BACKGROUND:Increased epicardial adipose tissue (EAT) has adverse effects in cardiovascular diseases, independent of BMI. Estrogen levels may affect EAT accumulation. Little is known about the predictors and potential impact of EAT in pulmonary arterial hypertension (PAH). RESEARCH QUESTION:Is EAT associated with estrogen levels, disease severity, and mortality in PAH? STUDY DESIGN AND METHODS:We conducted a retrospective cohort study of patients with PAH enrolled in the Penn Pulmonary Hypertension registry and used chest CT scans to quantify EAT. Serum estrone and estradiol levels were also measured. RESULTS:A total of 221 patients were included in the analysis, with median follow-up of 88 months. Mean age was 55.1 years, 74.7% were female, mean BMI was 27.20 kg/m2, and the most common PAH etiology was connective tissue disease-associated PAH (43.0%) followed by idiopathic or heritable PAH (35.3%). Median EAT volume was 52.1 mL/m2. Of the 102 patients with a follow-up chest CT scan, EAT increased over time in 74 (71.8%). High EAT volume (hazard ratio, 2.62; 95% CI, 1.62-4.24; P < .001) and greater accumulation of EAT over time (hazard ratio, 1.09; 95% CI, 1.01-1.17; P = .03) were both independently associated with worse survival. Patients with high EAT volume had lower serum estrone (13.70 vs 30.60 pg/mL; P = .009) and estradiol (6.05 vs 19.40 pg/mL; P = .002) levels compared with those with low EAT volume. INTERPRETATION:In patients with PAH, high EAT and a greater rate of accumulation of EAT volume were independently associated with worse survival. Higher EAT volume was also associated with lower estrogen levels. The association of EAT volume with survival was independent of BMI and disease severity, suggesting that EAT may be a marker for a unique PAH phenotype. Future research should investigate the role of EAT-modifying therapies in PAH and consider incorporating EAT into PAH risk models.

BACKGROUND: Obesity is increasingly prevalent in pulmonary arterial hypertension (PAH) but is associated with improved survival, creating an "obesity paradox " in PAH. It is unknown if the improved outcomes could be attributable to obese patients deriving a greater benefit from PAH therapies. RESEARCH QUESTION: Does BMI modify treatment effectiveness in PAH? STUDY DESIGN AND METHODS: Using individual participant data, a meta-analysis was conducted of phase III, randomized, placebo-controlled trials of treatments for PAH submitted for approval to the U.S. Food and Drug Administration from 2000 to 2015. Primary outcomes were change in 6-min walk distance (6MWD) and World Health Organization (WHO) functional class. RESULTS: A total of 5,440 participants from 17 trials were included. Patients with overweight and obesity had lower baseline 6MWD and were more likely to be WHO functional class III or IV. Treatment was associated with a 27.01-m increase in 6MWD (95% CI, 21.58-32.45; P < .001) and lower odds of worse WHO functional class (OR, 0.58; 95% CI, 0.48-0.70; P < .001). For every 1 kg/m(2) increase in BMI, 6MWD was reduced by 0.66 m (P = .07); there was no significant effect modification of treatment response in 6MWD according to BMI (P for interaction = .34). Higher BMI was not associated with odds of WHO functional class at end of follow-up; however, higher BMI attenuated the treatment response such that every 1 kg/m(2) increase in BMI increased odds of worse WHO functional class by 3% (OR, 1.03; P for interaction = .06). INTERPRETATION: Patients with overweight and obesity had lower baseline 6MWD and worse WHO functional class than patients with normal weight with PAH. Higher BMI did not modify the treatment response for change in 6MWD, but it attenuated the treatment response for WHO functional class. PAH trials should include participants representative of all weight groups to allow for assessment of treatment heterogeneity and mechanisms.

Objective: To determine if A-kinase anchoring protein 13 (AKAP13) interacts with the vitamin D receptor (VDR) to alter vitamin Ddependent signaling in fi broid cells. Uterine leiomyomas (fibroids) are characterized by a fi brotic extracellular matrix and are associated with vitamin D deficiency. Treatment with vitamin D (1,25-dihydroxyvitamin D3) reduces fi broid growth and extracellular matrix gene expression. A-kinase anchoring protein 13 is overexpressed in fi broids and interacts with nuclear hormone receptors, but it is not known whether AKAP13 may interact with the VDR to affect vitamin D signaling in fi broids. Design: Laboratory studies. Setting: Translational science laboratory. Intervention(s): Human immortalized fi broid or myometrial cells were treated with 1,25-hydroxyvitamin D3 (1,25(OH)2D3) and transfected using expression constructs for AKAP13 or AKAP13 mutants, RhoQL, C3 transferase, or small interfering ribonucleic acids (RNAs). Main Outcome Measure(s): Messenger ribonucleic acid (mRNA) levels of AKAP13, fi bromodulin, and versican as measured by quantitative real-time polymerase chain reaction. Glutathione S-transferase-binding assays. Vitamin D-dependent gene activation as measured by luciferase assays. Result(s): 1,25(OH)2D3 resulted in a significant reduction in mRNA levels encoding AKAP13, versican, and fi bromodulin. Small interfering RNA silencing of AKAP13 decreased both fi bromodulin and versican mRNA levels. Glutathione S-transferase-binding assays revealed that AKAP13 bound to the VDR through its nuclear receptor interacting region. Cotransfection of AKAP13 and VDR significantly reduced vitamin D-dependent gene activation. RhoA pathway inhibition partially relieved repression of vitamin D-dependent gene activation by AKAP13. Conclusion(s): These data suggest that AKAP13 inhibited the vitamin D receptor activation by a mechanism that required, at least in part, RhoA activation. (Fertil Steril Sci (R) 2021;2:303-14. (c) 2021 by American Society for Reproductive Medicine.)