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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

RATIONALE: Hemodynamic assessments direct care among children with pulmonary hypertension, yet the use of cardiac catheterization is highly variable, which could impact patient care and research. OBJECTIVES: We analyzed hemodynamic findings from right heart catheterization (RHC) and left heart catheterization and acute vasodilator testing (AVT) and the safety of catheterization in children with World Symposium on Pulmonary Hypertension (WSPH) group 1 and 3 subtypes in a large multicenter North American cohort. METHODS: Of 1,475 children enrolled in the Pediatric Pulmonary Hypertension Network Registry (2014–2020), there were 1,383 group 1 and 3 patients, of whom 671 (48.5%) underwent RHC at diagnosis and were included for analysis. RESULTS: Compared with those without diagnostic RHC, these children were older, less likely to be an infant or preterm, more often female, treated with targeted pulmonary hypertension medications at diagnosis, and had advanced World Health Organization functional class. Catheterization was performed without a difference in complication rates between WSPH groups. Pulmonary capillary wedge pressure was well correlated with left ventricular end-diastolic pressure and left atrial pressures. Results of AVT using three different methods were comparable; positive AVT results were observed in 8.0–11.8% of subjects, did not differ between WSPH groups 1 and 3, and were not associated with freedom from the composite endpoint of lung transplantation or death during follow-up. CONCLUSIONS: In a large pediatric pulmonary hypertension cohort, diagnostic RHC with or without left heart catheterization in WSPH group 1 and 3 patients was performed safely at experienced pediatric pulmonary hypertension centers. Hemodynamic differences were noted between group 1 and 3 subjects. Higher mean pulmonary arterial pressure and mean pulmonary arterial pressure/mean systemic arterial pressure ratio were associated with a higher risk of death/transplantation. Findings suggest overall safety and potential value of RHC as a standard diagnostic approach to guide pulmonary hypertension management in children.

Background Current mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry). Methods and Results We identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan‐Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment‐naïve patients, we compared survival based on initial treatment strategy. The median age was 56 years (44–68 years), and 76% were women. Of the 935 patients, 483 (52%) were ≤6 months from PAH diagnosis. There were 121 deaths (12.9%) during a median follow‐up time of 489 days (281–812 days). The 1‐, 2‐, and 3‐year mortality was 8% (95% CI, 6%–10%), 16% (95% CI, 13%–19%), and 21% (95% CI, 17%–25%), respectively. When stratified into low‐, intermediate‐, and high‐risk PAH, the mortality at 1, 2, and 3 years was 1%, 4% to 6%, and 7% to 11% for low risk; 7% to 8%, 11% to 16%, and 18% to 20% for intermediate risk; and 12% to 19%, 22% to 38%, and 28% to 55% for high risk, respectively. In treatment‐naïve patients, initial combination therapy was associated with better 1‐year survival (adjusted hazard ratio, 0.43 [95% CI, 0.19–0.95]; P =0.037). Conclusions Mortality in the intermediate‐ and high‐risk patients with PAH remains unacceptably high in the PHAR, suggesting the importance for early diagnosis, aggressive use of available therapies, and the need for better therapeutics.

Abstract 2077 Introduction: Pulmonary arterial hypertension (PAH) has been accepted to be a clinical entity associated with hemoglobinopthies, mostly reported in sickle disease and thalassemia intermedia (TI). Anecdotal cases of PAH in other chronic hemolytic disorders have been reported; many of which have been associated with a prior splenectomy. The pathogenesis of PAH in the non sickle-cell RBC hemolytic disorders has not been well defined and the large variability in its frequency and severity are not clear. We aimed to characterize biomarkers in thalassemia and in other RBC disorders and evaluate the specific role of splenectomy (spleen.) in these diseases. Patients and Method: A total of 106 patients were analyzed: Forty two were regularly transfused thalassemia major (TM), 34 had TI (16 with Hb E/beta thalassemia, 11 with beta thalassemia, and 7 with hemoglobin H-Constant Spring (Hb H-CS); 18 with hereditary spherocytosis (HS) or pyruvate kinase (PK) deficiency, 2 with an unstable Hb (Hb Koln), and 10 with a history of splenectomy for non-RBC related reasons (trauma or chronic ITP). PAH was determined by using a Doppler echocardiogram showing a tricuspid regurgitation jet velocity (TRV) of >2.5m/s. Markers of platelet activation (P- selectin, soluble CD40 (sCD40L); abnormal exposure of Phosphatidyl Serine (PS) on RBCs, thrombin generation (thrombin-anti-thrombin, TAT); increased ventricular pressure strain (brain natriuretic peptide (BNP); plasma free Hb, LDH and NOx, and endothelin-1, soluble vascular cell adhesion molecule (sVCAM) were analyzed. Result: Nineteen (56%) of the TI patients (15 with beta-TI and 4 with Hb H-CS) had abnormally elevated TRV (Mean 3.0±0.5). The 2 patients with Hb Koln had increased TRV. There were no PAH cases detected among patients with membrane or RBC enzyme deficiencies, neither was there an increased TRV in patients who had been splenectomized without a RBC disorder. There were also no cases of increased TRV in the transfused TM cohort. Patients with TI, in addition to a prior splenectomy and increased hemolysis had increased platelet activation, abnormal RBC PS exposure and anemia. TI patients also had an increase in ET-1 levels, a potent vasoconstrictor. The 2 patients with Hb Koln had increased thrombin generation in addition to hemolysis and absence of spleen. Conclusions: PAH was not detected in splenectomized patients with only a mild chronic hemolytic disorder or in those without a RBC disorder. In addition to the absence of spleen, a higher rate of hemolysis, resulting in NO scavenging and increase in ET-1 and the involvement of platelet activation or thrombin generation are likely required for the development of dysregulation of the pulmonary vascular function. PAH is rare in TI patients which have not undergone splenectomy; absence of spleen likely enhances the effects of thrombocytosis and platelet activation. Our data indicates that PAH is common in patients with Hb H-CS, mostly splenectomized, and should be screened for. In addition our data shows that blood transfusions reduce the elements of anemia, hemolysis and coagulation activation and prevent the development of PAH in splenectomized and non-splenectomized patients. Disclosures: No relevant conflicts of interest to declare.