Association Between Reproductive Aging In Women And Cardiovascular Disease

Cardiovascular disease(CVD)is the leading cause of morbidity and mortality worldwide.The incidence rate of female CVD tends to be younger.The proportion of young and middle-aged female CVD inpatients under 55 years old increased significantly,and the fatality rate from cardiovascular events in young and middle-aged women is even higher than that of man of the same age.Atherosclerosis is the pathologic foundation in CVD,which is a progressive process.It usually takes a long time from initial pathological lesion to the occurrence of clinical manifestation.Along with the development of globalization and the prolonged human life expectancy,the burden of CVD in women will increase accordingly.Therefore,it is very important to pay more attention to the prevention of female CVD in order to improve female overall health and reduce female CVD burden worldwide,especially in low-and middle-income countries.Reproductive aging is a fundamental biological event during a women’s life,of which essence is ovarian failure.Menopause is not only the beginning sign of female reproductive aging but also a marker of somatic aging in women.The CVD risk of premenopausal women is significantly lower than that of men at the same age due to protective effect of high level of endogenous estrogen for women,while the incidence risk of CVD is obviously increased in postmenopausal women.Because women spent about one-third of their life in postmenopausal stage,menopausal transition is a critical period during one women’s life,which has an important effect on women’s health.Meanwhile,it also provides a unique window of opportunity to prevent future health problems in women.It is important to study the association between female reproductive aging and CVD,so as to reduce the health impact resulting from menopause,and thereby improve health condition as well as quality of life in postmenopausal women.ObjectivesThe aims of the study are: through using the baseline and follow-up data of female community residents from a population-based prospective cohort study,to analyze the relationship of female reproductive aging with the risk of death and cardiovascular events,and also to analyze the association between female reproductive aging and subclinical carotid atherosclerosis,as well as to analyze the association between female reproductive aging and cardiovascular risk factors;and thus to provide evidence for prevention and control of female CVD.1.To study the association between signs of female reproductive aging,such as menopause,age at menopause,as well as menopause staging,and the risk of death and cardiovascular events.2.To study the association between signs of female reproductive aging,such as menopause,age at menopause,as well as menopause staging,and subclinical carotid artery atherosclerosis,including plaque and intima-media thickening.3.To study the relationship of premenopausal cardiovascular risk factors levels and abnormal status with age at menopause.MethodsThis study was a population-based prospective cohort study.The data were based on baseline survey and follow-up visits of female residents in Beijing cohort as a part of Chinese Multi-Provincial Cohort Study(CMCS).The baseline study was performed in 1992.Subsequently,three face-to-face onsite investigations were carried out in 2002,2007 and2012,respectively.During three site follow-up,carotid artery ultrasonography was added to be conducted in one community residents.The registration form for coronary heart disease(CHD),stroke,and all-cause death was used to register cardiovascular events or death events.The subjects were followed up every one to two years.Cardiovascular events and death events were reported by the staff of health station at primary level,and the registration forms were verified by hospital records or death certificates.Baseline study and follow-up visits used questionnaire survey,physical examination and laboratory examination to obtain personal information,demographic information,smoking history,height,weight,waist circumference,systolic blood pressure,diastolic blood pressure,fasting blood glucose,serum total cholesterol(TC),triglyceride,low density lipoprotein cholesterol(LDL-C)and high density lipoprotein cholesterol.Age at menopause was categorized as: < 40 years(premature menopause),40-44 years(early menopause),45-49 years(relatively early menopause),50-51 years(normal menopause;reference),52-53 years(relatively late menopause),and ≥54 years(late menopause).Cox regression model with time-varying coefficients,restricted cubic spline model and multinomial logistic regression model were used for statistical analysis.The covariates in multivariate models were adjusted differently according to different analysis,which included baseline age,cardiovascular risk factors at baseline level or time-varying status,time-varying menopause,age at menopause,oral estrogen due to menopause,etc.The hazard ratio(HR)and 95% confidence interval(CI)were calculated by Cox regression model,and the relative odds ratio(ROR)and 95% CI were calculated by multinomial logistic regression model.Results1.The first part of the results: Of 2116 female residents in CMCS Beijing cohort who participated in the baseline survey of 1992,a total of 2104 women were followed up by the end of 2018 and eligible for final analysis.The mean age at baseline was 45.2 ± 7.8 years.During the follow-up period,124 died and 196 had an incident CVD event(33 fatal CVD and 163 non-fatal CVD).Among women who had CVD events,84 had CHD and 117 had stroke(98 with ischemic stroke and 22 with hemorrhagic stroke).In the fully adjusted Cox regression model with time-varying coefficients,compared with women who had normal menopause,women with early menopause had a higher risk of ischemic stroke(HR=2.16,95%CI: 1.04-4.51;P=0.04),and women with relatively early menopause had a higher risk of death(HR=1.99,95%CI: 1.24-3.21;P=0.005)as well as a higher risk of ischemic stroke(HR=2.05,95%CI: 1.15-3.63;P=0.01),but no significant difference on risk of death or cardiovascular events between women with normal menopause and women with late or relatively late menopause,after adjusted for time-varying menopause,oral estrogen due to menopause,time-varying cardiovascular risk factors,baseline age,family history of CVD,and white blood cell count.In the analysis of the combined effect of age at menopause and cardiovascular risk factors,compared with women who had menopause at age 50-51 years and optimal levels of cardiovascular risk factors at baseline,women who had menopause before age 50 years and at least one abnormal risk factor at baseline had a higher risk of death(HR=11.33,95%CI: 1.54-83.17;P=0.02),CVD(HR=3.87,95%CI: 1.54-9.74;P=0.004),ischemic CVD(HR = 4.35,95% CI: 1.56-12.11;P = 0.005),CHD(HR=7.96,95%CI: 1.07-59.44;P=0.04),and stroke(HR=2.95,95%CI: 1.04-8.38;P=0.04).2.The second part of the results: A total of 879 female residents in CMCS Beijing cohort who had at least one carotid ultrasonography result were selected into the study.The average age at baseline was 48.6 ± 8.1 years.During the follow-up period,573 women(65.2%)were detected carotid plaque and 430 women(48.9%)were detected increased intima-media thickness(IMT).After adjustment for age at baseline,age at menopause,use of oral estrogen due to menopause,and time-varying cardiovascular risk factors in Cox regression model,time-varying menopause was significantly associated with risk of developing carotid plaque(HR=1.93,95%CI: 1.05-3.54;P=0.03).Subgroup analysis according to TC(< 5.17mmol/L,5.17 ～ 6.2mmol/L,≥6.2mmol/L)or LDL-C(<3.37mmol/L,3.37 ～ 4.14mmol/L,≥4.14mmol/L)at baseline showed that the risk of new detection of increased IMT in women with premature menopause was 4.86 times(HR=4.86,95%CI: 1.36-17.36,P=0.01)higher than women with normal menopause when their TC level at 5.17 to 6.2 mmol/L,and the risk of new detection of increased IMT in women with premature menopause was 5.19 times(HR=5.19,95%CI: 1.18-22.81,P=0.03)higher than women with normal menopause when their LDL-C level at 3.37 to 4.14 mmol/L.3.The third part of the results: A total of 1433 premenopausal women residents in CMCS Beijing cohort who had complete data on cardiovascular risk factors at the baseline survey in 1992 were selected as subjects for final analysis.The mean age at baseline was40.8 ± 4.5 years.In multinomial logistic regression model,compared with normal weight women,overweight women had higher risk of menopause at 45-49 years(ROR=1.76,95%CI: 1.25-2.47,P=0.001)and also menopause at >51 years(ROR=1.70,95%CI:1.21-2.39,P=0.002);compared with normal weight women without central obesity,overweight women with central obesity had higher risk of menopause at <45 years(ROR=3.13,95%CI: 1.20-8.13,P=0.02),and menopause at 45-49 years(ROR=2.76,95%CI:1.71-4.46,P<0.001),as well as menopause at >51 years(ROR=1.82,95%CI: 1.13-2.93,P=0.01),after adjusted for age and cardiovascular risk factors at baseline.Conclusions1.Early menopause increases the risk of death and ischemic stroke in women;furthermore,early menopause combines by abnormal cardiovascular risk factors to increase the risk of death and cardiovascular events in women.2.Menopausal women,irrespective of age at menopause,have an increased risk of carotid plaque;and premature menopause increases risk of increased IMT among women with moderately elevated serum cholesterol.3.Age at menopause in overweight women is later than that in normal weight women.Overweight women with central obesity have higher risk of not only early menopause but also late menopause than normal weight women without central obesity.