Hill, Nicholas S.

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 Rationale: The 7th World Symposium on Pulmonary Hypertension highlighted the importance of patient-reported outcomes in clinical assessment of pulmonary arterial hypertension (PAH). Patient-reported outcomes, such as health-related quality of life (HRQOL), have been associated with morbidity and mortality in PAH, but the added value of HRQOL measures to validated risk prediction models remains unknown. Methods: Adults with RHC-proven PAH from the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics (PVDOMICS) Study, a multi-center observational study, were included in this study. The Pulmonary Hypertension Association Registry (PHAR) was used as a validation cohort. HRQOL was measured using the emPHasis-10 score, where higher scores reflect worse HRQOL. Noninvasive risk assessment was measured by REVEAL Lite 2 risk score, categorized into 3-strata. Cox proportional hazard models were used to model survival evaluating the interaction between risk strata and HRQOL scores, adjusting for age, sex, and incident diagnosis. Harrell's C-statistics were calculated to compare discriminative performance. Results: From the PVDOMICS and PHAR cohorts, 265 and 2671 individuals with PAH and complete emPHasis-10 and REVEAL Lite 2 scores were included. Both cohorts had similar demographics, with an average age of 52±13 and 56±16 years, 75% and 72% female, 81% and 75% White, in the PVDOMICS and PHAR cohorts respectively. Over 87% of PVDOMICS were prevalent cases of PAH, while in the PHAR half were incident. Most individuals (62%) in PVDOMICS were REVEAL Lite 2 low risk, with 16% intermediate and 22% high risk; by contrast, in PHAR 33% were low, 29% intermediate, and 38% high risk. REVEAL Lite 2 scores demonstrated weak to moderate correlation with emPHasis-10 scores in both cohorts (PVDOMICS r=0.48 p<0.001; PHAR r=0.33 p<0.001). Notably, the full range of emPHasis-10 scores were observed in the low-risk individuals across both cohorts. In the PVDOMICS adjusted Cox models, higher emPHasis-10 scores predicted poorer survival (p=0.047) particularly among low-risk individuals (interaction versus high-risk group p=0.08). Similar adjusted models in PHAR demonstrated emPHasis-10 to be a confounder (p=0.001) without significant interaction by risk strata (low vs high-risk interaction p=0.94), but the greatest change in median survival time was observed in the low-risk group (Figure 1). Addition of emPHasis-10 to REVEAL Lite 2 scores improved discrimination in predicting survival (PVDOMICS: C-statistic 0.71 vs 0.73; PHAR: C-statistic 0.67 vs 0.69). Conclusions: Across two multicenter cohorts of incident and prevalent PAH, HRQOL as measured by the emPHasis-10 score improved discrimination for survival, particularly among individuals with lower risk scores.

Abstract Rationale: Although guidelines recommend the use of provocative testing to diagnose pulmonary venous hypertension (PVH) that is unapparent at normal resting right heart catheterization (RHC), the incremental value of provocative testing is unknown. We aim to evaluate the incremental diagnostic capability of inhaled nitric oxide (iNO), fluid challenge (FC) or invasive cardiopulmonary exercise testing (iCPET) to unmask PVH using previously defined hemodynamic cutoffs. Methods: We included subjects from the NHLBI-funded Pulmonary Vascular Disease Phenomics (PVDOMICS) study. Our analysis included patients with World Symposium on Pulmonary Hypertension (WSPH) Group 2 disease (G2PH) and G2PH comparators (WSPH Group 2 phenotype without a diagnosis of PH) as determined by the PI or adjudication panel. We then applied a protocol-driven provocative approach based on the feasibility of modalities available in most catheterization labs. Using a pulmonary capillary wedge pressure (PCWP) cutoff of >15, frequencies were identified for subjects based on resting PCWP and with iNO. Frequencies were also identified for: those who received FC with a PCWP cutoff of ≥18 or those who received iCPET with PCWP cutoff of >20 (upright) or >25 (supine). Results: There were 419 subjects identified with WSPH Group 2 disease (Figure). Roughly half were found to have a PCWP >15 during resting RHC (N = 207). Of the remaining subjects with a resting PCWP ≤15 (N = 150), 42 subjects were found to have a PCWP >15 with iNO administration (40.0%). Of the remaining 63 subjects with PCWP ≤15 following iNO administration, nearly half (N = 26, 48.0%) demonstrated a PCWP ≥18 following FC while 8 subjects (14.8%) demonstrated an elevated PCWP following iCPET. Conclusions: There is a high proportion of G2PH patients (∼35%) who appear hemodynamically similar to precapillary PH at rest. Inhaled nitric oxide vasodilatory challenge unmasks G2PH in many patients. In situations where iNO does not disclose the G2PH phenotype, provocation with FC or iCPET can be useful as a supplementary provocative maneuver. Future directions will focus on agnostically assessing the utility of provocation based on grouping subjects by resting hemodynamics as well as assessing the use of provocation in other forms of PH.

Abstract Rationale: Prior studies report association between pulmonary artery (PA) dilation on computed tomography (CT) imaging and pulmonary hypertension (PH). These studies predate expansion of PH hemodynamic diagnostic criteria and do not report patient mortality. As such, little is known about the presence of vascular changes in mild PH or their association with survival. We sought to investigate these relationships in individuals without significant parenchymal lung disease. Methods: We obtained CT images for subjects with group 1 or 2 PH, disease comparators, and healthy controls enrolled in the Pulmonary Vascular Disease Phenomics (PVDOMICS) study. We used Osirix imaging software to measure the main, left, and right PA (MPA, LPA, and RPA) and MPA:aorta (PA:Ao) ratio by diameter and cross-sectional area at locations consistent with prior studies. We evaluated associations with mortality and mean PA pressure (mPAP) using multivariable Cox and linear regression models adjusting for age, sex, and BMI. Descriptive statistics are presented as mean ± SD. Results: We identified 558 subjects (59 controls, 138 comparators, and 361 PH [267 group 1, 94 group 2]). 79 subjects had mPAP < 21 mmHg, 39 had mPAP 21-24 mmHg, and 371 had mPAP ≥ 25 mmHg. Increased MPA, LPA, and RPA diameter and area, PA:Aodia, and PA:Aoarea were associated with decreased survival (all p < 0.001) after multivariable adjustment. First versus third quantiles of all measurements were associated with mortality, with adjusted hazard ratio of 2.99 [95% CI 1.77, 5.05] for MPA diameter (2.84 vs 3.82 cm), 3.74 [2.07, 6.74] for MPA area (7.26 vs 12.74 cm2) and 5.24 [2.58, 10.66] for LPA area (4.55 vs 7.03 cm2). All measures significantly increased alongside PH severity from mPAP < 20 to 21-24 to ≥ 25 mmHg (see figure 1 for MPA diameter). All measures positively correlated with mPAP, including MPA diameter (ρspearman = 0.55) and PA:Aodia (ρ = 0.56). After multivariable adjustment, Q1 to Q3 increments in MPA diameter and PA:Aodia were associated with mPAP increase of 12.5 [10.7, 14.4] and 13.9 [11.9, 15.8] mmHg, respectively. BMI showed no correlation with PA size (ρ = 0.076 for MPA area, -0.051 for PA:Aodia). Conclusions: PA size increases alongside PH severity using updated hemodynamic criteria and is associated with incremental increases in PA pressure and mortality. LPA dilation demonstrates particularly strong association with mortality. PA size does not correlate with BMI. These novel findings enhance our understanding of vascular changes across the PH disease spectrum.

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.

Aims: Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status. Mitochondrial transmembrane potential, superoxide production, and mass were measured by flow cytometry in fresh platelets. Metabolomics analysis was performed on plasma samples. Global arginine bioavailability was calculated as the ratio of arginine/(ornithine+citrulline). Results: Global arginine bioavailability is consistently lower than controls in all PH groups. Although the mitochondrial mass is similar across all PH groups and controls, superoxide production and transmembrane potential vary across groups. Mitochondrial superoxide is higher in group 1 PAH and lowest in group 3 compared with other groups, while transmembrane potential is lower in group 1 PAH than controls or group 3. The alterations in mitochondrial functions of group 1 PAH are associated with changes in fatty acid metabolism. Mitochondrial transmembrane potential in group 1 PAH is associated with transplant-free survival. Conclusion: While alterations in mitochondrial function are found in all PH groups, group 1 PAH has a unique mitochondrial phenotype with greater superoxide and lower transmembrane potential linked to fatty acid metabolism, and clinically to survival. Antioxid. Redox Signal. 42, 361–377.

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 The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved. Methods and results We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular–pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660–0.737, p &lt; 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656–0.734, p &lt; 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference −0.072, 95% CI −0.123 to −0.020, p = 0.006, and −0.043, 95% CI −0.067 to −0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p &gt; 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p &lt; 0.05 for all). Conclusions Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH.

Abstract Aims Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2–3), but this group is not well-characterized. Methods and results Patients with PH enrolled in the prospective, NHLBI-sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2–3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2–3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2–3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2–3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N-terminal pro-B-type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2–3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6-min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30–0.86), and patients with G2–3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38–0.86). Conclusions Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2–3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. Clinical Trial Registration: ClinicalTrials.gov NCT02980887.