Mortality In Pulmonary Arterial Hypertension Research Articles

The role of the TAPSE/sPAP ratio as a predictor of mortality in pulmonary arterial Hypertension: Its value for patient risk stratification

BackgroundThe tricuspid annular plane systolic excursion and systolic pulmonary artery pressure (TAPSE/sPAP) ratio has been proposed as an indicator of ventriculo-arterial coupling, predicting right ventricular failure (RVF) and mortality in patients with pulmonary arterial hypertension (PAH). ObjectiveTo evaluate the usefulness of the TAPSE/sPAP ratio in predicting outcomes and improving risk stratification in patients with PAH. Methods156 patients with PAH were included. Clinical, functional, echocardiographic, and haemodynamic variables, along with the TAPSE/sPAP ratio, were analysed based on etiological PAH subgroups and outcomes. Additional statistical measures, such as the area under the curve (AUC), net reclassification index (NRI), and integrated discrimination improvement, assessed the predictive ability of TAPSE/sPAP in combination with the ESC/ERS risk score, and other risk assessment strategies (COMPERA and Reveal Lite 2). ResultsMost patients were female (86.5%), with a median age of 45.5 (IQR: 29–58) years. The TAPSE/sPAP ratio for the whole group was 0.26 (IQR: 0.190–0.347) mm/mmHg, which was similar among different aetiologies, but different between deceased and surviving patients (0.14 vs. 0.27 mm/mmHg, respectively, P<0.001). A TAPSE/sPAP ratio <0.18 mm/mmHg independently predicted mortality (AUC: 0.859, 95% CI: 0.766– 0.952; P<0.001). Integration with the ESC/ERS risk score improved predicted mortality (AUC: 0.87 vs. 0.75, p=0.002) and risk stratification, reclassifying 14.28% of events and 36.92% of non-events, with an NRI of 39.4% (P<0.001). Likewise, integration with other scores improved predicted ability of COMPERA and REVEA Lite2; COMPERA+TAPSE/sPAP (AUC: 0.837 vs 0.742; p=0.005) and REVEAL Lite 2 +TAPSE/sPAP (AUC: 0.840 vs. 0.713; p<0.001). ConclusionsA TAPSE/sPAP ratio <0.18 mm/mmHg predicts mortality in PAH. The combination of the TAPSE/sPAP ratio with the ESC/ERS risk score improved risk stratification, and reclassification emphasizing the potential of ESC/ERS+TAPSE/sPAP as a valuable tool for risk assessment and clinical decision-making in PAH patients. Integration of TAPSE/sPAP ratio with other scores (COMPERA and (REVEAL Lite 2) also improved the risk stratification and reclassification of these risk scores.

Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial

Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. Gossamer Bio.

(865) - Hemodynamically Derived Right Ventricular Diastolic Stiffness Predicts Mortality in Pulmonary Arterial Hypertension

(865) - Hemodynamically Derived Right Ventricular Diastolic Stiffness Predicts Mortality in Pulmonary Arterial Hypertension

Pulmonary Hypertension and Right Ventricle: A Pathophysiological Insight.

Pulmonary hypertension (PH) is a pulmonary vascular disease characterized by elevated pulmonary vascular pressure. Long-term PH, irrespective of its etiology, leads to increased right ventricular (RV) pressure, RV hypertrophy, and ultimately, RV failure. Research indicates that RV failure secondary to hypertrophy remains the primary cause of mortality in pulmonary arterial hypertension (PAH). However, the impact of PH on RV structure and function under increased overload remains incompletely understood. Several mechanisms have been proposed, including extracellular remodeling, RV hypertrophy, metabolic disturbances, inflammation, apoptosis, autophagy, endothelial-to-mesenchymal transition, neurohormonal dysregulation, capillary rarefaction, and ischemia. Studies have demonstrated the significant role of oxidative stress in the development of RV failure. Understanding the interplay among these mechanisms is crucial for the prevention and management of RV failure in patients with PH.

The effect of sildenafil on maternal mortality in pulmonary arterial hypertension associated with congenital heart disease

Abstract Background Maternal mortality in pulmonary arterial hypertension (PAH) is very high, around 30–56%, so that patients with PAH and congenital heart disease (CHD) are advised to prevent pregnancy with class I-C recommendations. If the pregnancy continues, it must be handled by a multidisciplinary team with pulmonary hypertension (PH) experts, at the PH referral center. One of the PH-specific drug included in the FDA criteria B for pregnant women available in Indonesia is sildenafil. Sildenafil was reported to improve clinical symptoms and pregnancy outcomes in pregnant women with mild-moderate PAH. Sildenafil also had a tendency to reduce all-cause mortality although it was not statistically significant. Pulmonary hypertension specific drugs could reduce maternal mortality15.8% in subjects with PAH. However, research on sildenafil in maternal clinical outcomes is still very limited. Purpose This study aims to determine the effect of sildenafil on maternal mortality with PAH associated with CHD. Methods This study is an analytic observational study with a retrospective cohort method. Patient data were taken from the maternal registry, the Congenital HeARt Disease in adult and Pulmonary Hypertension (COHARD-PH) registry, and from the medical records of our general hospital who met the research criteria from August 2015 to December 2022. We assess the effect of sildenafil compared with controlled (without sildenafil) group. The clinical outcome of the study was maternal death during pregnancy and/or after delivery up to 42 days due to all causes (all causes mortality). Results Of 68 pregnant women who met the inclusion and exclusion criteria there were 32 subjects in the sildenafil group and 36 subjects in the control group. Maternal mortality was found to be higher (17.6%) in the group without sildenafil vs 9.7% in the sildenafil group. The majority causes of death were HP crisis (7 patients), 1 patient died from thromboembolism (HELLP syndrome), and 1 patient died from massive bleeding due to retained placenta. In the bivariate analysis, it was found that the NYHA functional class had a significant effect on maternal mortality with a p value &amp;lt;0.05, but not significantly from multivariate analysis. In the bivariate and multivariate analysis, general anesthesia had a statistically significant effect on maternal mortality with p=0.018. Of the 9 pregnant women who died, 5 patients received general anesthesia. Of the five patients, NYHA III-IV was found in 4 subjects (4/5 = 80%) and the other patient was NYHA II but subject came in at 63% saturation. All of the subjects are Eisenmeinger syndrome. Conclusion Sildenafil can reduce maternal mortality by 45% although it is not statistically significant. Further studies with larger data are needed to confirm this result.Basic Characteristics of SubjectsRelationship of Sildenafil with Maternal

Urinary proteomic analysis for biomarker discovery of pulmonary arterial hypertension-induced right ventricular failure

Abstract Background Right ventricular failure (RVF) is one of the independent and strong predictors of mortality in pulmonary arterial hypertension (PAH). Urine is more suitable and sensitive for biomarker discovery with no need for homeostatic control compared to blood. Purpose The purpose of this study is to investigate candidate urinary biomarkers for RV structural and functional monitoring during PAH progression. Methods The urinary proteome of 21 monocrotaline (MCT)-induced PAH rats (8 controls, 8 of compensated RV group, 5 of decompensated RV group) were identified using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). And the differential proteins were verified by parallel reaction monitoring (PRM)-targeted quantitative proteomics. Candidate biomarkers were further validated using ELISA in the urine of PAH patients. Results In total, 1811 urinary proteins were identified with at least 1 unique peptide (FDR≤1%). Compared to the control group of rats, 118 and 184 proteins were altered in the compensated and decompensated groups, respectively, and 62 differential proteins were found between the two stages (2.0-fold change, p&amp;lt; 0.05). The canonical pathways revealed that complement system, glutathione metabolism and iron homeostasis were enriched in the compensated stage, while interferon signaling, fibrosis, Wnt signaling and epithelial-mesenchymal transition were enriched in the failing stage. Four proteins confirmed by PRM, which were also of good discrimination ability of two RV stages were selected for further validation. ELISA results of the urine of PAH patients showed that IL18BP, IFNABR, LGALS3BP and α2-AP were sequentially elevated as disease progressed. Correlation analysis with clinical indicators showed that these proteins were positively correlated with right atrial pressure and right heart dilation, and negatively correlated with cardiac index and tricuspid annular plane systolic excursion. The combination of these four proteins panel could significantly distinguish PAH patients from healthy controls (AUC=0.985, 95%CI 0.955-1) and performs well in distinguishing high-risk PAH patients from low-risk ones (AUC=0.922, 95%CI 0.807-1). Conclusions Novel RVF candidate urinary biomarkers were found through in-depth proteomic analysis of PAH rat model. The panel of these four proteins, which were significantly correlated with RV structural remodeling and systolic function, showed good performance in diagnosis and risk stratification of PAH patients.Figure 1.Study workflowFigure 1.Main results of the study

Abstract 16157: Impaired Branched Chain Amino Acid Metabolism in Porcine Right Atrial Dysfunction

Background: Right atrial (RA) dysfunction is prevalent and an early predictor of mortality in pulmonary arterial hypertension (PAH). At present, the underlying pathobiology of RA dysfunction is not well defined, and thus approaches are needed to delineate potential therapeutic pathways to hopefully improve outcomes in PAH. Methods: Surgical pulmonary artery banding induced right ventricular and right atrial dysfunction in male piglets. 6 weeks post-banding, cardiovascular magnetic resonance imaging quantified cardiac structure/function. Right atrial and ventricular tissue was subjected to quantitative proteomics and targeted metabolomics. Results: PAB piglets had decreased RA ejection fraction (RAEF) and increased RA end-systolic volume. Pathway analysis revealed proteins responsible for branched chain amino acid (BCAA) degradation, including MCEE (Methylmalonyl CoA Epimerase), DLD (Dihydrolipoamide Dehydrogenase), HIBADH (3-hydroxyisobutyrate Dehydrogenase), ACAT1 (Acetyl-CoA Acetyltransferase 1), and IVD (Isovaleryl-CoA Dehydrogenase), were reduced in PAB RAs, which was not observed in RV tissue. Targeted metabolomics analysis demonstrated BCAAs were elevated in the RA of PAB piglets and BCAA levels were strongly and inversely associated with RAEF. Conclusions: Deranged BCAA metabolism is uniquely observed in the dysfunctional RA, which offers a new therapeutic target for this important clinical problem.

Associations of Histamine Metabolites with Disease Severity and Mortality in Pulmonary Arterial Hypertension.

Associations of Histamine Metabolites with Disease Severity and Mortality in Pulmonary Arterial Hypertension.

Fibrosis-4 Index as an Independent Predictor of Mortality in Pulmonary Arterial Hypertension

Fibrosis-4 Index as an Independent Predictor of Mortality in Pulmonary Arterial Hypertension

Abstract P3115: Disruption Of Assembly By Estrogen Limits Microtubule Proliferation In Failing Heart Cells

Right heart failure, resulting from high pressure in the pulmonary artery, is the leading cause of mortality in pulmonary arterial hypertension (PAH). Interestingly, females with PAH have superior right ventricular (RV) function, which can mostly explain improved survival in female patients. Microtubules are long filaments that regulate cellular contractility and transport within cardiac cells. The excess proliferation of microtubules is associated with pathological t-tubule remodeling in failing RV cardiomyocytes. Previous work suggests that the female hormone estrogen disrupts microtubule assembly. Here, we explored whether estrogen treatment could ameliorate the pathological proliferation of microtubules. By utilizing iPSC-derived cardiomyocytes with live-cell confocal imaging, we show that estrogen treatment leads to long pausing during microtubule growth, like the microtubule inhibitor colchicine. Additionally, estrogen treatment rescues microtubule overgrowth in endothelin-stressed primary cardiomyocytes (Fig. 1). We examined the molecular mechanism using purified tubulin, the building block of microtubules, and estrogen. In cell-free experiments, estrogen induced long pauses in microtubule growth. Our preliminary data suggest that estrogen, like colchicine, binds to free tubulin and co-polymerizes with it, disrupting microtubule assembly independent of estrogen receptors. We conclude that estrogen’s ability to limit microtubule proliferation could contribute to sex differences in RV function in PAH. Figure 1: Primary cardiomyocytes. Microtubule proliferation in endothelin-treated cells was rescued with estradiol.

Blockage of the adenosine A2B receptor prevents cardiac fibroblasts overgrowth in rats with pulmonary arterial hypertension

Sustained pressure overload and fibrosis of the right ventricle (RV) are the leading causes of mortality in pulmonary arterial hypertension (PAH). Although the role of adenosine in PAH has been attributed to the control of pulmonary vascular tone, cardiac reserve, and inflammatory processes, the involvement of the nucleoside in RV remodelling remains poorly understood. Conflicting results exist on targeting the low-affinity adenosine A2B receptor (A2BAR) for the treatment of PAH mostly because it displays dual roles in acute vs. chronic lung diseases. Herein, we investigated the role of the A2BAR in the viability/proliferation and collagen production by cardiac fibroblasts (CFs) isolated from RVs of rats with monocrotaline (MCT)-induced PAH. CFs from MCT-treated rats display higher cell viability/proliferation capacity and overexpress A2BAR compared to the cells from healthy littermates. The enzymatically stable adenosine analogue, 5′-N-ethylcarboxamidoadenosine (NECA, 1–30 μM), concentration-dependently increased growth, and type I collagen production by CFs originated from control and PAH rats, but its effects were more prominent in cells from rats with PAH. Blockage of the A2BAR with PSB603 (100 nM), but not of the A2AAR with SCH442416 (100 nM), attenuated the proliferative effect of NECA in CFs from PAH rats. The A2AAR agonist, CGS21680 (3 and 10 nM), was virtually devoid of effect. Overall, data suggest that adenosine signalling via A2BAR may contribute to RV overgrowth secondary to PAH. Therefore, blockage of the A2AAR may be a valuable therapeutic alternative to mitigate cardiac remodelling and prevent right heart failure in PAH patients.

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

Abstract 13527: The Development of a Remote Pulmonary Arterial Hypertension Risk Score Utilising Remote Monitoring Technology to Monitor Parameters Associated With Mortality in Pulmonary Arterial Hypertension

Background: In patients with pulmonary arterial hypertension (PAH) risk stratification is used to aid clinical decision making and guide treatment categorising patients as low (&lt;5%), intermediate (5-10%), or high mortality risk (&gt;10%) at 1 year based on hospital investigations. Risk stratification based on remote parameters may facilitate early evaluation of clinical efficacy following treatment change or indicate clinical stability/deterioration, thereby permitting early intervention. Methods: Patients with PH were identified from the ASPIRE (6/YH/0352) database 2/2001-6/2019. Random allocation was used to form a derivation (n=3832). Univariate Cox Regression and stepwise forward multivariate analysis were undertaken in the derivation cohort to identify parameters that may be remote monitored that were associated with mortality. Mortality weighted z-scores of age, incremental shuttle walk test (ISWT), heart rate (HR) and total pulmonary resistance (TPR) were summed to give an individual remote risk score value. LOESS regression was used to determine 1 year risk thresholds applied to a PAH validation cohort (n=590). Results: Multivariate analysis of the derivation cohort demonstrated that ISWT, HR and TPR had statistically significant relationships to mortality. Survival analysis showed increased mortality with each decile of baseline risk score with the 10 th decile at increased risk of mortality compared the 1 st decile (OR 5.5, 95%CI 4.3-7.0, each decile p&lt;0.01, Figure). In patients with PAH, LOESS derived thresholds identified patients at low, intermediate and high risk with 1 year mortalities of 4.6, 9.8 and 15.1% respectively (low-int OR 1.9, low-high OR 2.7,p&lt;0.01,Figure). Conclusion: A score of remote monitored parameters, when applied at diagnosis, accurately categorised patients as low, intermediate, or high risk. This system may be applied to remote monitored physiological data to provide real time risk stratification.

Abstract 13542: Associations of Pulmonary Artery Stiffness With Mortality in Pulmonary Arterial Hypertension

Introduction: Pulsatility, the relative area change of the pulmonary artery (PA) during the cardiac cycle has been associated with impaired prognosis in pulmonary arterial hypertension (PAH), but other measurements of stiffness are not well explored. Hypothesis: Multiple indices of PA stiffness derived from cardiac magnetic resonance (CMR) and right heart catheterization (RHC) predict outcome in PAH Methods: Retrospective chart review on 108 patients with PAH who had a clinically indicated CMR and RHC within 90 days, and for the primary endpoint of all-cause mortality. From CMR and RHC data, PA areas and indexes of stiffness (pulsatility, compliance, capacitance, distensibility, elastic modulus, and the pressure-independent stiffness index beta) were measured. Data was analyzed using Cox-proportional hazards models. Results: We included 108 patients with average age of 51 (+/- 13) years, 79% female with a mean PA pressure of 46 +/-12 mmHg, and a mean right ventricular ejection fraction (RVEF) of 38 +/-14%. After a median follow-up of 6 years, 58 (54%) patients had died. Most indices of increased stiffness were associated with higher mortality after adjusting for age, sex, diuretic use, mean PA pressure and RVEF ( Table ). Conclusions: Among patients with PAH, most measurements of PA stiffness strongly correlated with mortality.

The SOCE Machinery: An Unbalanced Knowledge between Left and Right Ventricular Pathophysiology.

Right ventricular failure (RVF) is the most important prognostic factor for morbidity and mortality in pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) caused by left heart diseases. However, right ventricle (RV) remodeling is understudied and not targeted by specific therapies. This can be partly explained by the lack of basic knowledge of RV remodeling. Since the physiology and hemodynamic function of the RV differ from those of the left ventricle (LV), the mechanisms of LV dysfunction cannot be generalized to that of the RV, albeit a knowledge of these being helpful to understanding RV remodeling and dysfunction. Store-operated Ca2+ entry (SOCE) has recently emerged to participate in the LV cardiomyocyte Ca2+ homeostasis and as a critical player in Ca2+ mishandling in a pathological context. In this paper, we highlight the current knowledge on the SOCE contribution to the LV and RV dysfunctions, as SOCE molecules are present in both compartments. he relative lack of studies on RV dysfunction indicates the necessity of further investigations, a significant challenge over the coming years.

Assessment of Clinical Worsening End Points as a Surrogate for Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Clinical worsening (CW) is a composite end point commonly used in pulmonary arterial hypertension (PAH) trials. We aimed to assess the trial-level surrogacy of CW for mortality in PAH trials, and whether the various CW components were similar in terms of frequency of occurrence, treatment-related relative risk (RR) reduction, and importance to patients. We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to December 2020) for trials evaluating the effects of PAH therapies on CW. The coefficient of determination between the RR for CW and mortality was assessed by regression analysis. The frequency of occurrence, RR reduction, and importance to patients of the CW components were assessed. We included 35 independent cohorts (9450 patients). PAH therapies significantly reduced CW events (RR, 0.64 [95% CI, 0.55-0.73]), including PAH-related hospitalizations (RR, 0.61 [95% CI, 0.47-0.79]), treatment escalation (RR, 0.57 [95% CI, 0.38-0.84]) and symptomatic progression (RR, 0.58 [95% CI, 0.48-0.69]), and modestly reduced all-cause mortality when incorporating deaths occurring after a primary CW-defining event (RR, 0.860 [95% CI, 0.742-0.997]). However, the effects of PAH-specific therapies on CW only modestly correlated with their effects on mortality (R2trial, 0.35 [95% CI, 0.10-0.59]; P<0.0001), and the gradient in the treatment effect across component end points was large in the majority of trials. The weighted proportions of CW-defining events were hospitalization (33.5%) and symptomatic progression (32.3%), whereas death (6.7%), treatment escalation (5.6%), and transplantation/atrioseptostomy (0.2%) were infrequent. CW events were driven by the occurrence of events of major (49%) and mild-to-moderate (37%) importance to patients, with 14% of the events valued as critical. PAH therapies significantly reduced CW events, but study-level CW is not a surrogate for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy, and importance to patients and are thus not interchangeable. URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42020178949.

Identification of LTBP-2 as a plasma biomarker for right ventricular dysfunction in human pulmonary arterial hypertension.

Although right ventricular (RV) function is the primary determinant of morbidity and mortality in pulmonary arterial hypertension (PAH), the molecular mechanisms of RV remodeling and the circulating factors reflecting its function remain largely elusive. In this context, the identification of new molecular players implicated in maladaptive RV remodeling along with the optimization of risk stratification approaches in PAH are key priorities. Through combination of transcriptomic and proteomic profiling of RV tissues with plasma proteome profiling, we identified a panel of proteins, mainly related to cardiac fibrosis, similarly upregulated in the RV and plasma of patients with PAH with decompensated RV. Among these, we demonstrated that plasma latent transforming growth factor beta binding protein 2 (LTBP-2) level correlates with RV function in human PAH and adds incremental value to current risk stratification models to predict long-term survival in two independent PAH cohorts.

Proteomic and Metabolomic Analyses of Right Ventricular Failure due to Pulmonary Arterial Hypertension.

Right ventricular failure (RVF) is the independent and strongest predictor of mortality in pulmonary arterial hypertension (PAH), but, at present, there are no preventive and therapeutic strategies directly targeting the failing right ventricle (RV). The underlying mechanism of RV hypertrophy (RVH) and dysfunction needs to be explored in depth. In this study, we used myocardial proteomics combined with metabolomics to elucidate potential pathophysiological changes of RV remodeling in a monocrotaline (MCT)-induced PAH rat model. The proteins and metabolites extracted from the RV myocardium were identified using label-free liquid chromatography–tandem mass spectrometry (LC-MS/MS). The bioinformatic analysis indicated that elevated intracellular Ca2+ concentrations and inflammation may contribute to myocardial proliferation and contraction, which may be beneficial for maintaining the compensated state of the RV. In the RVF stage, ferroptosis, mitochondrial metabolic shift, and insulin resistance are significantly involved. Dysregulated iron homeostasis, glutathione metabolism, and lipid peroxidation related to ferroptosis may contribute to RV decompensation. In conclusion, we depicted a proteomic and metabolomic profile of the RV myocardium during the progression of MCT-induced PAH, and also provided the insights for potential therapeutic targets facilitating the retardation or reversal of RV dysfunction in PAH.

Thyroid-stimulating hormone and mortality in pulmonary arterial hypertension

IntroductionPulmonary arterial hypertension (PAH) remains a serious and life-threatening illness. Thyroid dysfunction is relatively understudied in individuals with PAH but is known to affect cardiac function and vascular tone in...

Mortality in Pulmonary Arterial Hypertension in the Modern Era: Early Insights From the Pulmonary Hypertension Association Registry.

BackgroundCurrent mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry).Methods and ResultsWe identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan‐Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment‐naïve patients, we compared survival based on initial treatment strategy. The median age was 56 years (44–68 years), and 76% were women. Of the 935 patients, 483 (52%) were ≤6 months from PAH diagnosis. There were 121 deaths (12.9%) during a median follow‐up time of 489 days (281–812 days). The 1‐, 2‐, and 3‐year mortality was 8% (95% CI, 6%–10%), 16% (95% CI, 13%–19%), and 21% (95% CI, 17%–25%), respectively. When stratified into low‐, intermediate‐, and high‐risk PAH, the mortality at 1, 2, and 3 years was 1%, 4% to 6%, and 7% to 11% for low risk; 7% to 8%, 11% to 16%, and 18% to 20% for intermediate risk; and 12% to 19%, 22% to 38%, and 28% to 55% for high risk, respectively. In treatment‐naïve patients, initial combination therapy was associated with better 1‐year survival (adjusted hazard ratio, 0.43 [95% CI, 0.19–0.95]; P=0.037).ConclusionsMortality in the intermediate‐ and high‐risk patients with PAH remains unacceptably high in the PHAR, suggesting the importance for early diagnosis, aggressive use of available therapies, and the need for better therapeutics.