RATIONALE:Low levels of dehydroepiandrosterone (DHEA) and its sulfated form (DHEA-S) occur in pulmonary arterial hypertension (PAH) and are associated with worse right ventricular (RV) function. OBJECTIVES:We sought to determine whether DHEA improved RV function measured by cardiac magnetic resonance imaging in PAH. METHODS:We conducted a randomized, double-blind, placebo-controlled crossover trial of DHEA in PAH participants. The primary outcome was change in RV longitudinal strain after 18 weeks. MEASUREMENTS AND MAIN RESULTS:Twenty-six participants were randomized to DHEA first or placebo first, 20 (77%) were female. DHEA had no effect on RV longitudinal strain. DHEA improved RV short axis radial strain (20.7% [95% CI 16.7, 24.6] to 23.1% [95% CI 19.5, 26.7] vs. placebo (21.1% [95% CI 18.1, 24.0] to 19.3% [95% CI 16.5, 22.2])(p = 0.031), as well as emPHasis-10 scores (p = 0.037) and Short Form-36 physical component scores (p = 0.044) in the second treatment period. DHEA may have worsened RV circumferential strain as compared to placebo (p = 0.05, both treatment periods). Active treatment with DHEA significantly increased serum DHEA-S levels (p < 0.0001); higher DHEA-S levels were associated with improved PAH metrics. Active treatment with DHEA significantly increased serum testosterone levels (p < 0.01, both treatment periods). There was no difference in adverse events. CONCLUSIONS:DHEA treatment did not improve RV longitudinal strain in this crossover trial but had variable and possibly beneficial effects on other PAH endpoints. DHEA was safe and well tolerated. DHEA increased DHEA-S and testosterone levels, which may explain the discordant results.Clinical trial registered with www.clinicaltrials.gov (NCT03648385).

Background:Both rare and common variants in the SRY-Box Transcription Factor 17 (SOX17) locus are associated with pulmonary arterial hypertension (PAH). SOX17 dysregulation leads to pulmonary artery endothelial cell (PAEC) dysfunction and the obstructive remodelling that characterises PAH. Hypothesis:Impaired SOX17 expression contributes to the pathogenesis of PAH. Restoring the function of SOX17 or its downstream targets using compounds that mimic its transcriptomic signature will rescue PAEC dysfunction and prevent PAH development. Methods and Results:We defined thousands of genes with direct SOX17 genomic binding sites and identified important potential binding partners, including ETS-transcription factors such as ERG by ChIP-seq in PAECs. Through the integration of three PAEC RNA-seq datasets involving overexpression and silencing of SOX17, we defined a robust SOX17 transcriptomic signature. In PAH patients, circulating plasma protein levels of 10 SOX17 signature genes were associated with the SOX17 common risk variants. This included EFNB2 and UNC5B; knockdown of these genes altered the viability and apoptosis of PAECs in response to TNFα treatment. The drug-transcriptome database Connectivity Map (CMap) was used to predict novel potential therapeutic compounds to correct the SOX17 transcriptomic signature. Five compounds were selected for in vitro testing and were able to partially reinstate SOX17 target gene expression in PAECs. One compound, BX-912, was selected for in vivo testing as it corrected the levels of multiple target genes, including suppressing Runt-related transcription factor-1 (RUNX1). BX-912 blocked the development of pulmonary hypertension in mice lacking the SOX17 enhancer associated with human disease. Conclusion:We have demonstrated the therapeutic potential of targeting SOX17 in PAH through correction of its gene targets, identifying BX-912 as a lead compound with in vivo efficacy.

Pulmonary arterial hypertension (PAH) is characterized by molecular heterogeneity, which has limited personalized approaches to treatment selection. In this study, the authors assembled a novel pipeline that leveraged pulmonary artery endothelial cell biopsies acquired at the point of care to build individualized interactomes that served as the basis for a systems pharmacology analysis. Concordance between the molecular targets of a prescribed PAH pharmacotherapy class and interactome topology was associated with improved clinical outcomes using a retrospective in silico trial design. These data suggest that clinically actionable individualized treatment selection is feasible in PAH with relevance to other complex cardiovascular diseases.

The liver's contribution to pulmonary arterial hypertension (PAH) pathogenesis remains unclear. We hypothesized that the liver promotes inflammatory injury to the pulmonary endothelium. PAH patients without liver disease with pulmonary artery endothelial cell (PAEC) biopsies were included. Unsupervised CART analysis of liver serologies identified subclinical dysfunction clusters; machine-learning models informed differential expression and protein-protein interaction network assembly. PAEC transcriptomes were compared to liver and lung data from monocrotaline and Sugen-Hypoxia rats. Liver fibrosis was assessed in rat and human PAH livers. Among 25 PAH patients (76% female, median age 61 [30-84] years), CART identified clusters distinguished by Model for End-Stage Liver Disease Sodium (MELD-Na) ≥ 12, which was associated with higher Fibrosis-4 scores and higher pulmonary vascular resistance (ß = 0.5 Wood units per point increase in MELD-Na, 95% CI 0.2-0.8, p = 0.005) after adjustment for right atrial pressure. Subjects with MELD-Na ≥ 12 had decreased 6-min walk distance (353 [120-576] m vs. 411 [300-600] m, p = 0.03). In comparing the two clusters, a protein-protein interaction network analysis identified IL-6 as the primary hub of a transcriptional module enriched for leukocyte chemotaxis and myeloid leukocyte migration (all FDR < 0.05) among the High-MELD-Na group. Rat livers demonstrated immune activation and a trend toward increased fibrosis (20.8 vs. 16.6% area stained, p = 0.09), and human PAH livers without liver disease showed an intermediate fibrotic phenotype between controls and portopulmonary hypertension, though this did not reach statistical significance. Our observations support a lung-liver axis in PAH even in the absence of liver disease, warranting further study.

Genome-wide association studies have identified rare and common mutations associated with increased risk of pulmonary arterial hypertension (PAH), but the mechanism by which impaired SOX17 expression increases PAH risk is not known. Notably, SOX17 plays a critical role in endothelial identity during development by suppressing RUNX1 through binding to its promoter and directing stem and progenitor cells toward an endothelial rather than a hematopoietic cell fate. RUNX1 functions as a key regulator of myeloid differentiation, aberrant angiogenesis and adverse cardiac remodeling. Previously, we found that RUNX1 inhibition reverses pulmonary hypertension (PH) in multiple animal models. Here, we hypothesize that impaired expression of SOX17 in PAH leads to endothelial cell (EC) dysfunction by failing to suppress RUNX1. METHODS:Human pulmonary artery endothelial cells (HPAECs) with stable SOX17 CRISPR/Cas9 knockout or RUNX1 overexpression were generated and examined for endothelial and hematopoietic gene expression, proliferation, migration, apoptosis, and angiogenesis. Immortalized lymphoblastoid cell lines (LCLs) from PAH patients with SOX17 mutations and healthy controls were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into ECs. The effect of RUNX1 inhibition on Sugen/hypoxia-PH was examined in rats, SOX17 enhancer knockout (SOX17enhKO) mice, and Cdh5-CreERT2;Runx1(flox/flox);SOX17enhKO triple transgenic mice. SOX17 and RUNX1 expression were analyzed in peripheral blood samples from PAH patients (n=359). RESULTS:HPAECs with SOX17 deletion or RUNX1 overexpression exhibited decreased expression of EC markers, enhanced proliferation and migration, defective angiogenesis, and decreased apoptosis. RUNX1 siRNA knockdown or RUNX1 inhibition by Ro5-3335 partially restored the endothelial properties in SOX17 KO HPAECs. ECs differentiated from SOX17 mutant PAH patient iPSCs exhibited upregulated RUNX1 expression and loss of endothelial identity, which was also partially restored by RUNX1 siRNA or Ro5-3335. In addition, SOX17enhKO mice had increased RUNX1 expression and susceptibility to Sugen/hypoxia-induced PH (SuHx-PH). Treatment with RUNX1 inhibitors or inducible endothelial-specific deletion of RUNX1 rescued SuHx-PH susceptibility in SOX17enhKO mice. RUNX1 inhibitors Ro5-3335 and Ro24-7429 also reversed SuHx-PH in wild-type rats. In addition, plasma RUNX1 expression was higher in PAH patients lacking detectable SOX17 expression than in patients with detectable SOX17 expression. CONCLUSIONS:Impaired SOX17 expression increases the risk of PAH through insufficient suppression of RUNX1, leading to pulmonary endothelial dysfunction. RUNX1 inhibition mitigates PH associated with SOX17 deficiency and may represent a novel therapeutic strategy for PAH, especially those with rare or common SOX17 mutations.

TOPIC IMPORTANCE:Pulmonary hypertension (PH) represents a pathophysiologically diverse and clinically intricate spectrum of disorders characterized by elevated pulmonary arterial pressures and progressive right ventricular dysfunction. The management of PH has evolved considerably over recent decades; these developments underscore the dynamic nature of the field and the necessity for continual reappraisal of diagnostic and therapeutic frameworks. The European Society of Cardiology/European Respiratory Society and the World Symposium on Pulmonary Hypertension were pivotal in addressing key PH topics, including hemodynamic definitions, disease classification, risk stratification, and evolving therapeutic agents, and generating consensus-driven recommendations that shape global clinical practice. REVIEW FINDINGS:The ability to translate these global recommendations to clinical practice within the United States may be limited by inherent differences in health care access, population-specific disease modifiers, unique pulmonary arterial hypertension subtypes, clinical practice preferences, and comorbidities. SUMMARY:The recent clinical trials have introduced new therapies and indications that are reshaping the treatment landscape; however, these developments have not been addressed in guidelines or reviews from professional societies in the United States. The purpose of this review is to synthesize and interpret the latest international recommendations from a US perspective. We discuss multiple barriers to implementation of these recommendations, addressing racial, ethnic, and geographic disparities, treatment costs, and insurance limitations that are unique to the US health care system, and its effects on treatment delays and patient outcomes. Ultimately, this provides a framework for the development of a roadmap to increasing the quality of PH care in the United States.

Pulmonary arterial hypertension (PAH) is characterized by molecular heterogeneity and variable pharmacotherapeutic responses. We used an in silico clinical trial design to test whether transcriptomic data from pulmonary artery endothelial cell biopsies collected during right heart catheterization could be used to build individualized protein-protein interactomes and inform treatment response. Twenty-five PAH participants (56 [range: 30-84] yr; 91% female; 81%, white) and three controls contributed 32 and three cell biopsy specimens, respectively. Patient-specific interactomes varied widely in topology and complexity. All 32 individualized PAH interactomes were enriched significantly with key PAH endophenotypes genes such as hypoxia, oxidant stress, and apoptosis. Concordance between the molecular targets of a prescribed PAH pharmacotherapy class and the corresponding individualized interactome topology was associated with improvement in multiple PAH metrics, including a reduction in brain natriuretic peptide levels at 6 months (β -627.6 pg/mL, [95% CI -986.4, -268.8]; p = 0.003) and a decrease from high to intermediate REVEAL 2.0 Risk scores at 6 months (β -1.3 units, [95% CI -2.6, -0.04]; p=0.043) that persisted at 12 months (β -1.7, [95% CI -3.4, -0.1]; p=0.059). Integration of transcriptomics acquired at point-of-care with network medicine may individualize treatment selection and improve clinically relevant endpoints in PAH.

Background: Inflammation is a long-established hallmark of pulmonary arterial hypertension (PAH). In cardiovascular disease, the liver can modulate distal vascular inflammation but the liver-lung axis in PAH remains poorly characterized. Bone morphogenetic protein 9 (BMP9), encoded by growth differentiation factor 2 (GDF2) and primarily produced in the liver, is a critical ligand in PAH pathobiology and involved in systemic inflammation. We hypothesized that a preclinical Sugen-Hypoxia (SuHx) rat model of PAH would have hepatic inflammation and dysregulated BMP9 signaling. Methods: Livers were harvested from SuHx, monocrotaline (MCT) and control female and male rats. The left lobe of the liver in each SuHx animal was separated, randomly sectioned, paraffin embedded and stained with Hematoxylin and Eosin to assess for cellularity, Oil Red O for fatty deposition and CD68+ macrophages. Laboratory personnel were blinded for histological processing and quantification. SuHx and MCT livers were submitted for bulk RNA sequencing. SuHx livers were used to assess mRNA levels of GDF2 via qPCR, protein levels of TNF-α and IL-6 via ELISA and BMP9, BMP10, endoglin, BMPR2 and pSMAD 1/5/9 protein expression via immunoblot. Transcriptomic data were analyzed using DESeq2 in R. Results: Immunohistochemistry showed increased CD68+ macrophages in SuHx livers versus control, respectively (1.60% vs 0.93%, p=0.003) with a non-significant trend toward increased T-cell deposition (1.3% vs 1.6%, p=0.19). Livers from both MCT and SuHx rats demonstrated increased gene expression in pathways related to inflammation (e.g., Inflammatory response, TNFα signaling via NFκB, IL6 JAK STAT3 signaling, all p<0.05), and a nonsignificant alteration in TGFβ signaling (the family to which BMPs belong). Female SuHx rats had significantly increased relative hepatic BMP9 protein expression versus males (0.63 vs 0.21, p=0.02) but decreased BMPR2/pSMAD1/5/9 expression (p=0.02 and p<0.05, respectively) whereas males demonstrated the converse. There was no difference in BMP10 or endoglin expression (SuHx vs control or female vs male). Only the pre-pro-form of BMP9 was able to be detected. Conclusion: These data suggest an increased inflammatory infiltrate in SuHx rat livers – which to our knowledge has not previously been described – as compared to controls and MCT, a model with known hepatotoxicity. Hepatic BMP9 signaling is sexually dimorphic in experimental PAH; consistent with the well-established crosstalk between BMP and estrogen signaling. We hypothesize this represents production of nonfunctional mature BMP9 and dysregulated downstream signaling. Increased hepatic GDF2 expression may be a compensatory response to decreased circulating functional BMP9 as has been observed in human PAH.

Rationale:The adrenal steroid dehydroepiandrosterone (DHEA) and its sulfated form (DHEA-S) are deficient in pulmonary arterial hypertension (PAH) and lower levels are associated with worse right ventricular (RV) function, a decisive factor for survival in PAH. Objectives:We sought to determine whether DHEA improved RV function as measured by cardiac magnetic resonance imaging (MRI) in PAH. Methods:We conducted a randomized, double-blind, placebo-controlled crossover clinical trial of DHEA in participants with PAH at a single center. All participants and study staff were blinded. The primary outcome was change in RV longitudinal strain as measured by MRI after 18 weeks. Key secondary outcomes were the change in serum DHEA-S levels and other PAH end points after 18 weeks. Measurements and Main Results:A total of 26 participants were randomized to DHEA first or placebo first between 2019 and 2024, 20 (77%) of whom were females. Twenty-three (88%) participants completed the study; one participant completely withdrew. DHEA had no effect on RV longitudinal strain. DHEA improved RV short axis radial strain (20.7% [95% CI 16.7, 24.6] to 23.1% [95% CI 19.5, 26.7] compared to placebo (21.1% [95% CI 18.1, 24.0] to 19.3% [95% CI 16.5, 22.2])(p = 0.031), as well as emPHasis-10 scores (p = 0.037) and Short Form-36 physical component scores (p = 0.044) in the second treatment period. In both treatment periods, DHEA may have worsened RV circumferential strain as compared to placebo (p = 0.047, p = 0.052 respectively). Active treatment with DHEA significantly increased serum DHEA-S levels at the end of both treatment periods (p<0.0001), which was in turn associated with multiple study end points in the predicted direction (higher DHEA-S levels, improved PAH metrics). Active treatment with DHEA significantly increased serum testosterone levels as compared to placebo (p <0.01 for both treatment periods), which may have counteracted effects of DHEA supplementation. There was no difference in adverse events. Conclusions:DHEA treatment did not improve RV longitudinal strain in this pilot crossover trial but had variable and possibly beneficial effects on other PAH endpoints. DHEA increased DHEA-S and testosterone levels, which may explain some of the discordant results. DHEA is safe and well tolerated in PAH.Clinical trial registered with www.clinicaltrials.gov (NCT03648385).

RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive, debilitating disorder characterized by exertional dyspnea and physical fatigue. These symptoms may arise from a progressive worsening of cardiopulmonary function, while systemic manifestations, like skeletal muscle dysfunction and remodeling, can further limit exercise tolerance and quality-of-life in PAH.We aimed to determine whether there is a significant difference in skeletal muscle function (i.e., muscle mitochondrial oxidative capacity) in PAH patients compared to healthy people, matched by age, biological sex at birth and body mass. METHODS: Participant characteristics, medical history, PAH etiology and clinical data including hemodynamics were retrieved from medical records. Vital signs, resting dyspnea symptoms (RPD using modified 1-10 Borg dyspnea scale), and exercise performance (six-minute walk distance, 6MWD) were measured. Hemoglobin+myoglobin oxygen saturation was measured as the difference in absorption at 760 and 850 nm using near-infrared spectroscopy (NIRS). The NIRS-based test was done at rest, to noninvasively determine gastrocnemius muscle resting O2 saturation (TSI), vasoreactivity (TSI t50; index sensitive to aging and vascular pathologies), and muscle oxidative capacity from the mV'O2 recovery rate constant (k; greater k reflects greater muscle oxidative capacity). A paired t test assessed groups differences. RESULTS: Seven PAH and seven healthy controls were enrolled. All PAH subjects were on PAH treatments. The most common etiology of PAH was idiopathic (n=4, 57%), and 4(57%) had functional class II/III symptoms. The median(range) 6MWD was 472.5m (411.5-654.0), pulmonary vascular resistance was 4.21dyn/s/cm-5(2.15-7.60), and cardiac index was 3.14L/min/m2(2.37-4.08). Anthropometrics and vitals were similar between groups, but patients with PAH had a significantly lower resting gastrocnemius muscle O2 saturation (p=0.034) than controls. PAH also had a lower muscle tissue saturation index at rest (TSI, p=0.013) but similar calf microvascular vasoreactivity (TSI t50, p=0.614) compared to controls. Despite ∼32% lower muscle mitochondria oxidative capacity (k, p=0.040) and worse dyspnea (RPD, p=0.051), PAH patients performed similarly to healthy peers in 6MWD (p=0.657) (Table). CONCLUSIONS: Treated PAH patients have a significantly lower locomotor muscle oxidative capacity than healthy peers. The NIRS test shows promise as a methodology to evaluate peripheral skeletal muscle tissue oxygen saturation kinetics in PAH patients. Our pilot data seem to suggest that the loss of muscle mitochondrial oxidative capacity is a systemic manifestation of PAH, whereas preserved vasoreactivity may reflect a direct impact of PAH therapies. Larger cohort investigations are needed to confirm these findings. Support: R01HL151452 (to AA); R01HL141268 (to CV)

Rationale: Paracardial adipose (PAT) is metabolically active and has been linked to cardiovascular disease. Despite being highest in volume over the right ventricle (RV), PAT has not been studied in pulmonary arterial hypertension (PAH) or RV dysfunction. PAT releases inflammatory cytokines and adipokines that have separately been linked to PAH. We aimed to determine whether PAT area was associated with RV morphology and function measured by cardiac magnetic resonance imaging (CMR) and 6-minute walk distance (6MWD). Methods: This was a cross-sectional case-control study that included baseline CMRs obtained from PAH participants enrolled in the Effects of Dehydroepiandrosterone in Pulmonary Hypertension (EDIPHY) randomized clinical trial (NCT03648385) and age (within 5 years), biological sex, and body mass index (BMI) (within 3 kg/m2) matched controls obtained from a CMR imaging repository. Controls had been referred for evaluation of but ultimately excluded from having arrhythmogenic RV cardiomyopathy. We manually outlined areas of PAT for each PAH and control CMR and measured markers of RV function, in a blinded manner. PAT area was measured by a pulmonary fellow, who was trained over several sessions by a thoracic radiologist. 6MWD was collected as part of the EDIPHY trial at the baseline visit. Results: There were 26 PAH participants with baseline CMRs, most with 1-2 age, sex, and BMI matched controls. PAH participants were predominantly post-menopausal females (n = 12, 46%) with an average age of 48 years old. The two leading causes of PAH were idiopathic (n = 10, 38%) and associated with connective tissue disease (n = 9, 35%). PAH participants tended to have higher PAT area compared to matched controls ((ln[cm2] 2.57, 2.43-2.71) vs. (ln[cm2] 2.42, 2.23-2.62), p = 0.18) (Figure panel A). In PAH participants, increasing PAT area may have been associated with lower RV end-diastolic (Figure panel B) and end-systolic volume (Figure panel C), higher RV ejection fraction (Figure panel C), longer six-minute walk distance (Figure panel D), but increasing pulmonary artery diameter (Figure panel E), especially among females (p = 0.08). Conclusion: PAH patients may have higher PAT area as compared to matched controls. Paradoxically, increasing PAT area may be associated with improved RV function and better exercise capacity, yet increasing pulmonary artery diameter. These preliminary observations need to be examined longitudinally along with circulating inflammatory markers including adipokines.

The American Lung Association and Pulmonary Hypertension Association convened a scientific roundtable of pulmonary hypertension experts to discuss the latest recommendations from the European Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (PH) and from the 7th World Symposium on Pulmonary Hypertension (WSPH). The aim of the roundtable was to discuss changes that were made compared to earlier recommendations and guidelines set out by the European Society of Cardiology and the European Respiratory Society in 2015, the 6th World Symposium on Pulmonary Hypertension in 2018, and the CHEST Guideline on Therapy for Pulmonary Arterial Hypertension in 2019. The overall objectives were to: 1) Create an educational resource for providers that summarizes currently available PAH guidelines, 2) Provide an expert critique of current guidelines, outlining strengths and weaknesses and resolving differences where guidelines do not agree. 3) Provide guidance for the incorporation of the recently approved drug, sotatercept into current guidelines. An executive summary was drafted following the roundtable meeting on April 8, 2024, and revised by the panel in September 2024, following publication of the proceedings from the 7th WSPH held in Barcelona June 29-July 1, 2024. The Executive Summary reviews changes to the hemodynamic criteria for defining pre- and post-capillary PH, exercise-induced PH, and PH associated with lung disease. Recommendations are given for proper diagnosis and clinical classifications of the various forms of PH. The role of screening for PH in high-risk populations and the use of risk scores for disease stratification are discussed. Finally, treatment algorithms for managing pulmonary arterial hypertension, PH associated with lung disease, and chronic thromboembolic pulmonary hypertension are presented.

This exploratory analysis assessed whether plasma biomarkers predict the response to switching from phosphodiesterase type 5 inhibitors (PDE5is) to the soluble guanylate cyclase stimulator riociguat in patients with pulmonary arterial hypertension. Selected biomarkers at baseline and their changes to Week 24 were evaluated in patients with and without a favorable response to riociguat in two trials: RESPITE, in which patients with an inadequate response to PDE5i were switched to riociguat; and REPLACE, in which patients at intermediate risk of 1-year mortality despite a PDE5i were randomized to remain on PDE5i or were switched to riociguat. A response was defined as absence of clinical worsening and at least two of the following criteria: 6-min walk distance increase by 10% or ≥ 30 m, World Health Organization functional class I/II, or N-terminal prohormone of brain natriuretic peptide reduction of ≥ 30% at Week 24. In REPLACE, responders had significantly higher baseline cyclic guanosine monophosphate (cGMP) and significantly lower baseline asymmetric dimethylarginine, and growth/differentiation factor 15 (GDF-15) than nonresponders. In RESPITE, responders had lower baseline GDF-15 than nonresponders, and nonresponders showed a significantly greater decrease in cGMP than responders. No baseline threshold value of any biomarker provided a good likelihood of predicting the response to riociguat. Overall, the biomarkers evaluated did not help to identify patients who were more likely to respond to switching from PDE5is to riociguat.

The liver's contribution to pulmonary arterial hypertension (PAH) pathogenesis remains unclear. We hypothesized that the liver promotes inflammatory injury to the pulmonary endothelium. PAH patients without liver disease with pulmonary artery endothelial cell (PAEC) biopsies were included. Liver serologies and imaging were analyzed by unsupervised classification and regression tree (CART) to identify subclinical liver dysfunction clusters. Two machine-learning models predicted cluster assignment and informed differential expression. PAEC transcriptomes were compared to liver and lung data from monocrotaline and Sugen-Hypoxia rats. Liver fibrosis was assessed in rat and human PAH livers. Among 25 PAH patients (76% female, median age 61 [30 - 84] years), CART identified clusters distinguished by Model for End-Stage Liver Disease Sodium (MELD-Na) ≥12, predicting higher pulmonary vascular resistance (ß=0.5 Wood units per point increase in MELD-Na, 95% CI 0.2-0.8, p=0.005) after adjustment for right atrial pressure. Subjects with MELD-Na ≥12 had decreased 6-minute walk distance (353 [120 - 576] m vs. 411[300 - 600] m, p=0.03), with upregulation of apelin, beta-catenin, and immune signaling. Rat lung ECs demonstrated survival and hepatic growth-factor signaling, while rat livers showed immune activation. Rat (20.8 vs 16.6 % area stained, p=0.09) and human PAH livers revealed fibrosis despite absent right ventricular failure, supporting a pathogenic lung-liver axis in PAH.

Pulmonary hypertension (PH) refers to an abnormal elevation in pulmonary arterial pressure (PAP) under resting conditions.PH is often encountered in patients with chronic heart and lung disease. Rarely, it occurs in the absence of any identifiableheart or lung abnormalities. Under these conditions, the increase in PAP may be caused by diffuse remodeling of the distal pulmonary circulation characterized by an obliterative vasculopathy that leads to a marked increase in pulmonary vascular resistance, progressive right heart failure, and usually death. This disease is referred to as pulmonary arterial hypertension(PAH) and has become the focus of intense basic science and clinical research over the past quarter century. Since 1995, five classes of drugs that encompass more than a dozen specific agents have been developed and approved for the treatment of PAH. The large number of drugs and the myriad forms of pulmonary vascular disease has made the evaluation and treatment of PH an intriguing challenge. This review discusses the most recent definitions of PH and current classification of the pulmonary hypertensive diseases. An overview of the importance and proper approach to diagnosis is provided as well as the impact of patient selection on the approach to management. An evidence-based approach is used to determine how initial therapy is chosen and how additional medications can be used in patients who do not achieve treatment goals. Finally, the results of recently completed clinical trials that evaluated the safety and efficacy of a new class of medications that have been developed to target the underlying pathophysiology of PAH are presented and the potential impact on the management of PAH is discussed. The purpose of this review is to present the reader with an update on the current approach to evaluation and management of PH with an emphasis on PAH.

Introduction: Pulmonary arterial hypertension (PAH) is a highly morbid cardiopulmonary disease characterized by substantial pathobiological and clinical heterogeneity, which is believed to underlie variable treatment-response observed in clinical trials and at point-of-care during real-world practice. Utilizing patient-specific pathogenetic information to inform drug selection for use in clinical practice is expected to improve clinical efficacy of PAH drugs, but such strategies are currently lacking. Methods: We conducted a retrospective analysis of 25 PAH patients (32 samples, receiving PAH therapies) undergoing right heart catheterization (RHC) for the routine clinical assessment of dyspnea at Rhode Island Hospital (Warren Alpert Medical School of Brown University) , along with 3 healthy controls. A minimally invasive "cell biopsy" approach was used to collect Pulmonary Arterial Endothelial Cells (PAECs) from the tips of pulmonary artery catheters. Transcriptomic RNA-seq was performed on mRNA isolated from cell passage 3 or 4 for all samples. We deployed an innovative network medicine method to construct sample-specific interactomes from the transcriptomic data and human protein-protein interactome. The individualized interactomes captured patient-specific molecular features, which could then be used to predict therapeutic response in PAH patients. Results: The individualized interactomes have a range of 5276 [4900, 7263] nodes and 7204 [6606, 12992] edges. We observed that an increase in 6MWD from baseline that was sustained at 12 months following treatment initiation was associated with higher fraction of drug targets in the individualized interactomes. By contrast, such a positive association was not observed in comparator drugs. Similarly, we observed a transition in BNP levels from elevated at baseline to within the normal range at 12 months that corresponded to an absolute decrease of ~250 pg/mL. Higher fraction of drug targets in the individualized interactomes was also associated with a significant improvement in REVEAL 2.0 Risk score at 6 months (p=0.004) and 12 months (p< 0.001). Conclusions: "Cell biopsies" taken at point-of-care for clinically indicated RHCs may be leveraged to predict therapeutic response and inform precision-based initiatives in pulmonary vascular disease through transcriptome-derived sample-specific interactomes and systems pharmacology tools.