Association of Age at Menopause With Incident Heart Failure: A Prospective Cohort Study and Meta‐Analysis

Appiah, Duke; Schreiner, Pamela J.; Demerath, Ellen W.; Loehr, Laura R.; Chang, Patricia; Folsom, Aaron R.

doi:10.1161/jaha.116.003769

Cited by 80 publications

(69 citation statements)

References 57 publications

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“…Even though this is the first study comparing the metabolic pathway for Ang II formation in freshly isolated CMs and NCMs in cardiac plasma membranes extracted from hearts of gonadal‐intact and ovariectomized hypertensive and normotensive rats, it remains to be determined whether the same differential results may be obtained in older animals. On the other hand, the clinical significance of the current findings is underscored by recent reports documenting that early onset menopause is, indeed, linked to incident HF later in life (Appiah et al, ; Ebong et al, ). In addition, there is a strong body of evidence implicating a significant contribution of local tissue‐derived cardiac and vascular RAS in age‐related remodeling (Strait & Lakatta, ).…”

Section: Limitationsmentioning

confidence: 58%

Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR

Ahmad

Sun

Lin

et al. 2017

Journal Cellular Physiology

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The relatively low efficacy of ACE-inhibitors in the treatment of heart failure in women after estrogen loss may be due to their inability to reach the intracellular sites at which angiotensin (Ang) II is generated and/or the existence of cell-specific mechanisms in which ACE is not the essential processing pathway for Ang II formation. We compared the metabolic pathway for Ang II formation in freshly isolated myocytes (CMs) and non-myocytes (NCMs) in cardiac membranes extracted from hearts of gonadal-intact and ovariectomized (OVX) adult WKY and SHR rats. Plasma Ang II levels were higher in WKY vs. SHR (strain effect: WKY: 62 ± 6 pg/ml vs. SHR: 42 ± 9 pg/ml; p < 0.01), independent of OVX. The enzymatic activities of chymase, ACE, and ACE2 were higher in NCMs versus CMs, irrespective of whether assays were performed in cardiac membranes from WKY or SHR or in the presence or absence of OVX. E2 depletion increased chymase activity, but not ACE activity, in both CMs and NCMs. Moreover, cardiac myocyte chymase activity associated with diastolic function in WKYs and cardiac structure in SHRs while no relevant functional and structural relationships between the classic enzymatic pathway of Ang II formation by ACE or the counter-regulatory Ang-(1-7) forming path from Ang II via ACE2 were apparent. The significance of these novel findings is that targeted cell-specific chymase rather than ACE inhibition may have a greater benefit in the management of HF in women after menopause.

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Section: Limitationsmentioning

confidence: 58%

Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR

Ahmad

Sun

Lin

et al. 2017

Journal Cellular Physiology

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“…Prior data have suggested that women with early menopause, and consequently a shorter reproductive period with fewer reproductive cycles and lower cumulative exposure to endogenous sex hormones, have an increased risk of CHD, stroke, and possibly HF (4–7). An analysis of the Framingham Heart Study population suggested that the increased CHD risk with early menopause may be influenced by a loss of the protective effects of endogenous sex hormones and an increase in thrombotic risk (27).…”

Section: Discussionmentioning

confidence: 99%

“…The protective effects of menstrual cycles are frequently hypothesized to explain why premenopausal women have a lower risk of cardiovascular disease (CVD) compared with postmenopausal women of similar age, although this is still a controversial hypothesis (2,3). Moreover, data suggest that women with early menopause have an elevated risk of coronary heart disease (CHD) and stroke, and there are conflicting data as to whether early menopause also predicts HF (4–7). …”

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confidence: 99%

Reproductive Factors and Incidence of Heart Failure Hospitalization in the Women’s Health Initiative

Hall

Nah

Howard

et al. 2017

Journal of the American College of Cardiology

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BACKGROUND Reproductive factors reflective of endogenous sex hormone exposure might have an effect on cardiac remodeling and the development of heart failure (HF). OBJECTIVES This study examined the association between key reproductive factors and the incidence of HF. METHODS Women from a cohort of the Women’s Health Initiative were systematically evaluated for the incidence of HF hospitalization from study enrollment through 2014. Reproductive factors (number of live births, age at first pregnancy, and total reproductive duration [time from menarche to menopause]) were self-reported at study baseline in 1993 to 1998. We employed Cox proportional hazards regression analysis in age- and multivariable-adjusted models. RESULTS Among 28,516 women, with an average age of 62.7 ± 7.1 years at baseline, 1,494 (5.2%) had an adjudicated incident HF hospitalization during an average follow-up of 13.1 years. After adjusting for covariates, total reproductive duration in years was inversely associated with incident HF: hazard ratios (HRs) of 0.99 per year (95% confidence interval [CI]: 0.98 to 0.99 per year) and 0.95 per 5 years (95% CI: 0.91 to 0.99 per 5 years). Conversely, early age at first pregnancy and nulliparity were significantly associated with incident HF in age-adjusted models, but not after multivariable adjustment. Notably, nulliparity was associated with incident HF with preserved ejection fraction in the fully adjusted model (HR: 2.75; 95% CI: 1.16 to 6.52). CONCLUSIONS In postmenopausal women, shorter total reproductive duration was associated with higher risk of incident HF, and nulliparity was associated with higher risk for incident HF with preserved ejection fraction. Whether exposure to endogenous sex hormones underlies this relationship should be investigated in future studies.

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“…Second, information on age at menopause and menarche, parity, and use of hormone replacement therapy, were not consistently available from charts. In developed countries, the average age of natural menopause of 51 years is used as a reference in cardiovascular studies, 39 and we interpreted our data with this knowledge. Third, while we were able to restrict our analysis to patients with less than 50% stenosis to exclude patients with higher plaque volumes given the correlation of stenosis with plaque volume, 24 our analyses were not adjusted for degree of stenosis.…”

Section: Discussionmentioning

confidence: 99%

Age-Specific Sex Differences in Magnetic Resonance Imaging-Depicted Carotid Intraplaque Hemorrhage

Singh

Moody

Zhang

et al. 2017

Stroke

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Background and Purpose Stroke rates are higher in males compared to females in the fourth through seventh decades of life, and higher rates may result from differences in carotid intraplaque hemorrhage (IPH), an unstable atherosclerotic plaque component. We report age-specific sex differences in the presence of MRI depicted carotid IPH. Methods Patients (n=1115) underwent MRI for carotid IPH between 2005 and 2014. Low-grade carotid stenosis patients (n=906) without prior endarterectomy were eligible for this cross-sectional study. Results Of the 906 patients included (mean age ± SD in years, 66.98 +/− 15.15), 63 (6.95%) had carotid IPH. In males and females, carotid IPH was present in 11.43% (48/420) and 3.09% (15/486), respectively (p<0.0001). Multivariable logistic regression analysis confirmed greater odds of carotid IPH in males for all ages: 45 to 54 (OR=45.45, 95% CI 3.43 to 500), 55 to 64 years (OR=21.74, 95% CI 3.21 to 142.86), 65 to 74 years (OR=10.42, 95% CI 2.91 to 37.04), and ≥75 years (OR=5.00, 95% CI 2.31 to 10.75). Male sex modified the effect of age on the presence of carotid IPH (β= 0.074, SE=0.036, p=0.0411). Conclusions Males have greater age-specific odds of MRI depicted carotid IPH compared to females. With increasing age post-menopause, the odds of carotid IPH in females becomes closer to that of males. Delayed onset of carotid IPH in females, an unstable plaque component, may partly explain differential stroke rates between sexes and further studies are warranted.

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Association of Age at Menopause With Incident Heart Failure: A Prospective Cohort Study and Meta‐Analysis

Cited by 80 publications

References 57 publications

Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR

Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR

Reproductive Factors and Incidence of Heart Failure Hospitalization in the Women’s Health Initiative

Age-Specific Sex Differences in Magnetic Resonance Imaging-Depicted Carotid Intraplaque Hemorrhage

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