Brittain, Evan L

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.

Introduction: PH increases RV afterload, often leading to RV systolic and diastolic failure. The metabolic mechanisms underlying RV dysfunction remain poorly understood and are largely unexplored across non-PAH forms of PH. Aims: We aimed to identify which metabolites and metabolic pathways associated with imaging measures of RV systolic function. Methods: We analyzed data from the multi-center PVDOMICS cohort, which includes echo, CMR, invasive hemodynamics, clinical phenotyping, and untargeted plasma metabolomics (via Metabolon). RV systolic function metrics selected as the outcome measures for this study were fractional area change (echo), global longitudinal strain (echo), and RVEF (CMR). Associations between non-xenobiotic, named metabolites and RV function measures were assessed using linear regression adjusted for age, sex, BMI, and PH group, with significance defined by FDR <0.05. Metabolite set enrichment analysis (MSEA) was performed to identify significantly enriched pathways (FDR <0.20). To complement MSEA, we conducted mean-aggregation analysis: we averaged metabolite concentrations within each pathway and tested associations with RV function using the same covariate adjustments (FDR <0.05). Results: We identified 979 participants with plasma metabolomics and at least one available outcome measure (317 Group 1 PH; 106 Group 2 PH; 140 Group 3 PH; 51 Group 4 PH; 26 Group 5 PH; 81 Healthy Controls; 258 Disease Comparators). Linear regression identified 170 metabolites from the 647 named metabolites significantly associated with all 3 RV metrics (Top 10 by average ranked p-value displayed in Image 1 ). MSEA revealed seven enriched pathways across all RV metrics: Androgenic Steroids, Pregnenolone Steroids, Progestin Steroids, Fatty Acid Metabolism (Acyl Choline), Histidine metabolism, Vitamin A metabolism, Gamma-glutamyl Amino Acid ( Image 2) . Mean aggregation analysis showed that higher concentrations of Androgenic/Pregnenolone Steroids and Vitamin A metabolites strongly associated with improved RV function, while higher levels of Fatty Acid Metabolism (Acyl Carnitine) and Acetylated Peptides associated with worse function ( Image 3 ). Conclusions: Using data from the multi-institutional PVDOMICS cohort, we provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Steroid hormones as well as Vitamin A and fatty acid metabolites emerged as central to RV systolic function.

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.

Abstract Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.

ABSTRACT Reduced functional capacity and poor sleep quality are common in pulmonary arterial hypertension (PAH). Wearable devices are an emerging, user‐friendly tool to capture activity and sleep information. We aimed to determine whether Fitbit‐derived activity and sleep trends provide clinically meaningful information in patients with PAH. Our prospective observational study recruited patients with PAH from across the United States using remote enrollment strategies and in‐person efforts. Participants wore a Fitbit device for 12 weeks at baseline and a subgroup with 1‐year follow‐up. A matched control cohort was generated from the All of Us Research Program and we evaluated changes in patients with PAH compared to matched controls. Among 110 patients with baseline monitoring, average daily steps correlated with 6MWD ( r = 0.61, p < 0.001) and percent rapid eye movement (REM) sleep ( r = 0.28, p = 0.008). In 44 PAH participants who completed baseline and 1‐year monitoring, there was a group‐time interaction for percent light sleep ( p = 0.024) and percent REM sleep ( p = 0.034), which demonstrated that sleep quality worsened in patients with PAH over 1 year compared to matched controls. Average daily steps decreased in patients with PAH from 5200 [IQR 3212–7458] at baseline to 4651 [IQR 2912–6827] at 1 year ( p = 0.008). In conclusion, our study demonstrated the potential clinical value of wearable devices by showing that activity and sleep quality are reduced in PAH compared to matched controls and these measures decline over time. Future studies should investigate if monitoring these health behaviors detects early functional decline and whether targeted interventions may improve outcomes.

BACKGROUND: Defining qualitative grades of echocardiographic metrics of right heart chamber size and function is critical for screening, clinical assessment, and measurement of therapeutic response in individuals with pulmonary vascular disease (PVD). In a population enriched for PVD, we sought to establish qualitative grades and prognostic value of right heart chamber size and function. METHODS: We investigated 1053 study participants in PVDOMICS (Redefining Pulmonary Hypertension Through the PVD Phenomics Program) to determine clinical and echocardiographic differences associated with increasing pulmonary vascular resistance severity. Right heart chamber size and function were qualitatively assessed using a percentile-based approach above the median values to create a clinical grading system for right heart adaptation. The relationship between echocardiographic categories and all-cause mortality was examined using survival analyses adjusted for potential confounders. RESULTS: A stepwise increase in adverse right heart remodeling was observed with a concomitant decrease in functional parameters by pulmonary vascular resistance strata ( P <0.001 for all). Mild, moderate, and severe categories of right heart chamber size and dysfunction were defined using a percentile-based approach across the spectrum of PVD. During a median follow-up of 2.07 years (interquartile range, 1.23–3.01 years), 130 participants died (11.4%). Progressive pulmonary vascular resistance increase and 2DE evidence of right heart dysfunction inclusive of fractional area change, and right ventricular global longitudinal strain were independently associated with increased all-cause mortality risk in multivariate analysis adjusted for age, disease duration, and male sex. CONCLUSIONS: In this well-characterized sample of adults with diverse etiologies and varying PVD severity, we define categories of abnormal right heart chamber size and function. Further, we demonstrate a stepwise relationship between these categories of abnormal morphology and function and all-cause mortality. Defining grades of right ventricular dysfunction in individuals with known PVD has important clinical implications for monitoring disease progression and response to therapies.

Abstract Aims There is a wide spectrum of diseases associated with pulmonary hypertension, pulmonary vascular remodelling, and right ventricular dysfunction. The NIH-sponsored PVDOMICS network seeks to perform comprehensive clinical phenotyping and endophenotyping across these disorders to further evaluate and define pulmonary vascular disease. Methods and results Echocardiography represents the primary non-invasive method to phenotype cardiac anatomy, function, and haemodynamics in these complex patients. However, comprehensive right heart evaluation requires the use of multiple echocardiographic parameters and optimized techniques to ensure optimal image acquisition. The PVDOMICS echo protocol outlines the best practice approach to echo phenotypic assessment of the right heart/pulmonary artery unit. Conclusion Novel workflow processes, methods for quality control, data for feasibility of measurements, and reproducibility of right heart parameters derived from this study provide a benchmark frame of reference. Lessons learned from this protocol will serve as a best practice guide for echocardiographic image acquisition and analysis across the spectrum of right heart/pulmonary vascular disease.

Pulmonary arterial hypertension (PAH) is a rare disease that carries a poor prognosis. For 45 years, the definition of pulmonary hypertension (PH) has been a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, based on expert opinion. Recent data indicate that the mortality risk starts in the mPAP range of 21–24 mmHg, which has recently been reflected in the World Symposium on PH consensus document defining PH as a mPAP > 20 mmHg. The mortality associated with these lower levels of pulmonary pressures suggests that these values reflect a more advanced disease stage than previously recognized. It is unknown whether interventions targeting patients with mPAP values in the range of 21–24 mmHg in the absence of left ventricular or hypoxic lung disease are of clinical benefit. Here we present historical perspective on the hemodynamic definition of PH, discuss recent epidemiologic data, and outline obstacles to enrolling and evaluating response to therapy in mild PAH patients, as well as potentially useful study designs.