Citations

Abstract Rationale Transthoracic echocardiography (TTE) is a very useful measure of cardiac function in patients with pulmonary hypertension (PH), along with right heart catheterization, which is considered to be the gold standard of measurement. It is non-invasive, quick and a good screening tool to assess the function of a failing right ventricle against elevated pulmonary pressures. Portopulmonary hypertension (POPH) is defined as PH associated with portal hypertension. The Tricuspid Annular Plane Systolic Excursion to Systolic Pulmonary Artery Pressure (TAPSE/SPAP) ratio has been found to be an effective prognosticator in different subtypes of PH. This study focuses on the role of TAPSE/SPAP ratio in prognosis of patients with POPH undergoing liver transplantation. Methods This was a single-center retrospective study of POPH patients undergoing liver transplantation at Mayo Clinic Florida from June 2003 to December 2023. It included patients with POPH with a mean pulmonary pressure >20 mm Hg undergoing liver transplantation. Patients with incomplete TTE data, coexisting renal failure on dialysis and requiring liver retransplant were excluded. This study included 27 patients. The last TTE report before liver transplantation was used for data analysis. The TAPSE/SPAP ratio was investigated as predictor of all-cause mortality following liver transplant using Cox regression and area under ROC curve. (Brackets contain 95% C.I.) Time to death after liver transplantation was considered. Patients were followed till August 1, 2024. (The correlation of this ratio-TAPSE/SPAP with some catheterization measured pulmonary pressures and indices have been included in Table 1.) Results Among 27 patients, 13 were female, 14 male. The most common causes of liver failure in these patients were non alcoholic fatty liver disease (NASH) and alcoholic liver disease. Rarely, some etiologies like sarcoidosis, autoimmune hepatitis, primary sclerosing cholangitis and hepatitis B/C were present. There were 7 deaths among total of 27 patients. The hazard ratio (HR) of TAPSE/SPAP for overall mortality by Cox regression was 0.01 (0.00-0.58), p = 0.03. The area under ROC curve was 0.76 (0.55-0.96), p = 0.01 [Also for TAPSE alone, the area under ROC curve was 0.74 (0.51-0.97), p = 0.05] Conclusion This study infers that TAPSE/SPAP ratio seems to be a good predictor of survival in POPH patients undergoing liver transplant, with a higher ratio associated with decreased all-cause mortality. It suggests that TAPSE alone might also be a good predictor with higher TAPSE associated with decreased mortality. This abstract is funded by: None

Abstract Rationale Portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are two distinct pulmonary vascular complications of liver disease. POPH is characterized by pulmonary hypertension and elevated pulmonary vascular resistance while HPS is characterized by intrapulmonary vasodilation and hypoxemia. POPH and HPS reflect opposing pulmonary vascular responses with markedly different therapeutic and transplant implications. Accurate distinction on imaging may aid clinical decision-making and risk stratification. We aimed to quantitatively characterize and compare chest CT imaging features of POPH and HPS compared to controls with isolated portal hypertension (PoH). Methods Three cohorts of HPS, POPH, and PoH were included (n = 5 per cohort). POPH patients with intrapulmonary vasodilation on contrast echocardiography were excluded. Contrast-enhanced chest CTs with slice thickness ≤ 1.5mm obtained closest to the time of diagnosis were selected (mean 2.7 years following diagnosis). CT images were analyzed using a deep learning algorithm developed in-house that segmented and computed volumes of central, interlobar, peripheral, upper peripheral, and lower peripheral pulmonary arteries (PAs); total, upper, and lower pulmonary veins (PVs); and the four cardiac chambers. Resulting volumes were indexed by body-surface area. One-way analysis of variance (ANOVA) was performed with a post-hoc pairwise Mann-Whitney U test for comparison. Results Patients with HPS were 80% male, had a mean age of 48.6±17.4, and mean MELD-Na of 15.4±3.4. The POPH cohort was 20% male, had a mean age of 56.8±11.9, and mean MELD-Na of 13.4±4.0. The PoH cohort was 100% male, had a mean age of 62.8±4.8, and mean MELD-Na of 12.8±8.8. HPS patients had smaller central PA volumes (mean 26.4±1.8 mm2/m2) compared to both PoH (mean 38.6±9.8 mm2/m2, p = 0.03) and POPH patients (44.8±10.8 mm2/m2, p = 0.008). HPS patients, however, had larger lower peripheral PA (mean 30.7±1.9 mm2/m2) and PV (mean 28.3±6.7 mm2/m2) volumes compared to PoH (PAs mean 20.1±4.8 mm2/m2, p = 0.008; PVs mean 18.2±2.8 mm2/m2, p = 0.02) and larger lower peripheral PA volumes compared to POPH patients (PAs mean 22.1±5.1 mm2/m2, p = 0.03). There was no significant difference in volumes between POPH and PoH for all segments. Conclusion Compared to PoH and POPH, HPS is associated with lower central PA volume and higher peripheral PA volume in the lower lungs. Volumes were similar between POPH and PoH; however, this may reflect limited statistical power given the small sample size. Larger studies are needed to further delineate imaging distinctions between POPH, HPS, and PoH. This abstract is funded by: NHLBI

Abstract Rationale Pulmonary hypertension (PH) develops in up to 50% of patients with advanced interstitial lung disease (ILD) and is associated with increased morbidity, mortality, and impaired quality of life. Early recognition is essential, as available therapy for ILD-PH has been shown to improve outcomes. Identifying physiologic markers of PH may facilitate earlier referral for right heart catheterization (RHC) and initiation of targeted treatment. Thus, this study aimed to (1) compare functional parameters between ILD patients with and without RHC-confirmed PH, and (2) assess the applicability of previously proposed ILD-PH screening criteria. Methods We retrospectively analyzed ILD transplant candidates with available pre-transplant pulmonary function tests (FVC%, DLCO%), echocardiographic right-ventricular systolic pressure (RVSP), six-minute walk distance (6MWD) with oxygen requirement, and RHC data. PH was defined according to the 2022 ESC/ERS criteria. Functional parameters were compared between patients with and without PH. Among those without a prior PH diagnosis, screening thresholds derived from previously published tools were applied (RVSP ≥ 35 mmHg, DLCO < 40%, FVC/DLCO > 1.6, 6MWD < 350 m, or oxygen use during 6MWD). Results Of 107 ILD patients evaluated, 90 had complete RHC data (48 ILD-PH, 42 ILD without PH). Group comparisons are summarized in Table 1. Patients with PH had lower DLCO% (median 18.5 [11.5-26.7] vs 26.5 [20.0-34.7], p = 0.08), higher FVC/DLCO ratios (2.68 [2.1-3.4] vs 1.7 [1.4-2.6], p = 0.08), and higher RVSP (55 [39.7-63.2] vs 39.5 [29-48] mmHg, p = 0.002). Oxygen requirement during 6MWD was more frequent in ILD-PH (79.2% vs 61.9%, p = 0.08). Among patients with PH, 38 (79.16%) had no formal diagnosis prior to pre-transplant RHC. Of these cases, all (100%) met ≥3 screening criteria, most commonly DLCO < 40% (n = 38, 100%), FVC/DLCO > 1.6 (n = 37, 97.3%), and 6MWD < 350 m (n = 33, 86.8%). Additionally, 32 patients (84.21%) met ≥4 criteria and 8 (21.05%) met all five criteria. Conclusion In ILD transplant candidates, patients with PH had worse functional profiles when compared to those without PH, and nearly 80% of PH cases were previously undiagnosed. Systematic application of validated PH screening tools in ILD populations may facilitate earlier recognition, potentially improving patient outcomes. This abstract is funded by: None

ABSTRACT Early-life nutrition profoundly influences long-term metabolic health, and breast milk not only provides nutrients but also conveys maternal signals shaping infant metabolic development. While postpartum exercise by lactating women benefits maternal health, its impact on milk-borne signaling remains largely undefined. Small extracellular vesicles (sEVs) in breast milk are key mediators of maternal–infant communication because of their selectively packaged bioactive cargo and resistance to infant digestive enzymes and acids, enabling delivery of their cargo to peripheral tissues. Here, we show that a single session of moderate-intensity postpartum aerobic exercise robustly increases human breast milk sEV concentration, which persists for multiple post-exercise milk collections. Exercise enriches breast milk with sEVs containing regulatory metabolic cargo (proteins, miRNAs, and metabolites), which translates into enhanced mitochondrial capacity in neonatal-stage cells. These findings implicate sEVs as an exercise-responsive signaling compartment in breast milk capable of connecting postpartum maternal physical activity to beneficial infant metabolic programming. Highlights Acute moderate-intensity exercise increases human breast milk sEV concentration The exercise-mediated sEV increase lasts for multiple subsequent milk expressions Exercise coordinates a multi-omic enrichment of sEVs in breast milk Exercised breast milk sEVs enhance mitochondrial respiration in UC-MSCs

Abstract Introduction Pulmonary arterial hypertension (PAH) is a progressive and deadly disease characterized by pulmonary vascular remodeling and eventual right heart failure. A mainstay of treatment for PAH is prostacyclin therapy which can be delivered via continuous subcutaneous (SQ) or intravenous (IV) infusion. Infusion site reactions are a common occurrence with SQ Treprostinil resulting in discontinuation in approximately 10% of patients. Given that switching from SQ to IV prostacyclin therapy contains risks associated with long-term central venous access such as blood stream infections and deep venous thrombosis, the development of better strategies to improve SQ Treprostinil tolerability are needed. Case Report We report two patients with PAH who developed delayed infusion site reactions to SQ Treprostinil. Both patients were female, in their 30s, with severe group 1 PAH (mean pulmonary artery pressures of 44 and 81 mmHg on right heat catheterization at diagnosis), who had been on SQ Treprostinil for approximately 6 years on a dose around 60 ng/kg/min. Within two weeks of starting a new SQ infusion site, each patient developed a raised, hyperemic site reaction in the area of the infusion catheter draining yellow fluid (Figure 1). Skin patch testing was done from an ampule of preservative-free Treprostinil demonstrating a type 1 hypersensitivity reaction. There was no skin reaction to the Tegaderm dressing alone. Dupilumab 300 mg weekly SQ injections were started for these type 1 hypersensitivity reactions with resolution of the site reactions and pain. Because of this, both patients were able to remain on their SQ Treprostinil infusions. Discussion Infusion site reactions to SQ Treprostinil are common and can necessitate discontinuation of the medication. SQ Treprostinil infusion site reactions typically occur within 48 hours of establishing a new SQ infusion site and are thought to be a local vasodilatory reaction to the Treprostinil itself. These reactions can be minimized by analgesic pain medication and by increasing the Treprostinil infusion concentration. Here we describe two infusion site reactions that occurred two weeks after establishing a new site and were consistent with a type 1 hypersensitivity reaction. These reactions were successfully treated with Dupilumab which allowed the patients to remain on SQ Treprostinil. This abstract is funded by: None

Abstract Rationale The pathophysiology and clinical impact of liver injury in pulmonary hypertension (PH) is poorly understood. Liver injury in PH is often attributed to hepatic congestion, but some studies have failed to find strong associations with hemodynamics, suggesting alternative mechanisms. We sought to define the prevalence of liver injury and patterns of liver injury across the spectrum of PH and to determine whether patterns of liver injury were associated with clinical characteristics, hemodynamics and outcomes. Methods We performed an analysis of the PVDOMICS study, a multicenter, prospective, longitudinal cohort study that enrolled incident and prevalent patients with PH and disease comparators. The prevalence of liver injury, defined as aspartate or alanine aminotransferase (AST or ALT) or total bilirubin above the upper limit of normal, and different patterns of liver injury [hepatocellular (elevated AST or ALT with normal bilirubin), cholestatic (elevated bilirubin) and no liver injury] was defined among participants with known or suspected PH. Associations between patterns of liver injury with demographics, hemodynamics, right ventricular function, exercise capacity and quality of life (QoL) were assessed. We used Cox proportional hazards models adjusted for age and sex to assess the association of liver injury patterns with transplant-free survival. Results Liver injury was present in 27.8% (288/1036) of participants (19.0% cholestatic and 8.8% hepatocellular). Patients with liver injury were less likely to be female and have prevalent disease with differences in PH classification (Table 1). Patients with hepatocellular liver injury had a higher body mass index. A cholestatic liver injury pattern was most consistently associated with worse functional class, biventricular filling pressures, pulmonary vascular resistance, right ventricular function, natriuretic peptide elevation, exercise capacity, and REVEAL risk scores. Total bilirubin levels and right atrial pressure as a marker of systemic congestion were weakly correlated (r2=0.02, p < 0.0001). Compared to no liver injury, cholestatic liver injury was associated with an increased risk of death in age and sex adjusted models (HR 1.6, 95% CI 1.3-2.1, p < 0.001) but hepatocellular liver injury was not (p > 0.05). Conclusions Liver injury is common among patients with known or suspected PH. In contrast to a hepatocellular injury pattern, a cholestatic liver injury pattern was most consistently associated with worse hemodynamics, exercise capacity, QoL and survival. However, the weak relationship between right atrial pressure and bilirubin suggests that systemic congestion alone is unlikely to completely explain cholestatic liver injury. Further study is needed to uncouple the pathophysiological basis of cholestasis in PH. This abstract is funded by: NHLBI

Abstract Rationale Sotatercept is a novel activin signaling inhibitor approved for the treatment of pulmonary arterial hypertension (PAH). Sotatercept has been studied in randomized clinical trials, but little is known regarding the real-world use of sotatercept. We sought to describe the safety, tolerability and efficacy of sotatercept in our clinical practice. Methods We performed a combined prospective and retrospective cohort study of all patients treated with sotatercept at Mayo Clinic Rochester since its approval in March 2024. Patients enrolled in a separate clinical trial of sotatercept were excluded from this analysis as their data will be reported separately. Clinical data was abstracted from the electronic health record. Follow-up data was collected at 6 ± 3 months after initiation of sotatercept. Data is summarized as n (%) and mean ± SD. We used paired t-tests to compare baseline and follow-up characteristics within individuals. Results Fifty-eight PAH patients treated with sotatercept were included. Patients were 48.4 ± 37.6 years old at treatment initiation and were predominantly female with a mean duration of PAH of 6.7 years and a range of PAH etiologies including portopulmonary hypertension, congenital heart disease, and pulmonary veno-occlusive disease (Table 1). Twenty-one (36%) of patients had mixed etiologies of PH. Six months after initiation of sotatercept, patients had a significant improvement in NTproBNP (1922 ± 4464 to 363 ± 596 pg/ml, p = 0.04), 6 minute walk distance (378.8 ±144.6 to 395.7±129.5 meters, p = 0.02) and right ventricular systolic pressure (74.6 ± 20.5 to 60.6 ± 20.3 mm Hg, p < 0.001). No patients permanently discontinued due to abnormal laboratory values. Mean highest hemoglobin achieved over the initial 6 months of treatment was 15.5 ± 2.1 g/dL and mean lowest platelet count was 181 ± 74K. Seven patients discontinued sotatercept at a range of 170-275 days after starting. Four patients discontinued due to possible treatment-related adverse effects: 1 each of gastrointestinal hemorrhage, retinal hemorrhage, hypoxia/intrapulmonary vasodilatation and spontaneous bilateral subdural hematomas. Three patients discontinued due to other reasons: newly diagnosed metastatic cancer leading to transition to hospice and two due to lack of improvement. Conclusions In this real-world registry of sotatercept in PAH, sotatercept was well-tolerated among patients with PAH and associated with improvements in exercise capacity, echocardiographic parameters, and NTproBNP. Overall discontinuation due to possible treatment-related adverse effects was low and reasons for discontinuation included bleeding and hypoxia attributed to intrapulmonary vasodilatation. This abstract is funded by: None

Abstract Rationale Non-selective beta-blockers (BB) are the standard of care for variceal prophylaxis in patients with cirrhosis. It is unclear whether BB negatively affect exercise capacity in patients with portopulmonary hypertension (POPH) or hepatopulmonary syndrome (HPS). We hypothesize that BB use is associated with shorter six-minute walk distance (6MWD) in HPS and POPH than in patients without pulmonary vascular complications of liver disease. Methods The Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) Study enrolled patients evaluated for liver transplantation or pulmonary hypertension at eight U.S. centers (2013-2017). We conducted a retrospective analysis of 333 patients with HPS, POPH, and portal hypertension without lung complications to evaluate whether disease state modified the association of BB on 6MWD. Multivariable linear regression adjusted for a priori covariates including age, sex, body mass index (BMI), MELD-Na, and WHO functional class. An interaction term between disease category and BB use was included. Results We included 85 patients with HPS, 48 with POPH, and 200 patients with liver disease. Compared to liver disease controls, those with HPS were younger, had higher MELD-Na scores, and more often had worse WHO functional class. POPH patients were similar to controls in age and liver disease severity but had higher WHO functional class. Sex, BMI, and left ventricular ejection fraction did not differ significantly between groups. Higher age, BMI, MELD-Na, and WHO functional class were all significantly associated with lower 6MWD while male sex was associated with higher 6MWD. Adjusting for age, sex, BMI, MELD-Na score, and WHO functional class, there was a significant interaction between BB use and disease category (p = 0.024). Patients with HPS had a 53.4 m longer 6MWD with BB use (95% CI 4.21- 102.5, p = 0.03 for interaction) compared to liver disease controls, whereas patients with POPH had a 72.4 m longer 6MWD (95% CI 7.60- 137.2, p = 0.03 for interaction) compared to liver disease controls. Conclusion The association of BB with 6MWD in advanced liver disease appears to be modified by whether a person has a pulmonary vascular complication including HPS or POPH. The mechanisms for these differences and their clinical implications require further study. This abstract is funded by: NIH T32 Grant

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 (<27 mm [females], <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 < 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 < 0.001), PH duration (6.78 ± 6.86 vs 2.24 ± 4.39 and 3.82 ± 5.47 years; p < 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 < 0.001). Aneurysmal PA subjects had higher mPAP (46 [36-57] vs 19 [16- 25] and 35 [28-47] mmHg, p < 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 < 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 < 0.02) and likelihood of death or transplant (p < 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 < 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