Rationale: Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men.Objectives: We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men.Methods: Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared with those from age-and body mass index-matched men without clinical cardiovascular disease.Measurements and Main Results: There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH.Conclusions: Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease.

Rationale: The aromatase inhibitor anastrozole blocks the conversion of androgens to estrogen and blunts pulmonary hypertension in animals, but its efficacy in treating patients with pulmonary arterial hypertension (PAH) is unknown.Objectives: We aimed to determine the safety and efficacy of anastrozole in PAH.Methods: We performed a randomized, double-blind, placebocontrolled trial of anastrozole in patients with PAH who received background therapy at two centers. Measurements and Main Results:A total of 18 patients with PAH were randomized to anastrozole 1 mg or matching placebo in a 2:1 ratio. The two co-primary outcomes were percent change from baseline in 17b-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: 240%; interquartile range [IQR], 261 to 226% vs. 24%; IQR, 214 to 14%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = 126 m) compared with placebo (median change = 212 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo 22%; IQR, 27 to 11%; P = 0.042). Anastrozole had no effect on circulating biomarkers, functional class, or health-related quality of life. There was no difference in adverse events.Conclusions: Anastrozole significantly reduced E2 levels in patients with PAH but had no effect on TAPSE. Anastrozole was safe, well tolerated, and improved 6-minute-walk distance in this small "proof-of-principle" study. Larger and longer phase II clinical trials of anastrozole may be warranted in patients with PAH.Clinical trial registered with www.clinicaltrials.gov (NCT 1545336).

High oestradiol (E2) and low dehydroepiandrosterone-sulfate (DHEA-S) levels are risk factors for pulmonary arterial hypertension (PAH) in men, but whether sex hormones are related to PAH in women is unknown.Post-menopausal women aged ≥55 years with PAH were matched by age and body mass index to women without cardiovascular disease. Plasma sex hormone levels were measured by immunoassay.Lower levels of DHEA-S (p<0.001) and higher levels of E2 (p=0.02) were associated with PAH. In PAH cases (n=112), lower DHEA-S levels were associated with worse haemodynamics (all p<0.01) and more right ventricular dilatation and dysfunction (both p=0.001). Lower DHEA-S levels were associated with shorter 6-min walking distance (6MWD) (p=0.01) and worse functional class (p=0.004). Each Ln(1 µg·dL) decrease in DHEA-S was associated with a doubling in the risk of death (hazard ratio 2.0, 95% CI 1.5-2.7; p<0.001). Higher levels of E2 were associated with shorter 6MWD (p=0.03) and worse functional class (p=0.01).High E2 and low DHEA-S levels are associated with the risk and severity of PAH in post-menopausal women. Hormonal modulation should be studied as a treatment strategy in PAH.

Women with PAH may spend most of their time being sedentary, and lower self-reported energy levels are associated with less daily activity. Interventions to improve symptoms such as fatigue may also increase physical activity levels in PAH.

Background/objectives Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited. Methods and results The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4,009) from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses. Conclusion Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV.

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IL-6 and tumor necrosis factor-α levels are associated with certain quality of life domains in patients with pulmonary arterial hypertension. Clinical trial registered with www.clinicaltrials.gov (NCT00384865).

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