Purpose of Review: Previous studies have demonstrated associations between the physiological changes accompanied with the onset of menopause and increased atherosclerotic cardiovascular disease (ASCVD) risk. This review surveys current literature surrounding the assessment of risk prediction in menopause and ASCVD, along with current treatment options.

Introduction

Cardiovascular disease (CVD) is the leading cause of death for women in the United States (US) and globally, accounting for 21.8% of deaths for females in the US in 2017. The burden of ASCVD, defined as fatal or nonfatal coronary heart disease or stroke, can be estimated using traditional risk factors such as hypertension, hyperlipidemia, diabetes, and obesity, with recent data supporting the addition of sex-specific risk factors affecting women to improve personalized risk prediction.¹ The menopausal transition has been extensively studied as a time of dynamic hormonal changes that may contribute to the development of ASCVD. Given the emerging data identifying greater ASCVD risk in women with premature menopause, defined as menopause prior to the age of 40, the recently updated Primary Prevention Guideline has acknowledged premature menopause as a risk-enhancing factor to take into consideration when engaging in clinician-patient risk discussions.² In this article, current data on the role of menopause on the risk and development of coronary atherosclerosis will be discussed and reviewed.

Pooled Cohort Equations for ASCVD Risk

In order to guide the primary prevention of ASCVD in patients at risk, current guidelines recommend calculating the 10-year ASCVD risk using the American Heart Association/American College of Cardiology pooled cohort equations (PCEs).² Emerging data documenting the association of premature menopause with ASCVD calls into question whether the PCEs underestimate risk in women with risk-enhancing factors such as premature menopause. A recent cohort study investigated whether there is an improvement in ASCVD risk prediction when adding premature menopause status to the PCEs. This study pooled cohort data from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, CARDIA study, Framingham Heart Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis (MESA), and Women's Health Initiative.³ The study found an independent positive association between premature menopause in women under 40 and increased ASCVD risk regardless of traditional risk factors, consistent with previous studies. However, in middle-aged women, the addition of premature menopause to PCEs for predicting 10-year risk did not significantly change the ASCVD risk. It was felt that premature menopause may not have had additive value in risk estimation given the concurrent development of traditional risk factors such as diabetes and hypertension during menopause that are already included in contemporary risk calculations.

Coronary Artery Calcium Scoring

Data from MESA previously demonstrated the association between coronary artery calcium (CAC) and myocardial infarction (MI) and stroke over a 10-year period.⁴ CAC scoring has been found to differentiate low versus high risk of development of CVD and coronary heart disease (CHD) mortality. This contrasts with the findings from a biracial cohort of Black and White women from the CARDIA (Coronary Artery Risk Development in Young Adults) Study, where CAC scores were compared between women who did and did not experience premature menopause. This study found that premature menopause was not associated with greater odds of any (>0) or significant (≥100) CAC.⁵ A potential explanation for these findings include subclinical changes in women that are not accurately captured by CAC scoring alone; given that women have been shown to have greater degree of mixed and non-calcified plaques on coronary computed tomography angiography (CCTA) when compared with men who have more calcified plaques.⁶ At this time, multiple prevention guidelines endorse that CAC scoring can be used in addition to traditional risk factors to reclassify an updated ASCVD risk, further refining and personalizing primary prevention plans with patients, and influencing the allocation of pharmacologic therapies to prevent ASCVD. An approach utilizing CCTA to define extent and morphology of plaques may be a useful addition to the CAC score for peri- and post-menopausal women, and is an important topic of further study.

Arterial Distensibility

Arterial distensibility, defined as an inverse measure of arterial stiffness in response to changes in pressure, has been previously shown to be a useful clinical predictor of ASCVD independent of traditional risk factors.⁷ Loss of arterial distensibility has been associated with hormonal changes during menopause, potentially accelerating the age-related increase of arterial stiffness. A recent study using data from the Study of Women's Health Across the Nation (SWAN) investigated the changes in arterial stiffness after menopausal women's final menstrual period (FMP).⁸ Arterial stiffness was measured with carotid-femoral pulse-wave velocity (cfPWV) exams and compared with the time since the FMP. The results of this study revealed significant increases in arterial stiffness within 1 year of the FMP, independent of aging, estradiol, and other CVD risk factors. Additionally, this study reported a difference in the development of arterial stiffness between Black and White women, suggesting that Black women may develop an earlier onset of adverse changes in stiffness compared to White women. These results may be helpful in determining when to initiate CVD interventions in women based on the timeline of their menopausal transition and progression of arterial stiffness.

Post-menopausal Hormone Therapy

Hormone therapy (HT) for post-menopausal women remains a controversial treatment as it relates to the prevention of ASCVD, as some studies have reported benefits while others have reported potential concerns. A recent community-based prospective cohort study sampled 161 women assigned to pre-, peri-, and post-menopausal status and collected internal common carotid artery diameter at baseline and 3-year follow-up to calculate distensibility index (DI).⁹ Effects of HT on arterial distensibility were also studied in groups of women who had transitioned between menopausal stages (pre- to peri- or pre- to post) at the 3-year follow-up. Results of this study demonstrated a significantly lower DI in postmenopausal women compared with premenopausal women, suggesting an association between menopausal changes such as estrogen loss and decreased vascular compliance. The largest decline in DI was noted in pre- and transitional menopausal women who were not taking HT, implying a potential impact of HT on arterial distensibility during the transitional period of menopause.

A meta-analysis of 23 randomized clinical trials which included initiation of HT prior to 60 years of age or within 10 years of menopause have demonstrated a significant reduction of MI and cardiac deaths.¹⁰ HT initiated within 10 years following menopause significantly reduced MI and cardiac death by almost 50%, whereas discontinuation of HT resulted in a transient increase in coronary deaths.^11-13

Furthermore, HT has been studied for its effects on slowing the progression of heart fat and atherosclerosis in recently menopausal women in data from the Kronos Early Estrogen Prevention Study (KEEPS).¹⁴ Deposition of epicardial adipose tissue (EAT) and pericardial adipose tissue (PAT) was recorded as a measure of heart fat, while carotid intimal media thickness (CIMT) was used as a measure of atherosclerotic progression. HT consisted of treatment with oral conjugated equine estrogens (o-CEE) or transdermal estradiol (t-E2) compared with placebo after 48 months. The results of this study demonstrated that changes in dosage of o-CEE treatment levels had associations with decreased CIMT progression as PAT increased, suggesting a therapeutic effect in slowing adverse effects of menopause on progression of atherosclerosis. The ELITE (Early versus Late Intervention Trial with Estradiol) Study demonstrated slower progression of CIMT in younger women randomized to HT as opposed to women greater than 10 years post-menopause not on HT.¹⁵ Some of the possible mechanisms mediating the ASCVD benefit of HT, especially with transdermal formulations, include improvement in body composition, lipid profile, increase in insulin sensitivity, a decrease in blood pressure, and finally, a direct vasodilatory and anti-inflammatory effect.^16,17

Despite reported benefits that HT might propose for menopause and ASCVD, there are also drawbacks. The Women's Health Initiative (WHI) clinical trial investigated the effects of postmenopausal HT on CHD with outcomes such as pulmonary embolism (PE), stroke, and overall mortality.¹⁸ The results demonstrated an increased risk of stroke within the cohort of postmenopausal women after hysterectomy, suggesting a potential concern with use of HT in CHD prevention.

Additional prospective studies are needed to further investigate the benefits and risks of post-menopausal HT in atherosclerotic disease.

Summary

Current guidelines recommend assessing a patient's risk of ASCVD using traditional risk factors such as hypertension, hyperlipidemia, diabetes, and obesity; furthermore, emerging data supports incorporating additional sex-specific considerations (such as menopause status) for women when engaging in clinician-patient discussions regarding overall cardiovascular risk and treatment plans. Diagnostic testing for subclinical disease, such as CAC scoring or potentially CCTA, may be useful in refining risk assessment and optimizing both lifestyle-based and pharmacologic-based preventive interventions. Additionally, dynamic vascular changes associated with menopause such as decreased aortic distensibility may be a predictor for increased cardiovascular risk. Although HT has yielded a controversial variety of results in previous studies regarding ASCVD risk, there may be a potential for its protection against the progression of atherosclerotic disease that should be further investigated.

Table 1: ASCVD Risk Assessment and Menopause: Current Evidence
Courtesy of Nayak T, Freaney P, Maganti K.

CAC Scoring
MESA	CAC scoring can be used to refine ASCVD risk prediction, and a CAC score of zero can be helpful in deciding when to defer the initiation of lipid-lowering therapies during personalized clinician-patient discussions.
CARDIA Study	Comparison between women with and without premature menopause revealed no significant differences in CAC scores, potentially due to subclinical changes associated with mixed or noncalcified plaques that are more commonly found in women.
PCE's and ASCVD risk
Premature Menopause and 10-Year Risk Prediction of ASCVD	Though there is an independent association between premature menopause and ASCVD, the addition of premature menopause to the PCEs did not significantly improve ASCVD risk prediction.
Arterial Distensibility
Carotid artery distensibility and hormone therapy and menopause: The Los Angeles Atherosclerosis Study	The menopausal transition was shown to be associated with reduced vascular compliance.
SWAN Study	Within 1 year of the FMP, significant changes in arterial stiffness are observed independent of other traditional risk factors.
Post-menopausal HT
KEEPS Study	Higher dosage HT was associated with slower atherosclerotic progression independent of PAT, suggesting a potential therapeutic target in post-menopausal women.
ELITE Study	HT was shown to have an association with slowing atherosclerotic progression in younger women compared to post-menopausal women.

References

1. Freaney PM, Khan SS, Lloyd-Jones DM, Stone NJ. The role of sex-specific risk factors in the risk assessment of atherosclerotic cardiovascular disease for primary prevention in women. Curr Atheroscler Rep 2020;22:46.
2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-2934.
3. Freaney PM, Ning H, Carnethon M, et al. Premature menopause and 10-year risk prediction of atherosclerotic cardiovascular disease. JAMA Cardiol 2021;6:1463-65.
4. Budoff MJ, Young R, Burke G, et al. Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J 2018;39:2401-08.
5. Freaney PM, Petito L, Colangelo LA, et al. Association of premature menopause with coronary artery calcium: the CARDIA study. Circ Cardiovasc Imaging 2021;14:e012959.
6. Plank F, Beyer C, Friedrich G, Wildauer M, Feuchtner G. Sex differences in coronary artery plaque composition detected by coronary computed tomography: quantitative and qualitative analysis. Neth Heart J 2019;27:272-80.
7. London GM, Cohn JN. Prognostic application of arterial stiffness: task forces. Am J Hypertens 2002;15:754-58.
8. Samargandy S, Matthews KA, Brooks MM, et al. Arterial Stiffness Accelerates Within 1 Year of the Final Menstrual Period: The SWAN Heart Study. Arterioscler Thromb Vasc Biol 2020;40:1001-08.
9. Shufelt C, Elboudwarej O, Johnson BD, et al. Carotid artery distensibility and hormone therapy and menopause: the Los Angeles Atherosclerosis Study. Menopause 2016;23:150-57.
10. Salpeter SR, Walsh JME, Greyber E, Salpeter EE. Brief report: Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med 2006;21:363-66.
11. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345:e6409.
12. Boardman H, Hartley L, Eisinga A, Main C, Figuls MR. Cochrane corner: oral hormone therapy and cardiovascular outcomes in post-menopausal women. Heart 2016;102:9-11.
13. Tuomikoski P, Lyytinen H, Korhonen P, et al. Coronary heart disease mortality and hormone therapy before and after the Women's Health Initiative. Obstet Gynecol 2014;124:947-53.
14. El Khoudary SR, Venugopal V, Manson JE, et al. Heart fat and carotid artery atherosclerosis progression in recently menopausal women: impact of menopausal hormone therapy: The KEEPS trial. Menopause 2020;27:255-62.
15. Hodis HN, Mack WJ, Shoupe D, et al. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause 2015;22:391-401.
16. Santen RJ. Use of cardiovascular age for assessing risks and benefits of menopausal hormone therapy. Menopause 2017;24:589-95.
17. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394:1159-68.
18. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-12.

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Vascular Medicine, Computed Tomography, Nuclear Imaging, Hypertension

Keywords: Postmenopause, Middle Aged, Estrogens, Conjugated (USP), Calcium, Prospective Studies, Menopause, Premature, Follow-Up Studies, Cardiovascular Diseases, American Heart Association, Blood Pressure, Cause of Death, Computed Tomography Angiography, Coronary Artery Disease, Hyperlipidemias, Insulin Resistance, Vascular Stiffness, Menopause, Aging, Estrogens, Hysterectomy, Longitudinal Studies, Estradiol, Risk Factors, Myocardial Infarction, Carotid Artery, Common, Pulmonary Embolism, Risk Assessment, Primary Prevention, Anti-Inflammatory Agents, Body Composition, Atherosclerosis, Adipose Tissue, Hypertension, Cardiology, Diabetes Mellitus, Obesity, Lipids, Stroke

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