Hassoun, P.M.

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.