BACKGROUND:The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex. METHODS:We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed. RESULTS:There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in women compared with men. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores. CONCLUSIONS:We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in women compared with men.

RATIONALE:Pulmonary artery (PA) dilation on computed tomography (CT) has been associated with moderate-to-severe -pulmonary hypertension (PH) using outdated diagnostic criteria. The association between PA size and mean PA pressure (mPAP) in mild PH and the prognostic implications of PA dilation remain unclear. OBJECTIVES:To investigate associations between PA size, mPAP, and survival in subjects without significant lung disease aside from PH. METHODS:PA size on CT was measured for individuals with group 1 or 2 PH and matched controls in the Pulmonary Vascular Disease Phenomics cohort. Outcomes included mPAP on right heart catheterization (RHC) and time to heart and/or lung -transplantation or death. MEASUREMENTS AND MAIN RESULTS:A total of 691 subjects were included, with 595 undergoing RHC. PA diameter and PA:aorta ratio demonstrated significant association with mPAP (ρ = 0.557 and 0.564, respectively). Size increased incrementally from no PH to mild PH to moderate-severe PH for PA diameter (27.64 [95% CI, 17.64-37.64] mm to 30.65 [95% CI, 18.99-42.31] mm to 36.00 [95% CI, 22.46-49.54] mm) and PA:aorta (0.89 [95% CI, 0.53-1.24] to 0.99 [95% CI, 0.63-1.35] to 1.19 [95% CI, 0.60-1.78]). PA diameter and PA:aorta demonstrated good discrimination of mPAP >20 mm Hg (area under the curve: 0.834 and 0.816, respectively). Transplant-free survival decreased across the continuum of PA diameter and PA:aorta (P <.001). Adjusted hazard ratio of third versus first quartile values was 2.36 (95% CI, 1.58-3.54) for PA diameter and 2.24 (95% CI, 1.52-3.30) for PA:aorta. CONCLUSIONS:In subjects without significant lung disease outside of PH, PA size on CT was associated with increased mPAP and decreased transplant-free survival across the spectrum of PH severity and demonstrated modest diagnostic discriminatory ability using updated hemodynamic criteria.

Background:Pulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways. Methods:We applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients. Results:WGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, β-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5α-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites. Conclusions:These findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.

Background The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. Methods We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC‐PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation‐free survival across the new PH clusters. We quantify metabolites of the arginine‐nitric oxide pathway and D‐dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. Results Clustering analysis identify 3 clear clusters in CC‐PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation‐free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D‐dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. Conclusions We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02980887.

BACKGROUND:Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure-a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS:The current analysis included pulmonary vascular disease phenomics participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS:The overall prevalence of unclassified PH in pulmonary vascular disease phenomics (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; P=0.006). Increased flow occurred in a minority of unclassified PH from both pulmonary vascular disease phenomics (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)-age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS:The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02980887.

BACKGROUND:With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS:Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS:Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy (P<0.0002), left ventricular strain impairment (P<0.0001), and decreased left ventricular compliance (P<0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction (P<0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P<0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P<0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS:Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

Digital models and digital twins of human circulatory transport could transform the way cardiovascular and haematological diseases are understood, monitored and treated. Digital twins are dynamic virtual representations of physical systems that continuously assimilate real-world data to simulate and predict system behaviour. However, translating digital twins into clinical practice remains challenging owing to the complexity of human physiology and the need for continuous bidirectional coupling between virtual models and their physical counterparts. Advances in medical-grade sensors, wearable devices, microfluidics, artificial intelligence and high-performance computing are accelerating the evolution of digital models into clinically meaningful digital twins. In this Review, we examine how digital twins can model the human circulatory system across scales, from macroscopic blood flow to molecular and cellular transport. We outline the essential components of a circulatory-transport digital twin, describe the pathophysiological conditions that can be digitally represented, and discuss approaches for acquiring and integrating physiological data, computational modelling strategies and model-based inference. We further survey applications of digital models and digital twins across various types of model inferences, from mechanistic insights to clinical decisions such as disease diagnosis, risk stratification, surgical planning and treatment planning. Finally, we identify key challenges and opportunities for next-generation circulatory digital twins capable of real-time monitoring, predictive simulation and closed-loop therapeutic control.

Background:World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods:We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results:Adjudicated Group 2 PH was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post/NonG2 participants, consistent with ventricular interdependence. RV/LV ratio ≥0.94 reduced discordant Post/NonG2 classification by 70.5%, and incorporation of PCWP/cardiac output slope improved physiologic specificity during exercise. Conclusions:Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment. Clinical Perspective:What Is New?: In the deeply phenotyped PVDOMICS cohort, resting pulmonary capillary wedge pressure demonstrated good overall discrimination for adjudicated Group 2 (left heart disease) pulmonary hypertension, yet intermediate values frequently either concealed latent left-heart disease or overclassified patients without intrinsic left-heart diseaseResting pulmonary capillary wedge pressure should be viewed as a continuous probability signal rather than a binary threshold, allowing additional physiologic testing to be targeted according to the degree of diagnostic uncertainty a clinician is willing to accept.A staged physiology-guided approach incorporating inhaled nitric oxide, ventricular geometry, and provocative testing improved concordance with adjudicated PH category and pre or post-capillary classification.What Are the Clinical Implications?: Pre- versus post-capillary classification should be interpreted within the broader clinical and physiologic context rather than relying on a single resting pulmonary capillary wedge pressure threshold.Intermediate pulmonary capillary wedge pressure values should prompt consideration of additional physiologic evaluation, with inhaled nitric oxide providing a practical intermediate step and provocative testing providing the greatest incremental diagnostic yield.Exercise pulmonary capillary wedge pressure/cardiac output slope and markers of ventricular interdependence may provide complementary information for resolving uncertainty when resting and dynamic hemodynamics are discordant.

BACKGROUND:Pulmonary vasodilators increase cardiac output (CO) in group 1 pulmonary hypertension (PH) and can cause high CO with unclear implications. Our objective was to describe the pathophysiology of high CO in group 1 PH. METHODS:Clinical characteristics were compared among PVDOMICS group 1 PH participants by low (cardiac index (CI) <2.2 L·min-1·m-2), normal or high output (CO ≥8 L·min-1 or CI ≥4 L·min-1·m-2). RESULTS:Of 449 group 1 PH participants, 23% (n=103) had low output, 68% (n=304) had normal CO and 9% (n=42) had high output. Increasing CO was associated with more intensive vasodilator use (triple therapy 11% versus 19% versus 33%, respectively; p=0.0008), with progressively lower pulmonary vascular resistance (p<0.0001). High output was associated with the lowest systemic vascular resistance (p<0.0001), with greater left ventricular (LV) and left atrial enlargement (p<0.001 for all). High flow resulted in an increase in LV and right ventricular (RV) work at rest, and absolute/relative RV work during exercise (p<0.0001 for all). Despite greater exercise oxygen delivery (p<0.0001), peripheral oxygen utilisation was impaired by oxygen extraction ratio (p=0.001) and arteriovenous oxygen difference (p=0.005), without incremental functional or survival benefit compared to normal output PH. After adjusting for baseline risk, high output had increased risk of death/transplantation compared to normal output (adjusted hazard ratio 2.1, 95% CI 1.2-3.7; p=0.007). In a validation cohort (n=37), 93% had normal CO at diagnosis, with the high output state developing in follow-up after vasodilator initiation. CONCLUSIONS:Around one in 10 patients with group 1 PH has a high output state, which is most common in prevalent PH and related to vasodilator intensity, with adverse cardiac remodelling and myocardial workload. Further studies are needed to determine optimal vasodilator dosing with high output and therapeutic interaction with vasodilator-sparing therapies such as sotatercept.

BACKGROUND:Although obesity and insulin resistance (IR) are established risk factors for left heart dysfunction, their clinical impact in group 1 pulmonary hypertension (PH) remains unclear. We sought to determine the impact of excess adiposity versus IR on biventricular hemodynamic and functional reserve in group 1 PH. METHODS:Homeostasis model of insulin resistance and adiposity indices (body mass index [BMI], fat mass, waist circumference) were measured among group 1 patients with PH recruited to PVDOMICS (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Functional capacity, and dynamic pulmonary capillary wedge pressure (PCWP) and right atrial pressure responses were compared stratified by obesity (BMI≥30 kg/m2) and IR status (HOMA-IR≥2.6) using repeated-measure mixed models. RESULTS:Among patients with group 1 PH (n=418), 158 (38%) had BMI≥30 kg/m2 (94 [60%] of whom had IR), and 260 (62%) had BMI<30 kg/m2 (74 [28%] of whom had IR). Among those with waist circumference measurement (n=375), 287 (77%) had excess adiposity by elevated waist/height ratio, with 214 (57%) having elevated waist circumference. Patients with obesity had worse quality of life, exercise capacity and left heart remodeling, along with higher resting/dynamic PCWP, right atrial pressure and cardiac output (P<0.0001 for all). Higher PCWP response with obesity persisted after adjusting for IR (IR-adjusted PCWP+2.5 mm Hg [95% CI, +1.4 to +3.6]; P<0.0001). All adiposity indices were consistently associated with PCWP response, but IR was not. Similar associations were observed between adiposity indices with higher right atrial pressure and cardiac output. Greater visceral adiposity as measured by body shape index (hazard ratio, 2.01 [95% CI, 1.16-3.47]; P=0.01) or weight-adjusted waist index (hazard ratio, 1.64 [95% CI, 1.10-2.46]; P=0.01) was associated with worse survival. CONCLUSIONS:Excess adiposity is common in group 1 PH, occurring in 4 out of 5 patients by the more sensitive waist/height ratio, in contrast to only 2 out of 5 patients having obesity by traditional BMI criteria. Excess adiposity is associated with higher biventricular filling pressures, cardiac output demand, worse functional status and reduced survival. These data support trials of adipose-reducing therapies in patients with group 1 PH and excess adiposity.

RATIONALE/OBJECTIVES:Image-based vascular biomarkers may help expedite evaluation of chronic thromboembolic pulmonary hypertension (CTEPH), which remains difficult to diagnose despite available effective therapies. We sought to determine if vascular heterogeneity and central redistribution on chest CT differed between CTEPH, pulmonary arterial hypertension (PAH), and control groups. MATERIALS/METHODS:We retrospectively included 108 patients who underwent right heart catheterization and chest CT (2011-2018). Automated CT image analysis was used to calculate volumes of all arteries, all veins, and small arteries/veins (area < 5 mm2). Vascular heterogeneity was assessed by partitioning each lung into isovolumetric segments and calculating coefficients of variation (CV) across segments. Central redistribution was assessed by measuring vascular volumes in central/peripheral lung zones (innermost/outermost fifth, respectively) and calculating central-to-peripheral volume ratios. We constructed multivariable linear regression models to compare vascular heterogeneity and redistribution between CTEPH and control/PAH groups. RESULTS:Of 108 patients, 21 had CTEPH, 47 had PAH, and 40 were controls. For vascular heterogeneity, we found consistently higher CVs (i.e. greater heterogeneity) in CTEPH vs. controls. For small arterial volume, CV was 0.09 units higher (95 % CI: 0.04-0.14, p = 0.0004) in the CTEPH group in adjusted models. Similarly, CVs were higher in CTEPH vs. PAH (p = 0.001). For vascular redistribution, we found greater central redistribution in CTEPH compared to controls/PAH; for small arterial volume, central-to-peripheral ratio was 1.52 units higher in CTEPH vs. controls (95 % CI: 0.78-2.26, p = 0.0001). CONCLUSION:Volumetric measures of heterogeneity and central distribution of pulmonary vessels can be quantified using CT techniques and may contribute to an image-based signature of CTEPH.

Rationale: Pulmonary hypertension (PH) is associated with significant morbidity and mortality. Ground-glass opacities (GGOs) are common in Group 1 PH, but their clinical significance is unclear. Objectives: We sought to characterize the clinical features and outcomes of patients with Group 1 PH with and without GGOs in the PVDOMICS study, a prospective multicenter cohort study aimed at deep phenotyping PH. Methods: Patients with incident and prevalent PH were enrolled across seven U.S. centers. We included patients with Group 1 PH and excluded those with parenchymal lung disease or without chest imaging, resulting in a cohort of 242 patients. Results: GGOs were common among patients with Group 1 PH (43% prevalence), associated with female sex, younger age, prostanoid use, and longer disease duration. GGOs were more common among patients with familial pulmonary arterial hypertension and pulmonary veno-occlusive disease. GGOs were associated with established markers of disease severity, including echocardiographic (right ventricular systolic pressure and tricuspid annular plane systolic excursion), biomarkers (N-terminal pro B-type natriuretic peptide), and worse hemodynamics (higher mean pulmonary artery pressure, pulmonary vascular resistance, and pulmonary artery wedge pressure). GGOs were associated with worse transplant-free survival (hazard ratio, 2.49; 95% confidence interval = 1.43-4.32; P = 0.001) and had independent prognostic value for predicting transplant-free survival after adjusting for European Society of Cardiology and European Respiratory Society risk stratification (hazard ratio, 2.19; 95% confidence interval = 1.20-3.99; P = 0.01). Conclusions: Overall, GGOs were associated with specific clinical characteristics and disease phenotypes, as well as worse hemodynamics, longer disease duration, prostanoid use, and worse survival. Future studies evaluating the pathophysiology and "omic" correlates of GGOs are warranted. Clinical trial registered with www.clinicaltrials.gov (NCT02980887).

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Rationale: Pulmonary artery (PA) dilation on CT has been associated with moderate-severe pulmonary hypertension (PH) using outdated diagnostic criteria. The association between PA size and mean PA pressure (mPAP) in mild PH and the prognostic implications of PA dilation remain unclear. Objectives: To investigate associations between PA size, mPAP, and survival in subjects without significant lung disease aside from PH. Methods: PA size on CT was measured for individuals with group 1 or 2 PH and matched controls in the Pulmonary Vascular Disease Phenomics cohort. Outcomes included mPAP on right heart catheterization (RHC) and time to heart and/or lung transplantation or death. Measurements and Main Results: 691 subjects were included, with 595 undergoing RHC. PA diameter and PA:aorta ratio demonstrated significant association with mPAP (ρ = 0.557 and 0.564, respectively). Size increased incrementally from no PH to mild PH to moderate-severe PH for PA diameter (27.64 [95% CI 17.64-37.64] to 30.65 [18.99-42.31] to 36.00 [22.46-49.54] mm) and PA:aorta (0.89 [0.53-1.24] to 0.99 [0.63-1.35] to 1.19 [0.60-1.78]). PA diameter and PA:aorta demonstrated good discrimination of mPAP > 20 mmHg (AUC 0.834 and 0.816, respectively). Transplant-free survival decreased across the continuum of PA diameter and PA:aorta (p < 0.001). Adjusted hazard ratio of third versus first quartile values was 2.36 [1.58-3.54] for PA diameter and 2.24 [1.52-3.30] for PA:aorta. Conclusions: In subjects without significant lung disease outside of PH, PA size on CT was associated with increased mPAP and decreased transplant-free survival across the spectrum of PH severity and demonstrated modest diagnostic discriminatory ability using updated hemodynamic criteria. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Pulmonary vascular disease is not a single condition; rather it can accompany a variety of pathologies that impact the pulmonary vasculature. Applying precision medicine strategies to better phenotype, diagnose, monitor, and treat pulmonary vascular disease is increasingly possible with the growing accessibility of powerful clinical and research tools. Nevertheless, challenges exist in implementing these tools to optimal effect. The 2023 Grover Conference Series reviewed the research landscape to summarize the current state of the art and provide a better understanding of the application of precision medicine to managing pulmonary vascular disease. In particular, the following aspects were discussed: (1) Clinical phenotypes, (2) genetics, (3) epigenetics, (4) biomarker discovery, (5) application of precision biology to clinical trials, (6) the right ventricle (RV), and (7) integrating precision medicine to clinical care. The present review summarizes the content of these discussions and the prospects for the future.

BACKGROUND: Echocardiographic metrics of right ventricular (RV) chamber size and function enhance prognostication, risk stratification, and measurement of therapeutic response in patients with pulmonary arterial hypertension (PAH), though the most effective metrics remain unclear. RESEARCH QUESTION: In a well-phenotyped cohort of patients with incident and prevalent PAH, can qualitative grades of RV echocardiographic function be established based on their association with functional outcomes, and do they demonstrate prognostic value beyond traditional risk scores? STUDY DESIGN AND METHODS: In the Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics (PVDOMICS) program, 405 (prevalent, n = 336; incident, n = 69) participants were investigated. Multivariable linear regression examined associations with 6-minute walk distance and the Comparative Prospective Registry for Newly Initiated Therapies (COMPERA) and the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 PAH risk scores. Penalized Cox regression was used to develop new models combining prior risk score variables with echo parameters. Cluster analysis combined with survival analysis adjusting for potential confounders was used to demonstrate prognostic significance. RESULTS: In both incident and prevalent PAH, reduced RV function was associated with increased N-terminal pro-B-type natriuretic peptide levels, reduced 6-minute walk distance, and increased COMPERA and REVEAL Lite 2.0 risk scores after adjusting for duration of PAH and relevant confounders. The addition of echocardiographic variables to models incorporating the COMPERA and REVEAL 2.0 scores yielded a 10% increase in the C-statistic. The severe RV dysfunction group was associated with increased all-cause mortality, with up to a threefold increase in mortality in multivariable models adjusted for relevant confounders, PAH duration, and invasive pulmonary vascular resistance. INTERPRETATION: Our results show that reduced RV function on echocardiography in PAH is associated with worsened outcomes in incident and prevalent PAH. Echocardiographic assessment of RV function provided additional value to existing PH risk prediction scores and invasive hemodynamics. Furthermore, defining severity of RV function through cluster analysis has important implications for risk prognostication, with potential application to monitor response to therapy.