El Khoudary, Samar R

Beyond conventional risk factors for cardiovascular disease, women face an additional burden of sex-specific risk factors. Key stages of a woman’s reproductive history may influence or reveal short- and long-term cardiometabolic and cardiovascular trajectories. Early and late menarche, polycystic ovary syndrome, infertility, adverse pregnancy outcomes (eg, hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, and intrauterine growth restriction), and absence of breastfeeding are all associated with increased future cardiovascular disease risk. The menopause transition additionally represents a period of accelerated cardiovascular disease risk, with timing (eg, premature menopause), mechanism, and symptoms of menopause, as well as treatment of menopause symptoms, each contributing to this risk. Differences in conventional cardiovascular disease risk factors appear to explain some, but not all, of the observed associations between reproductive history and later-life cardiovascular disease; further research is needed to elucidate hormonal effects and unique sex-specific disease mechanisms. A history of reproductive risk factors represents an opportunity for comprehensive risk factor screening, refinement of cardiovascular disease risk assessment, and implementation of primordial and primary prevention to optimize long-term cardiometabolic health in women.

Abstract Objective: Heart fat deposition has been linked to atherosclerosis, and both accelerate after menopause. Hormone therapy (HT) may differentially slow heart fat deposition and progression of atherosclerosis, depending on the specific HT agent or its route of administration. Our objective was to evaluate the effects of different HT agents, oral and transdermal, on associations between heart fat accumulation and atherosclerosis progression, measured by carotid intima-media thickness (CIMT), in recently menopausal women from the Kronos Early Estrogen Prevention Study (KEEPS) trial. Methods: KEEPS was a randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens (o-CEE) or 50 mcg/d transdermal 17β-estradiol (t-E 2 ), compared with placebo, on 48 months progression of CIMT. Epicardial adipose tissue (EAT) and paracardial adipose tissue (PAT) volumes were quantified by computed tomography. Results: In all, 467 women (mean age [SD] 52.7 [2.5]; 78.2% White; 30% on o-CEE, 30.8% t-E 2 , 39.2% placebo) with heart fat volumes and CIMT at baseline and 48 months were included. EAT and PAT changes were not associated with CIMT progression; however, the assigned treatment significantly modified the association between PAT (but not EAT) change and CIMT progression. In the o-CEE group, adjusted CIMT progression was 12.66 μm (95% confidence interval [CI] 1.80, 23.52) lower than in t-E 2 group ( P = 0.02), and 10.09 μm (95% CI 0.79, 19.39) lower than in placebo group ( P = 0.03), as per 1-SD increase in PAT. Conclusion: Compared with t-E 2 , o-CEE appears to slow down the adverse effect of increasing PAT on progression of atherosclerosis. Whether this beneficial association is specific to CEE or to the oral route of CEE administration is unclear and should be assessed further.

Background Heart fats (epicardial and paracardial adipose tissue [PAT]) are greater after menopause. Endogenous estrogen may regulate these fat depots. We evaluated the differential effects of hormone therapy formulations on heart fat accumulations and their associations with coronary artery calcification ( CAC ) progression in recently menopausal women from KEEPS (Kronos Early Estrogen Prevention Study). Methods and Results KEEPS was a multicenter, randomized, placebo‐controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens and 50 µg/d transdermal 17β‐estradiol, compared with placebo, on 48‐month progression of subclinical atherosclerosis among 727 early menopausal women. CAC progression was defined if baseline CAC score was 0 and 48‐month CAC score was >0 or if baseline CAC score was >0 and <100 and annualized change in CAC score was ≥10. Of 727 KEEPS participants, 474 (mean age: 52.7 [SD: 2.6]; 78.1% white) had computed tomography–based heart fat and CAC measures at both baseline and 48 months. Compared with women on placebo, women on oral conjugated equine estrogens were less likely to have any increase in epicardial adipose tissue (odds ratio for oral conjugated equine estrogens versus placebo: 0.62 [95% CI, 0.40–0.97]; P =0.03). PAT did not change in any group. Changes in epicardial adipose tissue and PAT did not differ by treatment group. CAC increased in 14% of participants. The assigned treatment modified the association between PAT changes and CAC progression ( P =0.02) such that PAT increases were associated with CAC increases only in the transdermal 17β‐estradiol group. Conclusions In recently menopausal women, oral conjugated equine estrogens may slow epicardial adipose tissue accumulation, whereas transdermal 17β‐estradiol may increase progression of CAC associated with PAT accumulation. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00154180.