Lammi, Matthew R.

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: 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 Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. The extent of medication nonadherence in PAH is uncertain and may be linked to adverse outcomes. There has been a lack of multicenter, registry-based studies assessing medication nonadherence and patient-centered outcomes in PAH. Objectives To determine the prevalence of self-reported nonadherence in Pulmonary Hypertension Association Registry (PHAR) participants with PAH or chronic thromboembolic pulmonary hypertension and the relationship of nonadherence with several patient-centered outcomes (mortality, hospitalization rates, emergency department visits, and health-related quality of life). Methods Self-reported PAH medication nonadherence was captured at PHAR enrollment and during follow-up visits. Predictors of nonadherence were modeled using generalized estimating equations assuming a binary distribution. Outcomes associated with nonadherence were modeled using generalized estimating equations with a Poisson distribution. Results A total of 1,543 patients were included, of whom 1,092 (70.8%) were female and 1,340 (86.8%) had PAH. The overall rate of any self-reported nonadherence was 6.1% (95% confidence interval [CI], 5.3–6.9). Predictors of nonadherence included self-reported male sex at birth (odds ratio [OR], 1.4; 95% CI, 1.0–1.9; P = 0.02), poverty (OR, 1.6; 95% CI, 1.2–2.3; P = 0.01), not being married or partnered (OR, 1.5; 95% CI, 1.1–1.9; P = 0.01), having Medicaid or no health insurance (OR, 2.1; 95% CI, 1.5–2.9; P < 0.001), and having completed high school but not having a college degree (OR, 1.7; 95% CI, 1.1–2.9; P < 0.001). PHAR participants who reported any nonadherence had 50.0% more emergency department visits (P < 0.001), 13.3% more hospital admissions (P = 0.03), and 61.9% more days hospitalized (P = 0.01). No relationship was observed between nonadherence and the type or number of PAH therapies or all-cause mortality. Participants reporting nonadherence had worse mean Short Form-12 scores (P < 0.001) and worse emPHasis-10 scores (P = 0.02). Conclusions The rate of self-reported nonadherence in PHAR registrants was low but was associated with male sex and several social determinants of health. Although the complexity or type of PAH regimen did not appear to influence nonadherence, nonadherence was associated with numerous adverse patient-centered outcomes, including greater healthcare use and worse health-related quality of life. Because of limitations in the structure of the gathered data, relationships between exposure and outcomes were not temporally definitive; these observations warrant additional prospective studies.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, morbid, potentially curable subtype of pulmonary hypertension that negatively impacts health‐related quality of life (HRQoL). Little is known about differences in HRQoL and hospitalization between CTEPH patients and idiopathic pulmonary arterial hypertension (IPAH) patients. Using multivariable linear regression and mixed effects models, we examined differences in HRQoL assessed by emPHasis‐10 (E10) and SF‐12 between CTEPH and IPAH patients in the Pulmonary Hypertension Association Registry, a prospective multicenter cohort of patients newly evaluated at a Pulmonary Hypertension Care Center. Multivariable negative binomial regression models were used to estimate incidence rate ratios (IRR) for hospitalization amongst the two groups. We included 461 IPAH patients and 169 CTEPH patients. Twenty‐one percent of CTEPH patients underwent pulmonary thromboendarterectomy (PTE) before the end of follow‐up. At baseline, patients with CTEPH had significantly worse HRQoL (higher E10 scores) (ß 2.83, SE 1.11, p = 0.01); however, differences did not persist over time. CTEPH patients had higher rates of hospitalization (excluding the hospitalization for PTE) compared to IPAH patients after adjusting for age, sex, body mass index, WHO functional class and six‐minute walk distance (IRR 1.66, 95%CI 1.04–2.65, p = 0.03). CTEPH patients who underwent PTE had improved HRQoL as compared to those who were medically managed, but patients who underwent PTE were younger, had higher cardiac outputs and greater six‐minute walk distances. In this large, prospective, multicenter cohort, CTEPH patients had significantly worse baseline HRQoL and higher rates of hospitalizations than those with IPAH. CTEPH patients who underwent PTE had significant improvements in HRQoL.

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health‐care utilization. We performed a cross‐sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6‐min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow‐up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow‐up, and have increased health‐care utilization.

Abstract Rationale Obesity is associated with pulmonary arterial hypertension (PAH), but its impact on outcomes such as health-related quality of life (HRQoL), hospitalizations, and survival is not well understood. Objectives To assess the effect of obesity on HRQoL, hospitalizations, and survival in patients with PAH. Methods We performed a cohort study of adults with PAH from the Pulmonary Hypertension Association Registry, a prospective multicenter registry. Multivariate linear mixed-effects regression was used to examine the relationship between weight categories and HRQoL using the Short Form-12 and emPHasis-10. We used multivariable negative binomial regression to estimate hospitalization incidence rate ratios (IRRs) and Cox regression to estimate hazard ratios (HRs) for transplant-free survival by weight status. Results A total of 767 subjects were included (mean age of 57 years, 74% female, 33% overweight, and 40% with obesity), with median follow-up duration of 527 days. Overweight patients and patients with obesity had higher baseline emPHasis-10 scores (worse HRQoL), which persisted over time (P &lt; 0.001). Patients who are overweight and obese have a trend toward increased incidence of hospitalizations compared with normal-weight patients (IRR, 1.34; 95% confidence interval [95% CI], 0.94–1.92 and IRR, 1.33; 95% CI 0.93–1.89, respectively). Overweight patients and patients with obesity had lower risk of transplant or death compared with normal-weight patients (HR, 0.45; 95% CI, 0.25–0.80 and HR, 0.39; 95% CI, 0.22–0.70, respectively). Conclusions In a large multicenter, prospective cohort of PAH, patients who were overweight or obese had worse disease-specific HRQoL despite better transplant-free survival compared with normal-weight patients. Future interventions should address the specific needs of these patients.

Abstract Rationale Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH. Objectives To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use. Methods The Pulmonary Hypertension Association Registry is a U.S.-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, 6-minute walk distance, therapy, and health care use. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations. Results Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the western United States. The Meth-APAH group was younger and had a poorer socioeconomic status and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater; 95% confidence interval [CI], 0.07 to 0.37) and worse PAH-specific (emPHasis-10) health-related quality of life (−5.4; 95% CI, −8.1 to −2.8). There was no difference in dual combination therapy; however, participants with Meth-APAH were less likely to be initiated on triple therapy (odds ratio [OR], 0.43; 95% CI, 0.24 to 0.77) or parenteral therapy (OR, 0.10; 95% CI, 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (incidence rate ratio, 2.30; 95% CI, 1.71 to 3.11) and more likely to be hospitalized (incidence rate ratio, 1.42; 95% CI, 1.10 to 1.83). Conclusions Meth-APAH represents a unique clinical phenotype of PAH, most common in the western United States. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.