline and follow-up, including PAH-targeted therapy and binary therapy (both CTD and PAH-targeted therapy). A total of 266 CTD-PAH patients were enrolled and the 10-year survival rate was 59.9% (median follow-up time: 4.85 years). Underlying CTD (SSc), baseline 6-min walking distance and SaO2 were independent risk factors for 10-year survival. The proportion of patients receiving PAH-targeted combination therapy increased from 10.1% (2009-2014)-26.5% (2015-2019) and that of binary therapy increased from 14.8% to 35%. The 1-year survival rate increased from 89.8% (2009-2014)-93.9%, and the 3-year survival rate increased from 80.1% (2009-2014)-86.5% (both p > 0.05). The 4-strata strategy performed well in predicting 10-year survival at follow-up (C-index = 0.742). The 10-year survival rate of CTD-PAH patients was reported for the first time. The 10-year prognosis was poor, but there was a tendency for more standardized treatment and better survival in patients enrolled after 2015. The recommended 4-strata model at follow-up can effectively predict 10-year survival in CTD-PAH patients.

Characteristics, treatments and survival of pulmonary arterial hypertension associated with congenital heart disease in China: Insights from a national multicenter prospective registry

The purpose of this registry was to provide insights into the characteristics, treatments and survival of patients with PAH-CHD in China. Patients diagnosed with PAH-CHD were enrolled in this national multicenter prospective registry. Baseline and follow-up data on clinical characteristics, PAH-targeted treatments and survival were collected. A total of 1060 PAH-CHD patients (mean age 31 years; 67.9% females) were included, with Eisenmenger syndrome (51.5%) being the most common form and atrial septal defects (37.3%) comprising the most frequent underlying defect. Approximately 33.0% of the patients were in World Health Organization functional class III to IV. The overall mean pulmonary arterial pressure and pulmonary vascular resistance were 67.1 (20.1) mm Hg and 1112.4 (705.9) dyn/s/cm5, respectively. PAH-targeted therapy was utilized in 826 patients (77.9%), and 203 patients (19.1%) received combination therapy. The estimated 1-, 3-, 5-, and 10-year survival rates of the overall cohort were 96.9%, 92.9%, 87.6% and 73.0%, respectively. Patients received combination therapy had significantly better survival than those with monotherapy (p=0.016). NT-proBNP >1400 pg/ml, SvO2 ≤ 65% and Borg dyspnea index ≥ 3 and PAH-targeted therapy were independent predictors of mortality. Hemoglobin > 160g/L was a unique predictor for mortality in Eisenmenger syndrome. Chinese PAH-CHD patients predominantly exhibit Eisenmenger syndrome and have significantly impaired exercise tolerance and right ventricular function at diagnosis, which are closely associated with long-term survival. PAH-targeted therapy including combination therapy showed a favorable effect on survival in PAH-CHD. The long-term survival of Chinese CHD-PAH patients remains to be improved.

Pulmonary artery compliance in different forms of pulmonary hypertension

ObjectivePulmonary artery compliance (PAC), estimated as stroke volume (SV) divided by pulmonary artery pulse pressure (PP), may be a predictor of survival in pulmonary arterial hypertension (PAH). Resistance–compliance (RC) time,...

Interest of TAPSE/sPAP ratio for noninvasive pulmonary arterial hypertension risk assessment.

Although ventriculoarterial coupling is associated with better survival in pulmonary arterial hypertension (PAH), existing PAH risk assessment method has not considered echocardiographic criteria of right ventricular to pulmonary artery coupling. We aimed to test the prognostic value of the echocardiographic tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio for noninvasive PAH risk assessment. We retrospectively studied a cohort of 659 incident PAH patients from 4 independent French PH centers (training cohort: n=306, validation cohort n=353) who underwent follow-up TAPSE/sPAP measurement in addition to previously validated noninvasive risk stratification variables. The primary composite outcome was 3-year all-cause mortality or lung transplantation from re-evaluation. Mean age was 55 ± 17 years-old with a majority of female (66%). The three main PAH causes were connective tissue disease (26%), idiopathic (24%) and porto-pulmonary (19%). The primary composite outcome occurred in 71 (23%) patients. Multivariable Cox regression analysis retained 3 noninvasive low-risk criteria as associated with the primary composite outcome: NYHA I-II (p=0.001), NTproBNP <300 ng/L or BNP <50 ng/L (p=0.004), and TAPSE/sPAP >0.33 mm/mmHg (p=0.004). The more the low-risk criteria achieved at follow-up, the better the event-free survival both in the training and validation cohort (log-rank p < 0.001). In the training cohort, the c-index for these 3 criteria, for COMPERA 2.0 and for the noninvasive French Pulmonary Hypertension Network method were 0.75, 95%CI(0.70-0.82), 0.72 95%CI(0.66-0.75), 0.71 95%CI(0.62-0.73), respectively. The 3 following dichotomized low-risk criteria: TAPSE/sPAP >0.33 mm/mmHg, NYHA I-II and NTproBNP <300 ng/L or BNP <50 ng/L allow to identify low-risk PAH patients at follow-up.

Abstract 15151: Identification of Novel Right Ventricular Function Phenotypes in Pulmonary Arterial Hypertension Using Unbiased K-Means Clustering

Introduction: Survival in pulmonary arterial hypertension (PAH) is associated with right ventricular (RV) function rather than pulmonary vascular resistance (PVR). At present, RV function is not incorporated in current risk assessment models and studies evaluating RV function are generally limited to single-center studies. The aim was to identify novel RV function phenotypes using unbiased k-means clustering in patients with PAH. Methods: Baseline clinical and hemodynamic data in patients with PAH were harmonized data from 5 PAH clinical trials (COMPASS3: n=98, EARLY: n=176, GRIPHON: n=720, MAESTRO: n=44, and SERAPHIN: n=728). Pearson correlation analysis was used to select variables that reduce the co-linearity (|r| &lt; 0.7) between hemodynamic variables used in the models. K-means clustering methods were applied to advanced RV hemodynamics including end-systolic pressure (ESP), arterial elastance (Ea), single-beat end-diastolic elastance (Eed), Pulse pressure (PP), stroke volume (SV) and RV stroke work (RVSW). Survival analysis was used to compare all-cause mortality among each cluster group. Results: Participants in the harmonized dataset (n=1766) had a mean PAP of 53 ± 17 mmHg, a cardiac output of 4.3±1.4 L/min, a wedge pressure of 9±4 mmHg and a PVR of 11.8±7.4 WU. K-means clustering identified four distinct RV cluster phenotypes that range from mild to severe RV dysfunction (Fig. A). Participants in RV cluster 1 (RV C1) have severe RV dysfunction with increased pressure/afterload, decreased cardiac function, and increased diastolic stiffness compared to RV cluster 4 (RV C4). (Fig. A) RV C1 had decreased six-minute walk distance compared to other clusters. RVC1 and RVC2 had increased risk of mortality compared to RV C4 (Fig. B). Conclusion: Applying K-means clustering to harmonized hemodynamic data from PAH clinical trial data identified 4 unique RV function phenotypes with different clinical outcomes.

The evolution of survival of pulmonary arterial hypertension over 15 years.

The prognosis of pulmonary arterial hypertension (PAH) remains dismal. Over the years, multiple therapeutic advances have been introduced. This study evaluates the evolution of PAH survival over the past 15 years. We included 293 consecutive adult patients diagnosed with PAH between 2005 and 2019 (median age: 61.8 years, 70.3% female). Patients were divided into three cohorts based on the time of diagnosis: 2005–2009, 2010–2014, and 2015–2019 (2005–2009: n = 56; 2010–2014: n = 111; 2015–2019: n = 126). Transplant‐free survival was measured from the date of right heart catheterization until patients reached the composite endpoint of lung transplant or death. Multivariable cox‐pulmonary hypertension regression was used to study the effect of the time of diagnosis. The final cox model was fitted in both younger and older patients to evaluate the difference between these groups. During a median follow‐up time of 4.1 (interquartile range: 2.2–7.3) years, 9 patients underwent lung transplantation and 151 patients died. The median overall transplant‐free survival was 6.2 (5.5–8.0) years. Patients older than 56 years at baseline who were diagnosed in 2005–2009 showed better survival compared to patients diagnosed in 2010–2014 and 2015–2019 with an adjusted hazard ratio of, respectively, 2.12 (1.11–4.03) and 2.83 (1.41–5.69). Patients younger than 56 years showed neither an improved nor deteriorated survival over time. In conclusion, survival in patients with PAH did not improve over time, despite more available therapeutic options. This might be partly due to the changed demographic characteristics of the PAH patients and a still important diagnostic delay.

Incorporation of noninvasive assessments in risk prediction for pulmonary arterial hypertension.

Risk assessment for pulmonary arterial hypertension (PAH) utilizing noninvasive prognostic variables could be more practical in real-world scenarios, especially at follow-up reevaluations. Patients who underwent comprehensive evaluations both at baseline and at follow-up visits were enrolled. The primary endpoint was all-cause mortality. Predictive variables identified by Cox analyses were further incorporated with the French noninvasive risk prediction approach. A total of 580 PAH patients were enrolled. During a median follow-up time of 47.0 months, 112 patients (19.3%) died. By multivariate Cox analyses, tricuspid annular plane systolic excursion (TAPSE), TAPSE/pulmonary arterial systolic pressure (PASP),and cardiopulmonaryexercise testing-derived peak oxygen consumption (VO2) remained independent predictors for survival. Regarding the French noninvasive risk prediction method, substituting N-terminal pro-b-type natriuretic peptide (NT-proBNP) with the newly derived low-risk criteria of a TAPSE ≥ 17 mm or a TAPSE/PASP > 0.17 mm/mmHg, or alternating 6-minwalking distance with a peak VO2 ≥ 44 %predicted retained the discrimination power. When recombining the low-risk criteria, the combination of World Health Organization functional class (WHO FC), TAPSE and peak VO2 at baseline, and the combination of WHO FC, NT-proBNP, and peak VO2 at follow-up showed better discriminative ability than the other combinations. In conclusion, Peak VO2, TAPSE, and TAPSE/PASP are significant prognostic predictors for survival in PAH, with incremental prognostic value when incorporated with the French noninvasive risk prediction approach, especially at reevaluations. For better risk prediction, WHO FC, at least one measurement of exercise capacity and one measurement of right ventricular function should be considered.

Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6Rα

Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

Time-Velocity Integral of Left Ventricular Outflow Tract Predicts Worse Long-Term Survival in Pulmonary Arterial Hypertension

BackgroundThe time-velocity integral of the left ventricular outflow tract (TVILVOT) has been demonstrated to correlate with heart failure hospitalization and mortality, but the association of TVILVOT with the severity and prognosis of pulmonary arterial hypertension (PAH) has not been evaluated. ObjectivesThe aim of this study was to investigate the predictive value of baseline TVILVOT in PAH. MethodsA total of 225 consecutive patients with a diagnosis of incident PAH were prospectively studied and echocardiology-derived TVILVOT was measured at enrollment followed by right heart catheterization examination within 48 hours. Cox proportional hazards analysis was performed to assess the association between baseline variables and mortality. ResultsDuring a median follow-up period of 33.8 months, 44 patients died of cardiovascular events. Baseline TVILVOT was significantly lower in the nonsurvivors compared with the survivors (P < 0.001). Baseline TVILVOT was positively correlated with stroke volume obtained by right heart catheterization (r = 0.709; P < 0.001), and inversely correlated with N-terminal pro–B-type natriuretic peptide (r = −0.533; P < 0.001), pulmonary vascular resistance (r = −0.423; P < 0.001). Multivariate analysis showed that baseline TVILVOT (hazard ratio: 0.856; 95% CI: 0.780-0.941; P = 0.001) was an independent predictor of cardiovascular mortality in PAH. Patients with a baseline TVILVOT <17.1 cm (median value) had a significantly worse survival than those with a baseline TVILVOT ≥17.1 cm (P < 0.001). ConclusionsThe findings of this study suggest that noninvasive TVILVOT provides a practical method to assess the severity and predict long-term outcome of PAH.

Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.

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.

Imaging of Improved Right Ventricular Coupling, Risk Status and Survival in Pulmonary Arterial Hypertension

<h3>Purpose</h3> 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. <h3>Methods</h3> The study retrospectively enrolled 677 PAH patients (55 % idiopathic) with follow-up clinical, right heart catheterization and echocardiographic evaluations within 12 months (IQR 180-344 days) after initiation of targeted therapies from 2005 to 2017 in 11 Italian centers. 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. <h3>Results</h3> The patients improved their functional class and 6-min walk distance, but a minority of them achieved or mainteined the low risk status as assessed either with the European or the REVEAL 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 (OR 4.93, C.I. 3.40-7.14; p=0.0001) and the REVEAL 2.0 score (OR 3.37, C.I. 2.32-4.90; p=0.0001). <h3>Conclusion</h3> Improvement of TAPSE/PASP under targeted therapies in PAH is associated with a low risk status and marked reduction in PVR.