Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women.

BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease. METHODS: Participants from the UK Biobank and Women's Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease. RESULTS: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Women's Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2×10-12). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P<2.2×10-16) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease. CONCLUSIONS: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.

Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long?

Menopausal hormone therapy (HT) was widely used in the past, but with the publication of seminal primary and secondary prevention trials that reported an excess cardiovascular risk with combined estrogen-progestin, HT use declined significantly. However, over the past 20 years, much has been learned about the relationship between the timing of HT use with respect to age and time since menopause, HT route of administration, and cardiovascular disease risk. Four leading medical societies recommend HT for the treatment of menopausal women with bothersome menopausal symptoms. In this context, this review, led by the American College of Cardiology Cardiolovascular Disease in Women Committee, along with leading gynecologists, women's health internists, and endocrinologists, aims to provide guidance on HT use, including the selection of patients and HT formulation with a focus on caring for symptomatic women with cardiovascular disease risk.

Pregnancy and Reproductive Risk Factors for Cardiovascular Disease in Women.

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.

History of infertility and sexual dysfunction in midlife women: Is there a link?

BACKGROUND: Infertility has been linked with an increased risk of sexual dysfunction in reproductive-aged women, with longer periods of infertility associated with a greater risk. AIM: The study's aim was to examine whether a history of infertility treatment in women is linked to sexual dysfunction during midlife. METHODS: The cross-sectional study was conducted among sexually active women, between the ages of 45 and 65 years, who sought consultation at the women's health clinics at a US tertiary care center. History of infertility treatment was assessed with a single question that asked participants if they were treated for infertility in the past. The association between a history of infertility treatment and sexual dysfunction-which was diagnosed by a combination of Female Sexual Function Index score ≤26.55 and Female Sexual Distress Scale-Revised score ≥11-was assessed in a multivariable logistic regression model that adjusted for multiple confounders. OUTCOMES: The primary outcome was sexual dysfunction in midlife women. RESULTS: The analysis included 5912 women, with a mean age of 54.1 years. Nearly 16% of women reported receiving treatment for infertility. More than half the women (55%) had sexual dysfunction: 56.3% of those with previous fertility treatments and 54.4% of those without any fertility treatment (P = .3). Receiving treatment for infertility in the younger years did not significantly increase the odds of sexual dysfunction in midlife in univariate (odds ratio, 1.08; 95% CI, 0.94-1.24; P = .3) and multivariable analyses (odds ratio, 1.11; 95% CI, 0.96-1.29; P = .17). CLINICAL IMPLICATIONS: While infertility is known to be predictive of sexual dysfunction in women during their reproductive years, there was no association between a history of infertility treatment and sexual dysfunction in midlife women in the current study. STRENGTHS AND LIMITATIONS: The study used validated questionnaires accounting for sexual complaints and distress and adjusted for multiple confounding factors. Limitations include the selection bias introduced by the study of women presenting for evaluation of sexual dysfunction, which may have been a result of factors stronger than the influence of infertility. Other limitations include the study's cross-sectional nature with suboptimal racial and ethnic representation. CONCLUSION: Although infertility is commonly associated with female sexual dysfunction in women of reproductive age, the association was not present in midlife women in the current study.

Association of Spontaneous Preterm Delivery and Future Maternal Cardiovascular Disease.

Cardiovascular disease (CVD) risk factors are well established. However, little is known about a woman's cardiovascular response to pregnancy, which appears to be an early marker of future maternal CVD risk. Spontaneous preterm delivery (sPTD) has been associated with a ≤3-fold increased risk of maternal CVD death later in life compared with having a term delivery. This review focuses on 3 key areas to critically assess the association of sPTD and future maternal CVD risk: (1) CVD risk factors, (2) inflammatory biomarkers of interest, and (3) specific forms of vascular dysfunction, such as endothelial function and arterial stiffness, and mechanisms by which each may be linked to sPTD. The association of sPTD with subsequent future maternal CVD risk suggests that a woman's abnormal response to pregnancy may serve as her first physiological stress test. These findings suggest that future research is needed to understand why women with sPTD may be at risk for CVD to implement effective interventions earlier in a woman's life.

Sex-Specific Physiology and Cardiovascular Disease.

Sex differences in cardiovascular diseases can be classified as those which are specific to one sex and those that differ in incidence, prevalence, etiology, symptomatology, response to treatment, morbidity, and mortality in one sex compared to the other. All sex differences in cardiovascular conditions have their basis in the combined expression of genetic and hormonal differences between women and men. This chapter addresses how understanding basic mechanisms of hormone responses, imaging diagnostics, and integration of genomics and proteomics has advanced diagnosis and improved outcomes for cardiovascular conditions, apart from those related to pregnancy that are more prevalent in women. These conditions include obstructive coronary artery disease, coronary microvascular dysfunction, spontaneous coronary artery dissection, diseases of the cardiac muscle including heart failure and takotsubo cardiomyopathy, and conditions related to neurovascular dysregulation including hot flashes and night sweats associated with menopause and effects of exogenous hormones on vascular function. Improvement in technologies allowing for noninvasive assessment of neuronally mediated vascular reactivity will further improve our understanding of the basic etiology of the neurovascular disorders. Consideration of sex, hormonal status, and pregnancy history in diagnosis and treatment protocols will improve prevention and outcomes of cardiovascular disease in women as they age.

A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve.

AIMS: The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling. MATERIALS AND RESULTS: Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041). CONCLUSIONS: In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01342029.

Role of Stress Cardiac Magnetic Resonance Imaging in Women with Suspected Ischemia but No Obstructive Coronary Artery Disease.

OBJECTIVE: Signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) is often a diagnostic dilemma in women. The use of stress cardiac magnetic resonance imaging (CMRI) for advanced diagnostic assessment in these patients is a non-ionizing radiation option, but the diagnostic utility in this population is unknown. We examined the diagnostic role of stress CMRI in our patient population of these women. METHODS: We analyzed 113 consecutive female patients from 2/2006-11/2007 who had prior cardiac evaluations for signs and symptoms of ischemia but no obstructive CAD who underwent stress CMRI, which included anatomic, functional, adenosine stress perfusion and delayed enhancement imaging. RESULTS: The population demographics of 113 women included a mean age of 55±12.2 years with an average body mass index (BMI) of 25 ± 4.5. Overall, 43% had hypertension, 4% had diabetes and 3% were smokers. Overall, 80/113 (70%) demonstrated abnormal stress CMRI results. The majority of patients demonstrated findings consistent with subendocardial perfusion abnormalities suggestive of coronary microvascular dysfunction (CMD). Of note, 3 patients (4%) were diagnosed with congenital coronary anomalies or cardiomyopathy not detected in prior cardiac evaluations. CONCLUSION: Among women with signs and symptoms of ischemia but no obstructive CAD, stress CMRI is frequently abnormal and is valuable in diagnosis of CMD. Stress CMRI appears useful for advanced diagnostic assessment in these diagnostically challenged patients.

The relation between excess adiposity and breast cancer in women: Clinical implications and management.

BACKGROUND: Breast cancer (BC) is the most common cancer in women. While the combination of improved screening, earlier detection, and advances in therapeutics has resulted in lower BC mortality, BC survivors are now increasingly dying of cardiovascular disease. Cardiovascular disease in the leading cause of non-cancer related mortality among BC survivors. This situation underscores the critical need to research the role of modifiable cardiometabolic risk factors, such as excess adiposity, that will affect BC remission, long-term survivorship, and overall health and quality of life. PURPOSE: First, this review summarizes the evidence on the connection between adipose tissue and BC. Then we review the data on weight trends after BC diagnosis with a focus on the effect of weight gain on BC recurrence and BC- and non-BC-related death. Finally, we provide a guide for weight management in BC survivors, considering the available data on the effect of weight loss interventions on BC.

Weight Gain in Midlife Women.

PURPOSE OF REVIEW: To summarize the evidence and clinical implications of weight and body composition changes during midlife in women and provide an overview of weight gain prevention and management in this population. RECENT FINDINGS: Aging-related changes such as decreased energy expenditure and physical activity are important culprits for weight gain in midlife women. The hormonal changes of menopause also influence body adiposity distribution and increase central adiposity. These body changes can have health consequences including the development of cardiometabolic diseases, osteoarthritis, cancer, worsening in cognition, mental health, and menopause symptoms. Midlife women experience changes related to aging, menopause, and lifestyle which favor weight gain. Clinical practice should focus on early counseling and anticipatory guidance on the importance of dietary changes and physical activity to attenuate this phenomenon. Future research should focus on the longitudinal relationship between weight trends in midlife and health consequences and mortality.

Menopause in the workplace: Challenges, impact, and next steps.

INTRODUCTION: Menopause is a natural part of a woman's life that coincides with a time when many women play significant roles in the workforce. Menopause symptoms, such as hot flashes, fatigue, and difficulty with concentration and memory, can have a negative effect on work productivity and efficiency. OBJECTIVES: This paper summarizes the impact of menopause in the workplace, with an emphasis on the impact of symptoms on employed women and how the workplace influences their experiences. It highlights economic implications, promotes awareness, and suggests potential next steps. METHODS: A search for papers was conducted between August and November 2023 in the PubMed and Medline databases. Papers were selected based on personal experience and interpretation of the findings. Recommendations for managing menopause symptoms in the workplace and guidance on an optimal workplace intervention strategy were provided. RESULTS: Women experiencing severe menopause symptoms are more likely to report adverse work outcomes, including absenteeism and job-related decisions such as quitting, retiring early, or declining promotions than women experiencing few symptoms. Factors such as a lack of awareness about menopause, inflexible work conditions, and high-stress jobs can exacerbate the severity of these symptoms. Additionally, unaddressed menopause symptoms contribute to both direct and indirect economic costs, including medical resource utilization and lost work productivity, resulting in a substantial economic burden. CONCLUSION: Menopause symptoms impair women's work experiences and productivity. In addition to dismantling the stigma associated with menopause, it is critical to create and implement menopause workplace policies and interventions aimed at supporting women in this universal life stage.

Menopause transition and cardiovascular disease risk.

The risk of cardiovascular disease (CVD) notably increases in the fifth decade of a woman's life, coinciding with the onset of menopause and occurring 10 years later than the similar age-related increase in men. Menopause marks a significant transition in a woman's life and is accompanied by cardiometabolic changes, including a shift in body composition, increased blood pressure, disruptions in lipoproteins, and insulin resistance. There is increasing evidence that the menopause transition is a risk factor for CVD, independent of age-related changes, especially considering that the earlier the onset of menopause, the greater is the CVD risk. Further, menopause-related symptoms such as vasomotor symptoms, sleep disturbances, and mood changes may all have a direct impact on CVD risk. In this review, we summarize the current literature regarding CVD in midlife women, focusing on the cardiometabolic changes related to ovarian aging versus chronological aging, as well as those related to specific menopause characteristics, including age, type of menopause and the use of menopause hormone therapy.

Weight loss response to semaglutide in postmenopausal women with and without hormone therapy use.

OBJECTIVE: To compare weight loss response and changes in cardiometabolic risk markers in postmenopausal women using semaglutide with and without menopause hormone therapy (HT) use. METHODS: Retrospective cohort study of postmenopausal women treated with semaglutide for overweight or obesity for ≥3 months. Endpoints: total body weight loss percentage (TBWL%) at 3, 6, 9, and 12 months after semaglutide initiation; and percentage of women achieving ≥5% and ≥10% TBWL and changes in cardiometabolic risk markers (glucose, blood pressure, and lipids) at 12 months. RESULTS: There were 16 women on HT and 90 on no-HT; mean age 56 ± 8 vs 59 ± 8 yr, P = 0.2 and mean BMI 36 ± 5 vs 39 ± 8 kg/m 2 , P = 0.1; respectively. Among women on no-HT, White race, dyslipidemia, and depression were more prevalent. Women on HT had a higher TBWL% at 3, 6, 9, and 12 months: 7 ± 3% vs 5 ± 4%, P = 0.01; 13 ± 6% vs 9 ± 5%, P = 0.01; 15 ± 6% vs 10 ± 6%, P = 0.02; and 16 ± 6% vs 12 ± 8%, P = 0.04; respectively. After adjusting for potential confounders, this association remained significant across time. At 12 months, a greater percentage of women on HT achieved ≥5% and ≥10% TBWL. Both groups experienced an improvement in cardiometabolic risk markers. CONCLUSION: In postmenopausal women with overweight or obesity treated with semaglutide, HT use was associated with an improved weight loss response. This association was maintained when adjusted for confounders. Larger studies should be conducted to confirm these results.

Proprotein convertase subtisilin/kexin 9 levels decline with hepatitis C virus therapy in people with HIV/hepatitis C virus and correlate with inflammation.

BACKGROUND: Proprotein convertase subtisilin/kexin 9 (PCSK9) raises low-density lipoprotein cholesterol (LDL-C) levels and is associated with inflammation, which is elevated in HIV and hepatitis C virus (HCV) infection. We compared PCSK9 levels in people with co-occurring HIV and HCV (HIV/HCV) vs. HIV alone, and evaluated the impact of HCV direct-acting antiviral (DAA) therapy on PCSK9. DESIGN: A prospective, observational cohort study. METHODS: Thirty-five adults with HIV/HCV and 37 with HIV alone were evaluated, all with HIV virologic suppression and without documented cardiovascular disease. Circulating PCSK9 and inflammatory biomarkers were measured at baseline and following HCV treatment or at week 52 (for HIV alone) and compared using Wilcoxon tests and Spearman correlations. RESULTS: At baseline, PCSK9 trended higher in HIV/HCV vs. HIV alone (307 vs. 284 ng/ml, P  = 0.06). Twenty-nine participants with HIV/HCV completed DAA therapy with sustained virologic response. PCSK9 declined from baseline to posttreatment 1 (median 7.3 weeks after end of therapy [EOT]) and posttreatment 2 (median 43.5 weeks after EOT), reaching levels similar to HIV alone; median within-person reduction was -60.5 ng/ml ( P  = 0.003) and -55.6 ng/ml ( P  = 0.02), respectively. Decline in PCSK9 correlated with decline in soluble (s)E-selectin and sCD163 ( r  = 0.64, P  = 0.002; r  = 0.58, P  = 0.008, respectively), but not with changes in LDL-C or other biomarkers. No significant change in PCSK9 occurred in the HIV alone group over 52 weeks. CONCLUSION: PCSK9 declined with DAA therapy in participants with HIV/HCV, correlating with declines in several inflammatory biomarkers but not LDL-C. Elevated PCSK9 with HCV may be linked to particular HCV-associated inflammatory pathways more so than cholesterol homeostasis.

Associations between childhood adversity and age at natural menopause.

OBJECTIVE: Adverse childhood experiences (ACEs) are reported in more than half of the women in the United States and have been shown to negatively impact the menopause experience. The objective of this study was to evaluate the association between ACEs and age at natural menopause. METHODS: This is a cross-sectional study conducted among participants of the Data Registry on the Experiences of Aging, Menopause, and Sexuality (DREAMS). The registry included women who were seen for consultations in the women's health clinic at Mayo Clinic, Rochester, between May 2015 and December 2016. Only postmenopausal women were included in this analysis. Childhood adversity was assessed with the validated ACE questionnaire. Age at natural menopause was self-reported. The association between ACEs and age at menopause was evaluated using a multivariable linear regression model adjusting for multiple confounders. RESULTS: A total of 350 women were evaluated. The mean age was 59.2 years, and a majority were White (92.9%), married/partnered (82%), and educated (91.2% with at least some college education). Women with a history of at least four ACEs were estimated to reach natural menopause 1.3 years sooner than women with no ACE in multivariable analysis, but the results were not statistically significant (95% confidence interval, -3.2 to 0.6; P = 0.18). CONCLUSIONS: Although stressful life experiences such as ACEs may negatively influence health for midlife women, this study did not find an association with the age at natural menopause.

Case report: Repeat coronary function testing in women with ischemia and no obstructive coronary artery disease.

Women with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). It can be diagnosed by coronary function testing (CFT), which is an invasive coronary angiogram procedure. Frequently, these women have persistent angina despite medical therapy, but it is not clear whether it is due to worsening or persistent CMD or inadequate therapy. In this brief report, we describe findings of repeat CFT in a case series of 12 women undergoing repeat CFT for the assessment of persistent angina in order to better understand the evolving pathology.

Cardiovascular Complications During Delivery Admissions Associated With Assisted Reproductive Technology (from a National Inpatient Sample Analysis 2008 to 2019).

Women who conceive through assisted reproductive technology (ART) have a known increased risk of obstetric complications. However, whether ART is also associated with higher risk of developing cardiovascular complications during delivery admissions has not been well established. We used data from the National Inpatient Sample (2008 to 2019) and used the International Classification of Diseases codes to identify delivery hospitalizations and ART procedures. A total of 45,867,086 weighted delivery cases were identified, of which 0.24% were among women who conceived through ART (n = 108,542). Women with an ART history were older at the time of delivery (median 35 vs 28 years, p <0.01) and had a higher prevalence of hypertension, gestational diabetes, and dyslipidemia (all, p <0.01). After adjustment for age, race/ethnicity, co-morbidities, multiple gestation, insurance, and income, ART remained an independent predictor of peripartum cardiovascular complications, including pre-eclampsia/eclampsia (adjusted odds ratio [aOR] 1.48, 95% confidence interval [CI] 1.45 to 1.51), heart failure (aOR 1.94, 95% CI 1.10 to 3.40), and cardiac arrhythmias (aOR 1.39, 95% CI 1.30 to 1.48), compared with natural conception. Likewise, the risk of acute kidney injury (aOR 2.57, 95% CI 2.25 to 2.92), ischemic stroke (aOR 1.73, 95% CI 1.24 to 2.43), hemorrhagic stroke (aOR 1.63, 95% CI 1.27 to 2.11), pulmonary edema (aOR 2.29, 95% CI 2.02 to 2.61), and venous thromboembolism (aOR 1.92, 95% CI 1.63 to 2.25) were higher with ART. However, odds of developing peripartum cardiomyopathy or acute coronary syndrome were not associated with ART. Length of stay (3 vs 2 days, p <0.01) and cost of hospitalization ($5,903 vs $3,922, p <0.01) were higher for deliveries among women with a history of ART. In conclusion, women who conceived with ART had higher risk of pre-eclampsia, heart failure, arrhythmias, stroke, and other complications during their delivery hospitalizations. This may, in part, contribute to their increased resource utilization seen.

Association of Migraine and Vasomotor Symptoms.

OBJECTIVE: To further examine a potential link between migraine and vasomotor symptoms as well as hypertension as a cardiovascular disease risk factor, potentially explaining the association in midlife women. PATIENTS AND METHODS: We conducted a cross-sectional analysis from the Data Registry on Experiences of Aging, Menopause, and Sexuality using questionnaire data from women aged 45 to 60 years seen in women's clinics at a tertiary care center from May 15, 2015, through January 31, 2022. A history of migraine was self-reported; menopause symptoms were assessed with the Menopause Rating Scale. Associations between migraine and vasomotor symptoms were evaluated utilizing multivariable logistic regression models adjusting for multiple factors. RESULTS: Of 5708 women included in the analysis, 1354 (23.7%) reported a migraine history. The total cohort had a mean age of 52.8 years, most (5184 [90.8%]) were White, and 3348 (58.7%) were postmenopausal. In adjusted analysis, women with migraine were significantly more likely to have severe/very severe hot flashes vs no hot flashes compared with women without migraine (odds ratio, 1.34; 95% CI, 1.08 to 1.66; P=.007). Migraine was associated with a diagnosis of hypertension in adjusted analysis (odds ratio, 1.31; 95% CI, 1.11 to 1.55; P=.002). CONCLUSION: This large cross-sectional study confirms an association between migraine and vasomotor symptoms. Migraine also was associated with hypertension, potentially providing a link with cardiovascular disease risk. Given the high prevalence of migraine in women, this association may help identify those at risk for more severe menopause symptoms.