The Association of Early Menopause with Increased Risk of Acute Myocardial Infarction: The INTERHEART China Study

Abstract

Background and Aim:

Little is known about whether early menopause in Chinese ethnicity is associated with acute myocardial infarction (AMI). We aimed to determine whether self-reported early menopause (either surgical or natural menopause at an age <50 year) was associated with first AMI in Chinese women.

Methods:

The study population was from the INTERHEART China Study, part of the INTERHEART global study. INTERHEART global study was a standardized case–control study that was designed to evaluate the risk factors for first AMI among 52 countries. Data for demographic factors, education, income, and cardiovascular risk factors were obtained by structured questionnaires. A standard set of questions that inquired about menstrual history was included in the interview.

Results:

Of the 1,771 Chinese women, 1,563 (88.3%) reported either natural or surgical menopause. In univariate logistic regression model, women with early menopause had higher risk of AMI (odds ratio [OR]: 1.51; 95% confidence interval [CI]: 1.23–1.87). After controlling for age, birth control measures, type of menopause, and other traditional risk factors (including waist/hip ratio, lifestyle factors, history of hypertension and diabetes, psychosocial factors, and apolipoprotein B [ApoB]/A1 [ApoA1]), the risk for AMI remained (OR: 1.36; 95% CI: 1.03–1.79). The population attributable risk for AMI in women with early menopause at <50 years was 10.1% (95% CI: 4.0–20.0) compared with women who had menopause at ≥50 years.

Conclusion:

Early menopause is associated with increased risk of AMI in Chinese women, independent of other traditional coronary heart disease risk factors.

Introduction

Cardiovascular disease (CVD) has been a major cause of death and global disability-adjusted life years for both genders combined in all regions of the world.¹ The high burdens of CVD worldwide are generally attributed to the increasing incidence of atherosclerotic diseases, probably due to urbanization and concomitant various higher cardiovascular risk factors.² INTERHEART, a large, international, standardized, case–control study, has identified potentially modifiable risk factors associated with myocardial infarction for both genders in 52 countries among 15,152 cases and 14,280 controls.³

Recent data from CVD statistics 2021 in European Society of Cardiology reported that females accounted for fewer new cases of ischemic heart disease compared with males (2.6 million in females vs. 3.2 million in males), but the number of deaths for CVD in females is higher compared with males (2.2 million in females vs. 1.9 million in males).⁴ Therefore, the early detection of women at high risk of CVD and modification of some aspects of lifestyle and medical therapy are of tremendous public health importance, potentially reducing the risk of an acute myocardial infarction (AMI) in females.⁵

Current CVD risk estimation systems are available, including Framingham 10-year risk scoring,⁶ SCORE (Systematic COronary Risk Evaluation),⁷ ASSIGN (CVD risk estimation model from the Scottish Intercollegiate Guidelines Network),⁸ QRISK3,⁹ PROCAM (Prospective Cardiovascular Münster),¹⁰ CUORE Project predictive equation,¹¹ ASCVD (Atherosclerotic CVD) Pooled Cohort equations,¹² Globorisk,¹³ and INTERHEART Modifiable Risk Score (IHMRS).¹⁴ However, reproductive history in AMI event rates among women population was inadequately reflected. Up to now, evidence have been demonstrated that premature menopause was a risk factor for CVD mainly in white populations and European descendants (Australia, Scandinavia, the U.S., Japan, and the UK).¹⁵ Whether early menopause in Chinese ethnicity is associated with AMI is not known.

In the current study, we used INTERHEART China Study to investigate association between early menopause and first AMI in Chinese women population, to evaluate the interactions between early menopause and other CVD risk factors to AMI, and further to evaluate whether this association of early menopause with AMI varies in different regions in China. Our study also estimated population attributable risk (PAR) of first AMI for early menopause in Chinese women.

Methods

Study participants

The current study used INTERHEART China Study, which is a part of the standardized case–control INTERHEART global study for the association of risk factors to AMI. Five thousand eight hundred fifty participants, including 2,932 cases of first AMI and 2,918 age- and sex-matched controls were recruited between February 1999 and March 2003 from 26 regional hospitals in 19 northern and 7 southern centers in mainland China.^3,16 Of the 5,850 participants, 1,771 (30.3%) were women, among whom there were 875 cases and 896 controls, and 208 (11.7%) were excluded due to missing data on age at menopause. The remaining 1,563 (88.3%) female participants (784 cases and 779 controls) who reported either natural or surgical menopause were evaluated for the association of menopause with AMI, and a total of 326 (41.6%) of 784 cases and 252 (32.3%) of 779 controls had early menopause. Detailed methods of INTERHEART China Study were described previously.¹⁷ Patients admitted to coronary care unit or equivalent cardiology ward and diagnosed with first incident AMI were enrolled within 24 hours of onset of symptoms.

All AMI patients were selected with diagnosis by clinical symptoms and electrocardiogram presenting significant changes, including new pathological Q waves or 1 mm ST elevation in any two or more contiguous limb leads, or a new left bundle branch block or new persistent ST-T wave changes diagnostic of a non-Q wave MI, or increased concentration of troponin in blood samples as defined in INTERHEART study protocol.¹⁸ Cases presenting with cardiogenic shock or history of any major chronic disease were excluded. At least one age-(±5 years) and sex-matched control (without a history of CVD) was recruited per case. These controls were selected from the community or from the recruiting hospital. A community-based control was either a visitor or a relative of a patient from a noncardiac ward or an unrelated visitor of another cardiac patient. A hospital-based control was defined as those at the same center with illness not obviously related to coronary heart disease or its risk factors. Cases were excluded if they had unstable angina, if an AMI could not be confirmed, if they had a history of a previous AMI, or if they had insufficient data.

The Ethics Committee of Beijing Hypertension League Institute approved the study and all participants provided informed consent with the principles outlined in the Declaration of Helsinki.

Procedures

Participants who consented to the study completed a structured questionnaire, attended a health examination, and had a venous blood sample taken. Information about demographic factors, socioeconomic status, lifestyle (smoking, leisure time, physical activity, and dietary patterns), personal and family history of CVD, hypertension, and diabetes mellitus were obtained. Hypertension and diabetes were defined by self-report of being previously diagnosed for these diseases. Height, weight, waist, and hip circumferences, and heart rate were determined by a standard protocol. Blood samples were drawn from every individual, and shipped to a central blood storage site at the Beijing Hypertension League Institute where samples were stored at −160°C in liquid nitrogen.

Plasma concentrations of triglyceride, total cholesterol, high-density lipoprotein cholesterol, apolipoproteins B (ApoB) and A1 (ApoA1) were analyzed by Roche/Hitachi 911 analyzer (Roche Diagnostics, Mannheim, Germany), Analytic techniques have been described in detail previously.³

Definitions of risk factors

The structured questionnaires and physical examinations were administered by trained personnel in a standardized manner.³ As part of the structured questionnaire, a standard set of questions, designed specifically for women, were inquired about history of menstruation. Age at menopause was determined with the questions: “Have your menstrual periods stopped permanently?” and “At what age did they stop (years)?” Type of menopause was determined with the question: “Why did they stop?” For this question, possible responses are “Menopause,” “Hysterectomy,” “Radiation,” and “Other.” Birth control measures were determined with two questions: “Have you ever used birth control pills or had birth control depot injections?” and “Are you currently using them?” For those who reported ever used birth control measures, questions: “Age when began?,” “Brand?,” and “For how many years?” were added. For those who currently not using, stopped age was obtained.

Hormone replacement therapy (HRT) was determined with the questions: “Have you ever used female hormone replacements?” For those who answered “Yes,” “several additional questions were applied to” “How long?,” “Are you still taking them?,” “Age stopped?,” “Which type of replacement have you used the most?” According to the China Kadoorie Biobank, the mean age at natural menopause standard deviation (SD) among 87,349 postmenopausal women was 48.7 (4.3) years.¹⁹ For our study, early menopause was defined as self-reported either natural or surgical menopause at age younger than 50 years.

Statistical analyses

We conducted univariate analyses using standard measures of central tendency and dispersion. Subgroups were compared using t-tests for continuous variables and χ² tests for categorical variables to understand the association of early menopause and other exposures of interest with AMI.

To determine the degree of association between the AMI and early menopause while adjusting for the covariates at various levels, unconditional logistic regression models were chosen over conditional models (e.g., matched analysis) because the results were approximately similar with both models, and undertaking a strict matched analysis would mean relevant loss of information because of the exclusion of unmatched cases and controls.³ Initial models were adjusted for age and waist/hip ratio (WHR), but subsequent models were adjusted for other established lifestyle risk factors, psychosocial factors, ApoB/ApoA1, birth control measures, and type of menopause. Interactions between age at menopause and other CVD risk factors (e.g., smoking, alcohol intake) were tested by logistic regression model. PAR and 95% confidence interval (CI) were calculated for early menopause in this study, using a method based on unconditional logistic regression.²⁰

For estimating variance, the reader is referred to Benichou and Gail.²¹ CI calculations were based on this method using a logit transformation approach. The PARs presented were adjusted for confounders in a similar manner to the corresponding logistic regression models for odds ratio (OR) estimates. PAR estimates were calculated using the Interactive Risk Attributable Program (IRAP) software (US National Cancer Institute, 2002).²² PAR = [Pr(E) (R-1)]/[Pr(E)(R-1)+1], where Pr(E) is probability of exposure to the risk factors and R is the relative risk of the disease in exposed versus unexposed subjects.³ The PAR of any given risk factor for AMI is an estimate of the portion of AMI that can be explained by the risk factor in the specified population.³ Statistical analyses were produced using R 2.15.0 software.^23,24 All tests were two sided and a p value of <0.05 was considered significant.

Results

The baseline characteristics of 1,771 (30.3%) female participants of controls and cases in INTERHEART China Study are shown in Table 1. The mean (SD) age menopause in controls and cases were 49.9 (SD = 2.7) and 49.5 (SD = 2.9) years (p = 0.002). Two hundred fifty-two (32.3%) of 779 in controls and 326 (41.6%) of 784 AMI patients had early menopause. Among AMI cases, there were more smoking (p < 0.001), history of hypertension (p < 0.001), history of diabetes (p < 0.001), depression (p < 0.001), moderate financial stress (p = 0.017), major life events (p < 0.001), and early menopause (p < 0.001), while less daily consumption of fruits and vegetables (p = 0.004); higher ApoB/ApoA1 levels (p < 0.001), while less SBP, and earlier age at menopause (p = 0.002) compared with controls. However, AMI cases and controls had similar BMI, WHR, and similar percentage of regular alcohol intake, physical activity, of stress at home and work, and of birth control measures and of natural menopause. The distribution of age at menopause in women in INTERHEART China Study is shown in Supplementary Figure S1.

Table 1.

Baseline Characteristics of Women in INTERHEART China Study

	Controls	Cases	p
No. of individuals	896	875
Age^a (years)	63.7 (9.0)	65.9 (9.0)	<0.001
BMI^a (kg/m²)	24.6 (3.0)	24.7 (3.5)	0.640
WHR^a	0.86 (0.08)	0.87 (0.09)	0.516
SBP^a (mmHg)	128.9 (18.7)	123.5 (21.4)	<0.001
Current and former smoking (%)	4.6	13.7	<0.001
Regular alcohol intake (%)	1.5	1.1	0.715
Physical activity (%)	6.2	4.2	0.073
Daily consumption of fruits and vegetables (%)	78.3	72.4	0.004
History of hypertension (%)	26.9	46.1	<0.001
History of diabetes (%)	3.8	17.7	<0.001
Depression (%)	8.4	20.8	< 0.001
Moderate financial stress (%)	44.7	51.5	0.017
Stress at home and work (%)	91.6	93.5	0.167
Major life events (%)	12.0	21.1	<0.001
ApoB/ApoA1^a	0.6 (0.18)	0.70 (0.24)	<0.001
Age at menopause^a (years)	49.9 (2.7)	49.5 (2.9)	0.002
Early menopause (%)	32.3	41.6	<0.001
Birth control measures (%)	4.3	5.1	0.598
Natural menopause (%)	98.5	99.1	0.279

Data are means (SD).

ApoB/ApoA1, apolipoproteinsB/A1; BMI, body mass index; SBP, systolic blood pressure; SD, standard deviation; WHR, waist/hip ratio.

The percentage of age at menopause by age group, menopause types, and hormone used in INTERHEART China Study are shown in Supplementary Figures S2–S4.

Association of early menopause and AMI

Age at menopause was categorized into two groups: <50 years of age, and ≥50 years of age, menopause at age ≥50 years was considered the reference category. Table 2 showed the age-adjusted and several multivariable-adjusted ORs with 95% CI for AMI were in relation to early menopause. Compared with women who had menopause at ≥50 years, risk of AMI was increased among women with early menopause at <50 years. The age- and WHR-adjusted ORs (Model¹) for early menopause was 1.51 (1.23–1.87). After adjustment for established lifestyle risk factors (Model²) and psychosocial factors (Model³), the effect sizes of the associations were attenuated slightly (1.44 [1.15–1.80] for Model² and 1.42 [1.13–1.79] for Model³). Moreover, the effect remained significant after controlling for ApoB/ApoA1 (Model⁴), type of menopause and birth control measures (Model⁵) (1.37 [1.04–1.79] for Model⁴ and 1.36 [1.03–1.79] for Model⁵). Among women, the calculated PAR of first AMI for early menopause at <50 years was 10.1% (95% CI: 4.0–20.0) compared with women who had menopause at ≥50 years.

Table 2.

Association Between Early Menopause and Risk of Acute Myocardial Infarction

Age at menopause	Cases (n)	Controls (n)	Model¹	Model²	Model³	Model⁵	Model⁴
≥50 Years old	458	527	Reference	Reference	Reference	Reference	Reference
<50 Years old	326	252	1.51 (1.23–1.87)	1.44 (1.15–1.80)	1.42 (1.13–1.79)	1.37 (1.04–1.79)	1.36 (1.03–1.79)

Model¹ adjusted for age, WHR.

Model² adjusted for Model¹+smoking, drinking, dietary, physical activity, hypertension, diabetes.

Model³ adjusted for Model²+depression, stress at home and work, financial stress, major life events.

Model⁴ adjusted for Model³+ApoB/ApoA1.

Model⁵ adjusted for Model⁴+type of menopause, birth control measures.

We investigated the association between age at menopause and age of first AMI. No difference was detected between subgroups (heterogeneity p value is 0.192) (Data not shown). Of 1,563 participants who reported either natural or surgical menopause in the INTERHEART China Study, 98.5% (1,540) experienced natural menopause, 1.1% (17) experienced surgical menopause (hysterectomy), 0.1% (2) experienced radiation, and 0.3% (4) were missing data. As shown in Supplementary Table S2, after excluding the surgical menopause (hysterectomy) and radiation, early menopause remained as a significant association with AMI, and early menopause indeed increased the risk of AMI. We tested the potential interaction of early menopause with established risk factors for AMI, and failed to detect any significant interaction between age at menopause and other conventional risk factors (Supplementary Table S3).

Discussion

The important finding of INTERHEART China Study is that early menopause is a risk factor for first AMI independent of traditional cardiovascular risk factors, and early menopause constitutes 10.1% of the PAR of first AMI. The results strongly suggest that the age of menopause should be considered within the context of a wide assortment of AMI risk factors.

In INTERHEART China Study, we found that early menopause at <50 years was associated with an increased risk of first AMI in Chinese women when menopause at ≥50 years was used as the reference group, which is consistent with the findings from recent pooled studies.^15,25 The association remained significant after adjusting for well-documented traditional CVD risk factors in a wide range of potential confounders, and the association of early natural menopause with AMI remained unchanged when excluding the women with surgical menopause as well as women, including all types of menopause. Additionally, interaction analyses showed that the association was not modified by other risk factors. A high proportion of previous studies conducted in Europeans indicated that the risk of CVD was increased in women with early menopause. A case–control study from Polish population showed that early menopause was a strong determinant of coronary artery disease (OR = 2.82, 95% CI: 1.91–4.19).²⁶

Another study, including 19,309 postmenopausal women from Norwegian population, reported a nearly 60% reduction in ischemic heart disease mortality in women with a late menopause ≥53 years compared with women <44 years of age at menopause during 29 years of follow-up.²⁷ The evidence from study conducted by Hu et al. (35,616 participants, Nurses' Health Study),²⁸ Løkkegard et al. (10,533 participants, Danish nurses),²⁹ Wellons et al. (2,509 women, including 987 white, 331 Chinese, 641 black, and 550 Hispanic, Multi-Ethnic Study of Atherosclerosis)⁵ showed the risk and 95% CI of coronary heart disease for women whose onset of menopause was younger than 45 years when menopause at ≥45 years was used as the reference group, were 1.53 (0.94–2.47), 2.2 (1.0–4.9), and 2.08 (1.17–3.70) after adjusting for vascular risk factors, respectively.

Recent results from western populations that showed the risk and 95% CI of coronary heart disease for women with premature menopause at age <40 years, early menopause 40–44 years, and relatively early menopause 45–49 years, menopause 52–54 years, and menopause ≥55 years when menopause at 50–51 years was used as the reference group, were 1.52 (1.34–1.74), 1.30 (1.20–1.41), 1.13 (1.06–1.20), 0.96 (0.90–1.02), 0.90 (0.85–0.97), and 0.59 (0.53–0.65) after adjusting for vascular risk factors, respectively.¹⁵ Growing evidence showed a similar trend that the earlier the onset of menopause, the higher the risk of coronary heart disease. Similar associations were also observed between types of surgical menopause.²⁵ Given our small sample size for surgical menopause, we did not detect its association. In addition, most participants were not aware of whether HRT was used or not, and in INTERHEART China there were 14 female participants who had ever used HRT, and they belonged to the group of natural menopause. Due to the small sample size, we could not analyze the effect of HRT on early menopause.

The results of INTERHEART China are in accord with previous study,²⁵ and early natural menopause indeed increased the risk of AMI after adjusting for well-documented traditional AMI risk factors. In the INTERHEART China Study, we tested the association between early menopause and age of first AMI, but no difference was detected between age of first AMI by age at menopause (p = 0.192) (Data not shown).

We did not detect the interactions between early menopause and other established risk factors, except for borderline significant interaction with WHR (p = 0.056), but we observed that smoking appeared to play a significant role in the development of female AMI (Table 1) and early menopause (Supplementary Table S1). Due to the relative low percentage of female smoking in Chinese female participants, current and former smokers were analyzed together. Around 11.5% of controls with early menopause smoked, compared with 6.3% of controls with menopause at ≥50 years (Supplementary Table S1), indicating that a higher tobacco exposure may be associated with early menopause. Special attention should be paid to the rising prevalence of female smoking, especially in low-income and middle-income countries.

Whether the relationship of smoking with AMI is modified by age at menopause in women remains to be investigated. The evidence from a Dutch population-based cohort, including 5,544 women at the age of 49–70 years who had experienced natural menopause showed that the rate ratio (1.41) of onset of menopause was increased among women who smoked during menopause.³⁰ Another study of 2,123 postmenopausal women participating in the Oslo Health Study confirmed current smoking was significantly associated with early menopause (OR = 1.59).³¹ Animal studies reported that exposure to polycyclic aromatic hydrocarbons, contaminants commonly detected in cigarette smoke, can cause extensive destruction of primordial follicles.³²

The mechanism by which early menopause increased the risk of AMI may be associated with smoking habit, abdominal obesity (higher WHR), and abnormal lipid levels. Several other menopause-associated factors, such as: insulin resistance, peripheral vasoconstriction, prothrombotic, and proinflammatory state, could also explain the increased risk of CVD.³³ Therefore, a series of mechanisms may explain why early menopause leads to increased risk of AMI.

The study demonstrated the growing importance of a nontraditional risk factor, early age at menopause, for AMI. In INTERHEART China Study, early menopause accounts for 10.1% of the risk of AMI among postmenopausal women. Such effect of PAR is comparable to PAR of diabetes in Chinese.¹⁷ Attention should be paid to early menopause, as a risk for AMI, especially accompanied with a rise in smoking among women, a harbinger of future increase in coronary heart disease.

Strengths

Our study has several strengths. First, the case–control study gains several advantages, making it possible efficient enrollment of large numbers of female cases and greater statistical power.³ Second, our study enrolled cases specifically targeted for first AMI, instead of recurrent cases or other types of CVDs, to avoid confounding that altered lifestyles or risk factor levels after an AMI. Third, our study included comprehensive well-documented established risk factor profile, including apolipoproteins (ApoB/A1 ratio). Fourth, the large number of cases and controls from 26 regional hospitals in 19 northern and 7 southern Chinese centers in China are well represented by Chinese females. Above all, INTERHEART China Study confirmed an association between early menopause and first AMI even though early menopause was defined at a relatively higher age than many prior studies.

Limitations

Our study has several potential limitations. First, a case–control design is potentially open to confounding if there is differential ascertainment of risk factors between cases and controls.³ Second, a retrospective design has the disadvantage of assessing the exposure variable, such as age at menopause, which may not be recalled precisely. Third, we could not detect the association between early surgical menopause and the risk of developing a first AMI due to the small number of surgical menopause individuals in our study. Further studies with larger sample size could clarify the relationship.

Conclusion

In conclusion, early menopause is an independent risk factor for AMI for Chinese females with PAR of 10.1%. Special attention should be paid to those experienced early menopause may have significant public health relevance for the prevention of AMI in Chinese women.

Footnotes

Authors' Contributions

T.L. contributed to data acquisition, analysis and interpretation, and drafted and critically revised the article. X.L. contributed to conception and design, data acquisition, and analysis. W.Z., H.G., and L.L. contributed to data acquisition, and analysis. X.W. contributed to conception and design, funding acquisition, data acquisition, analysis, and critically revised the article. All authors gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the Beijing Hypertension League Institute and the National Human Genetic Resources Sharing Service Platform, Beijing Innovation Center (Grant Number YCZYPT [2017]01–2).

Supplementary Material

Supplementary Figure S1

Supplementary Figure S2

Supplementary Figure S3

Supplementary Figure S4

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

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