Group, The PVDOMICS Study

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.

Abstract 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 disease Resting 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.

Abstract Introduction Interstitial lung disease-associated pulmonary hypertension (ILD-PH) is a clinically challenging entity that lies on a pathophysiologic spectrum between pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). We compared the metabolomes of patients with ILD-PH to those with PAH and ILD to characterize the PAH-ILD axis and determine whether ILD-PH patients can be phenotyped based on their metabolomic similarity to PAH. Methods Using untargeted metabolomics profiles from patients with PAH, ILD, and ILD-PH in the large, U.S.-based, NIH-funded, multi-center PVDOMICS cohort, we trained an anchor-based classifier on PAH and ILD metabolomes using supervised PLS-DA with a 75/25 train/test split. Primary and secondary PH or risk-group classifications in PVDOMICS were based on expert adjudication of clinical data including right heart catheterization hemodynamics, pulmonary function testing, chest imaging, and laboratory results. We then applied the trained model to each ILD-PH patient to assign a PAH similarity score. We classified patients as having a PAH-like or ILD-like metabolomic phenotype using an optimal PAH similarity score cutoff of 0.5 then compared PAH metabolomic similarity to expert-adjudicated primary and secondary WSPH classifications in PVDOMICS. We implemented FELLA, a network-based metabolomics enrichment method, to holistically characterize the biologic underpinnings of PAH, ILD-PH, and ILD metabolomes. Results We analyzed 244 patients with PAH, 54 with ILD, and 47 with ILD-PH. The anchor-based classifier demonstrated high train-test performance with a c-statistic of 0.81 and 78% agreement with expert-adjudicated diagnoses. Among the ILD-PH patients, 23 were classified as PAH-like and 24 as ILD-like (74% agreement with expert adjudication, Cohen’s kappa 0.49, Hedge’s g estimate of 0.86). FELLA enrichment revealed core glycolytic and bioenergetic pathways were enriched in both pure PAH and ILD-PH. Comparison of diffusion Z-scores between groups demonstrated subtle but biologically coherent differences in several reaction-level nodes, including lactate, NADPH oxidoreductase, and phosphofructokinase, which were enriched in ILD-PH. Conclusion Patients with ILD-PH demonstrate clinically relevant metabolomic phenotypes. Examination of the network biology underlying ILD-PH may point to potential therapeutic targets in this vulnerable subgroup with lagging clinical outcomes. This abstract is funded by: Pulmonary Fibrosis Foundation PFF Scholars Program

Abstract Rationale Prior studies demonstrate pulmonary artery (PA) enlargement on computed tomography (CT) in pulmonary hypertension (PH). Some patients exhibit markedly enlarged or “aneurysmal” PA dilation, but its clinical relevance remains unclear. We aimed to characterize clinical characteristics, hemodynamics, and survival probability of patients with aneurysmal PA size. Methods Demographics, clinical characteristics, and CT imaging were obtained for individuals with group 1 or 2 PH and matched controls in the Pulmonary Vascular Disease Phenomics cohort. PA diameter was measured using Osirix software. PA diameter was categorized based on previously reported values as normal (&lt;27 mm [females], &lt;29 mm [males]), enlarged (27-39 mm [females], 29-39 mm [males]), or aneurysmal (≥40 mm). Outcomes included mean PA pressure (mPAP) on right heart catheterization (RHC) and time to death or heart/lung transplant. Associations with mortality and mPAP were evaluated using multivariable Cox and linear regression models, adjusting for age, sex, and BMI. Descriptive statistics are presented as median [IQR]. Results 690 subjects met the inclusion criteria for survival analysis (364 WSPH group 1 or matched comparator, 241 group 2 or comparator, 85 healthy control), with 594 undergoing RHC. PA diameter was normal in 163 participants, enlarged in 414, and aneurysmal in 113. Aneurysmal PA, compared with normal or enlarged PA, was associated with younger age (53 ± 14 vs 55 ± 16 and 59 ± 15 years, respectively; p &lt; 0.001), non-White race (18.9% vs 8% and 17.2%; p = 0.034), pro-BNP (1950 ± 5708 vs 531 ±1651 and 110 ± 2258 pg/mL; p &lt; 0.001), PH duration (6.78 ± 6.86 vs 2.24 ± 4.39 and 3.82 ± 5.47 years; p &lt; 0.001), group 1 disease (77% vs 37% and 61%), and congenital heart disease (CHD)-PAH (10.6% vs 0.0% and 4.8%, p &lt; 0.001). Aneurysmal PA subjects had higher mPAP (46 [36-57] vs 19 [16- 25] and 35 [28-47] mmHg, p &lt; 0.001), pulmonary vascular resistance (PVR) (5.5 [3.6-9.4] vs 1.7 [1.0-2.3] and 4.1 [2.4-7.1] Woods units, p &lt; 0.001), cardiac index (CI; 2.73 [2.34-3.29] vs 2.55 [2.13-2.98] and 2.52 [2.12-3.10] L/min/m2, p &lt; 0.02) and likelihood of death or transplant (p &lt; 0.001; Figure 1). Conclusion “Aneurysmal” PA was more common in younger, non-White subjects with longer WSPH group 1 disease duration, CHD, and higher pro-BNP levels. Aneurysmal PA was associated with elevated mPAP, PVR, and CI, and reduced likelihood of survival. These findings highlight the need to further elucidate the pathophysiology and prognostic implications of aneurysmal PA remodeling in PH. This abstract is funded by: NHLBI and the Pulmonary Hypertension Association

Abstract Background We recently reported a strong association between CT markers of pulmonary artery (PA) dilation and mean PA pressure (mPAP) in subjects with World Symposium on Pulmonary Hypertension (WSPH) group 1 and 2 pulmonary hypertension (PH). The relationship between PA size and mPAP in subjects with WSPH group 3 PH, in which parenchymal changes may influence PA dilation, remains uncertain. We sought to investigate this relationship in subjects with and without PH who have significant parenchymal pulmonary disease or hypoxia. Methods We measured PA diameter and PA:aorta (PA:A) ratio on CT for all subjects with WSPH group 3 PH, matched disease comparators, and healthy controls in the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort. PH and comparator subjects were categorized by group 3 etiology into obstructive (including chronic obstructive pulmonary disease [COPD] and cystic fibrosis), interstitial (including idiopathic pulmonary fibrosis, unspecified interstitial lung disease, combined pulmonary fibrosis and emphysema, and chronic hypersensitivity pneumonitis), and non-parenchymal (including obesity hypoventilation syndrome, obstructive sleep apnea, and extrinsic restrictive disease) subgroups. Primary outcome was mPAP on right heart catheterization (RHC). Association with mPAP was evaluated using multivariable linear regression adjusted for age, sex, and BMI. Results 339 subjects met inclusion criteria (101 WSPH group 3 PH, 153 disease comparators, 85 healthy controls). 83 subjects had obstructive disease, 125 had interstitial disease, and 46 had non-parenchymal disease. PA diameter and PA:A were associated with mPAP in all subjects and in each subgroup (p &lt; 0.001; see figure 1). The association was notably stronger in the non-parenchymal group (ρ = 0.707 for diameter, 0.750 for PA:A) compared to obstructive (ρ = 0.566 for diameter, 0.529 for PA:A) and interstitial (ρ = 0.432 for diameter, 0.373 for PA:A) groups. Change in PA size between 25th and 75th percentile mPAP was lower in the interstitial group (3.88 mm, ratio 0.12) than in the obstructive (4.88 mm, ratio 0.17) and non-parenchymal (4.80 mm, ratio 0.19) groups (see figure 1). Conclusions PA size on CT is associated with mPAP in subjects with chronic lung disease with and without PH. This association is strongest in subjects without parenchymal lung disease but with features of hypercarbia or hypoxia alone. These data suggest that features of parenchymal lung disease in certain patients may limit expected PA dilation in response to elevated PA pressures. Further study is needed regarding the implications of these findings for early identification of PH in patients with chronic lung disease. This abstract is funded by: The NHLBI and Pulmonary Hypertension Association