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BACKGROUND: Patients with lung disease, sleep apnea, and chronic thromboemboli can develop pulmonary hypertension, currently classified as group 3 or 4. Many of these patients also have risk factors for heart failure with preserved ejection fraction (HFpEF), but the optimal approach to identify the disease overlap remains unclear. METHODS: Pretest probability for HFpEF was determined using the HFpEF-ABA (age, body mass index, atrial fibrillation) algorithm among adjudicated group 3 or 4 patients at risk for pulmonary hypertension in the PVDOMICS study (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Patients were stratified by current resting right heart catheterization criteria, and in a separate analysis, stratified only by HFpEF-ABA probability into low (<25%), intermediate, and high (≥75%) HFpEF probability groups. RESULTS: Among 598 patients with group 3 disease, 27% (n=161) had elevated pulmonary capillary wedge pressure (PCWP) with postcapillary pulmonary hypertension even at rest, which was associated with the highest exercise PCWP. However, regardless of this resting PCWP-based classification, a larger subset had intermediate-to-high HFpEF-ABA probabilities (32% [n=197] high and 57% [n=358] intermediate HFpEF probability). High HFpEF probability in group 3 disease was associated with higher resting and dynamic PCWP response to NO, fluid, and exercise ( P <0.0001 for all). These changes were comparable with more traditionally defined HFpEF without pulmonary vascular disease (n=61) but less severe than those with combined precapillary and postcapillary pulmonary hypertension HFpEF (n=31; interaction P =0.006). Increasing HFpEF probability in group 3 disease was associated with worse left heart remodeling, quality of life, 6-minute walk distance, and peak VO 2 ( P <0.0001 for all). Findings were replicated in group 4 disease (n=102). CONCLUSIONS: Quantifying pretest probability for HFpEF in patients with sleep apnea, lung disease, or chronic thromboemboli identifies a progressive gradient for dynamic PCWP abnormalities with worse functional status and quality of life. These subclinical left heart abnormalities are not universally detectable by resting right heart catheterization alone and call for further study of whether strategies to prevent or treat HFpEF might improve functional status in these patients with high risk of occult HFpEF.

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&lt;0.001; PHAR r=0.33 p&lt;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: 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 &lt; 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 &lt; 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 &lt; 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.

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.

Introduction: The right ventricle [RV] adapts to pulmonary hypertension [PH] by increasing contractility to maintain RV-PA coupling. With increased afterload, RV contractility cannot compensate, resulting in RV failure. TAPSE/RVSP ratio is a non-invasive measure of RV-PA coupling. We aim to assess TAPSE/RVSP ratio for predicting PH severity and survival across a spectrum of PH in the PVDOMICS cohort. Methods: PVDOMICS subjects from the 5 World Symposium PH groups and comparators were evaluated. TAPSE/RVSP ratio, in mm/mmHg, was derived for each group. PH subjects were stratified by TAPSE/RVSP ratio into low < 0.19, intermediate ≥ 0.19 to < 0.32, and high ratio > 0.32. The relationship between the ratio and RHC parameters (mean PA pressure [mPAP] and pulmonary vascular resistance [PVR]), and between-group differences were evaluated by one-way ANOVA. Kaplan-Meier curves and log-rank tests were used to characterize and compare survival between groups. Results: Data were available for 514 PH subjects (58 ± 15 yrs, 64% female) and 179 comparators (61 ± 13 yrs, 59% female). Mean TAPSE/RVSP ratio was 0.35 ± 0.18 in PH vs 0.63 ± 0.26 in comparators (p < 0.001). Mean TAPSE/RVSP across the PH groups 1-5 were similar, 0.33 ± 0.19, 0.33 ± 0.16, 0.37 ± 0.15, 0.41 ± 0.21 and 0.43 ± 0.29 (p=NS). Within PH subjects, 99 (19.2%) had low, 173 (33.7%) had intermediate and 242 (47.1%) had high ratio. Those with low ratio had higher mPAP (53.6 ± 11.8 mmHg), compared to intermediate (44.6 ± 11.7 mmHg) and high ratio (34.1 ± 10.2 mmHg) [p < 0.001]. Those with low ratio had higher PVR (10.1 ± 5.1 WU), compared to intermediate (6.8 ± 4.1 WU) and high ratio (4.1 ± 2.1 WU) [p < 0.001]. Survival was significantly higher for those with high TAPSE/RVSP ratio compared to those with low ratio (p < 0.001) [Figure]. Discussion: TAPSE/RVSP ratio correlates well with invasive markers to predict PH severity. This useful measure of RV-PA coupling also enables stratification for outcome, with ratio > 0.32 having the best survival rates.

Introduction: Assessment of right ventricular (RV) size and function by echo is challenging due to complex RV anatomy and requires integration of multiple measurements. We sought to compare accuracy of echo measures of RV size and function with cardiac MRI (CMR) in pulmonary hypertension (PH). Methods: We included patients with PH from the PVDOMICS Study who underwent both echo and CMR. Echo measures of RV size (basal dimension, area, 3D volume) and function (fractional area change [FAC], 3D RV ejection fraction [EF], RV global longitudinal strain [GLS], S’, TAPSE, Tei index) were compared to CMR derived RV volumes and RVEF. Agreement was assessed using Bland-Altman (BA) plots and Lin’s concordance correlation coefficients (ρ c ). Predictive trends were evaluated using linear regression. Results: The cohort included 446 subjects (58 ± 15 yrs, 36% male). Echo measures of RV size showed poor agreement with CMR, but substantial linear associations, when comparing CMR end diastolic volume (EDV) with: echo basal dimension (ρ c = 0.002; β = 60, R 2 = 0.47), end-diastolic area (ρ c = 0.04, β = 6.4, R 2 = 0.64), and 3D EDV (bias = 106, limits of agreement [LOA]: -14.1 to 225); and also when comparing CMR end-systolic volume (ESV) with: end-systolic area (ρ c = 0.08; β = 6.8, R 2 = 0.74) and 3D ESV (bias = 67.3, LOA: -31.8 to 166). Select echo measures of RV function demonstrated better agreement with CMR RVEF including: 3D RVEF (bias -0.23, LOA -17.9 to 17.5) and FAC (ρ c = 0.55; β = 0.89, R 2 = 0.50). Others exhibited modest or poor agreement including: RV GLS (ρ c = 0.11; β = -1.5, R 2 = 0.40), along with S’, TAPSE, and Tei index (ρ c ≤ 0.02; R 2 ≤ 0.19 for all). [Figure] Discussion: In this largest comparison of echo vs CMR measures of RV assessment in PH, echo measures of RV size agreed poorly with CMR, especially at larger RV volumes. RV functional assessment was best with echo 3D RVEF and FAC, which should be preferentially used for echo RV functional assessment. Consider CMR for more accurate volume assessment of RV size.