Background Left ventricular ( LV ) diastolic dysfunction often precedes heart failure with preserved ejection fraction, the dominant form of heart failure in postmenopausal women. The objective of this study was to determine the effect of oral estradiol treatment initiated early after ovariectomy on LV function and myocardial gene expression in female cynomolgus macaques. Methods and Results Monkeys were ovariectomized and randomized to receive placebo (control) or oral estradiol at a human‐equivalent dose of 1 mg/day for 8 months. Monkeys then underwent conventional and tissue Doppler imaging to assess cardiac function, followed by transcriptomic and histomorphometric analyses of LV myocardium. Age, body weight, blood pressure, and heart rate were similar between groups. Echocardiographic mitral early and late inflow velocities, mitral annular velocities, and mitral E deceleration slope were higher in estradiol monkeys (all P <0.05), despite similar estimated LV filling pressure. MCP1 (monocyte chemoattractant protein 1) and LV collagen staining were lower in estradiol animals ( P <0.05). Microarray analysis revealed differential myocardial expression of 40 genes (>1.2‐fold change; false discovery rate, P <0.05) in estradiol animals relative to controls, which implicated pathways associated with better calcium ion homeostasis and muscle contraction and lower extracellular matrix deposition ( P <0.05). Conclusions Estradiol treatment initiated soon after ovariectomy resulted in enhanced LV diastolic function, and altered myocardial gene expression towards decreased extracellular matrix deposition, improved myocardial contraction, and calcium homeostasis, suggesting that estradiol directly or indirectly modulates the myocardial transcriptome to preserve cardiovascular function.

Polycystic ovary syndrome (PCOS) and nonalcoholic fatty liver (NAFLD) share similar clinical presentations including obesity, insulin resistance (IR), and metabolic abnormality. The predictive factors of NAFLD in women with PCOS and specifically in Asian women are not well established. Associated factors for NAFLD assessed by ultrasound (US) among a group of PCOS and healthy women were determined and diagnostic accuracy between US and transient elastography (TE) for NAFLD was compared and correlated. Sixty-three women with ages ranging from 20 to 40 years participated in the present cross-sectional study. Forty-two women with PCOS as diagnosed by the Rotterdam criteria and 21 healthy women were recruited into the study. Women with underlying hepatic diseases and history of alcohol consumption >20 g/day were excluded. Biochemical and hormonal testing, anthropometrics, liver US, and TE were assessed. Waist circumference (WC) greater than 80 cm was the only predictive factor for NAFLD as assessed by US in the whole group (adjusted odds ratio [aOR] 5.49, 95% confidence interval [CI]: 1.85–16.26, p <0.001). The value of the TE-based controlled attenuation parameter (CAP) was significantly correlated with stage of steatosis as assessed by US (correlation coefficient = 0.696, p <0.001). The diagnostic accuracies of dichotomized CAP ≥236 dB/m assessed for NAFLD using US as the gold standard were 84% and 78% sensitivity and specificity, respectively, with the area under the curve at 0.81 (p <0.001). Abdominal obesity, rather than the presence of PCOS, was shown to be the independently associated factor for NAFLD. WC could be used as the primary screening tool before performing complicated intervention for detection of steatosis. TE is an alternative noninvasive detection tool in women with PCOS for NAFLD and hepatic fibrosis identification.

Objective To determine the effects of estrogen therapy (ET) on carotid artery inflammation when initiated early and late relative to surgical menopause. Methods and Results Female cynomolgus macaques consuming atherogenic diets were ovariectomized and randomized to control or oral estradiol (E2, human equivalent dose of 1 mg/d micronized E2) initiated at 1 month (Early menopause, n=24) or 54 months, (Late menopause, n=40) post-ovariectomy. Treatment period was 8 months. Carotid artery expression of markers of monocyte/macrophages (CD68, CD163), dendritic cells (CD83), NK cells (NCAM-1), and IFN-γ was significantly lower in the E2-treated animals in the early but not late menopause group (p<0.05). In contrast, carotid artery transcripts for T cell markers (CD3, CD4, CD8, and CD25), interleukin (IL)-10, type I collagen, MCP-1, MMP-9, and TNF-α were lower in E2-treated monkeys regardless of menopausal stage (p<0.05). Conclusions ET initiated soon after menopause inhibited macrophage accumulation in the carotid artery, an effect not observed when E2 was administered after several years of estrogen deficiency. No evidence for pro-inflammatory effects of late ET was observed. The results provide support for the timing hypothesis of postmenopausal ET with implications for interpretation of outcomes in the Women’s Health Initiative.