Inflammatory cell infiltrates are a prominent feature of aberrant vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that immune effector cells contribute to disease progression. Genome-wide blood expression profiling studies have attempted to better define this inflammatory component of PAH pathobiology but have been hampered by small sample sizes, methodological differences, and very little gene-level reproducibility. The current meta-analysis (seven studies; 156 PAH patients/110 healthy controls) was performed to assess the comparability of data across studies and to possibly derive a generalizable transcriptomic signature. Idiopathic (IPAH) compared with disease-associated PAH (APAH) displayed highly similar expression profiles with no differentially expressed genes, even after substantially relaxing selection stringency. In contrast, using a false discovery rate of ≤1% and I2 < 40% (low-to-moderate heterogeneity across studies) both IPAH and APAH differed markedly from healthy controls with the combined PAH cohort yielding 1,269 differentially expressed, unique gene transcripts. Bioinformatic analyses, including gene-set enrichment, which uses all available data independent of gene selection thresholds, identified interferon, mammalian target of rapamycin/p70S6K, stress kinase, and Toll-like receptor signaling as enriched mechanisms within the PAH gene signature. Enriched biological functions and diseases included tumorigenesis, autoimmunity, antiviral response, and cell death consistent with prevailing theories of PAH pathogenesis. Although otherwise indistinguishable, APAH (predominantly PAH due to systemic sclerosis) had a somewhat stronger interferon profile than IPAH. Meta-analysis defined a robust and generalizable transcriptomic signature in the blood of PAH patients that can help inform the identification of biomarkers and therapeutic targets.

Treatment with mineralocorticoid receptor (MR) antagonists beginning at the outset of disease, or early thereafter, prevents pulmonary vascular remodeling in pre-clinical models of pulmonary arterial hypertension (PAH). However, the efficacy of MR blockade in established disease, a more clinically relevant condition, remains unknown. Therefore, we investigated the effectiveness of two MR antagonists, eplerenone (EPL) and spironolactone (SPL), after development of severe right ventricular (RV) dysfunction in the rat SU5416-hypoxia (SuHx) PAH model. Cardiac magnetic resonance imaging (MRI) in SuHx rats at the end of week 5, prior to study treatment, confirmed features of established disease including reduced RV ejection fraction, RV hypertrophy, pronounced septal flattening with impaired left ventricular filling and reduced cardiac index. Five weeks of treatment with either EPL or SPL improved left ventricular filling and prevented the further decline in cardiac index compared to placebo. Interventricular septal displacement was reduced by EPL while SPL effects were similar, but not significant. Although MR antagonists did not significantly reduce pulmonary artery pressure or vessel remodeling in SuHx rats with established disease, animals with higher drug levels had lower pulmonary pressures. Consistent with effects on cardiac function, EPL treatment tended to suppress MR and pro-inflammatory gene induction in the RV. In conclusion, MR antagonist treatment led to modest, but consistent beneficial effects on interventricular dependence after the onset of significant RV dysfunction in the SuHx PAH model. These results suggest that measures of RV structure and/or function may be useful endpoints in clinical trials of MR antagonists in PAH patients.

Pulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction and microthrombi formation. The role of anticoagulation remains controversial, with studies demonstrating inconsistent effects on PAH mortality. Clinical anticoagulation practices are currently heterogeneous, reflecting physician preference. This study uses thrombelastography (TEG) and hematology markers to evaluate whether clot formation and fibrinolysis are abnormal in PAH patients. Venous blood was collected from healthy volunteers (n=20) and patients with PAH (n=20) on stable medical therapy for TEG analysis. Individual TEG parameters and a calculated coagulation index were used for comparison. In addition, hematologic markers, including fibrinogen, factor VIII activity, von Willebrand factor (vWF) activity, vWF antigen, and alpha2-antiplasmin, were measured in PAH patients and compared to healthy volunteers. Between group differences were analyzed using t tests and linear mixed models, accounting for repeated measures when applicable. Although the degree of fibrinolysis (LY30) was significantly lower in PAH patients compared to healthy volunteers (0.3%±0.6 versus 1.3%±1.1, p=0.04), all values were within the normal reference range (0-8). All other TEG parameters were not significantly different between PAH patients and healthy volunteers (p≥0.15 for all). Similarly, alpha2-antiplasmin activity levels were higher in PAH patients compared to healthy volunteers (103.7%±13.6 versus 82.6%±9.5, p<0.0001), but all individual values were within the normal range (75-132%). There were no other significant differences in hematologic markers between PAH patients and healthy volunteers (p≥0.07 for all). Sub-group analysis comparing TEG results in patients treated with or without prostacyclin-pathway targeted therapies were also non-significant. In conclusion, treated PAH patients do not demonstrate abnormal clotting kinetics or fibrinolysis by TEG. 

Introduction: Guidelines recommend indexing aortic valve area (AVA) to body surface area in grading the severity of aortic stenosis (AS), which overestimates severity in obese patients. The indexing of AVA to ideal or adjusted body weight has not been explored. Hypothesis: We hypothesized that using actual body weight compared to ideal or adjusted body weight in obese patients would result in overestimation of the severity of AS using AVAi. Methods: We conducted retrospective chart review on 305 individuals who received a transthoracic echocardiogram (TTE) at Tufts Medical Center from June 2021 to Sept. 2021 with AVA <1.5cm 2 . We selected 73 subjects with moderate AS (AVA 1-1.5cm 2 ). These subjects were divided into an overweight and obese group (BMI > 25; n = 56) and a normal weight group (BMI 18-24.9; n = 17). We recorded baseline characteristics and TTE data. AVAi was calculated with actual, ideal, and adjusted body weight. The primary outcome was reclassification, defined as a change in severity from severe AS to mild or moderate AS after recalculating AVAi using adjusted or ideal body weight. Results: The overweight and obese group was significantly younger (age 74.4±11.2 versus 80.7±5.7 years, P=0.018) with higher BSA (2.0±0.2 versus 1.7±0.2, P=0.010) compared to the normal weight group. The recorded median AVAi was 0.61 with interquartile range(IQR) of 0.17. There was no significant difference in blood pressure, ejection fraction, AVA, peak aortic velocity, peak gradient, and mean gradient. After calculating AVAi with adjusted and ideal body weight, 18 patients in the overweight and obese group were reclassified to a lower grade of AS based on AVAi (median AVAi 0.58, IQR 0.17), compared with 0 reclassifications in the normal weight group (0.67, 0.18). Patients who were reclassified had a significantly smaller AVA compared to patients who were not reclassified (1.09±0.11 versus 1.23±0.19 cm 2 , P<0.001), while no differences were observed in peak gradient, mean gradient, and peak velocity. Conclusions: Using actual body weight to calculate AVAi in overweight and obese patients can lead to overestimation of AS severity. Further research is needed to investigate the optimal indexing strategy for AVAi and the effects of classification on cardiovascular outcomes.