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Abstract

Background

The global burden and temporal trends of atherosclerotic cardiovascular disease (ASCVD) stratified by menopausal status have not been comprehensively described.

Methods

Age-standardized incidence rates (ASIR), prevalence rates (ASPR), disability-adjusted life year rates (ASDALYR), and death rates (ASDR) for ASCVD, including ischemic heart disease (IHD), ischemic stroke (IS), and lower extremity peripheral artery disease (LEPAD), were estimated among pre- and post-menopausal women from 1990 to 2021 using data from the Global Burden of Disease Study 2021. Temporal trends were quantified using average annual percent change, and the population attribution fractions were calculated for established ASCVD risk factors. Projections to 2041 were generated using the Nordpred model.

Results

In 2021, the highest IHD burden was observed in low-middle socio-demographic index (SDI) regions, whereas the highest LEPAD burden occurred in high SDI regions among both pre- and post-menopausal women. Among premenopausal women, ASIR and ASPR for IS demonstrated a negative correlation with SDI level. Between 1990 and 2021, premenopausal women exhibited increases in IHD ASIR (12.86%) and ASPR (11.43%), accompanied by reductions in ASDALYR (23.97%) and ASDR (24.35%). In contrast, postmenopausal women experienced a modest increase in ASPR (4.14%) along with declines in ASIR (10.61%), ASDALYR (34.99%), and ASDR (37.09%). The contribution of specific risk factors varied by menopausal status: elevated low-density lipoprotein cholesterol, systolic blood pressure, and body mass index were predominant among premenopausal women, whereas elevated fasting glucose and kidney dysfunction contributed more substantially among postmenopausal women. Projections to 2041 indicate continued increases in ASCVD incidence and prevalence numbers, particularly among postmenopausal women.

Conclusions

The burden of ASCVD varies significantly by menopausal status and across socio-demographic regions. Age-specific and regionally targeted screening, prevention, and resource allocation strategies are warranted to address the projected rise in ASCVD among women.

Keywords

atherosclerotic cardiovascular disease global burden of disease postmenopausal women premenopausal women

Introduction

Atherosclerotic cardiovascular diseases (ASCVDs), including ischemic heart disease (IHD), ischemic stroke (IS), and lower extremity peripheral arterial disease (LEPAD), represent the leading cause of mortality among women globally. The incidence of ASCVD continues to increase, largely driven by the growing prevalence of obesity and cardiometabolic conditions, thereby contributing substantially to the global disease burden.¹ Among ASCVD subtypes, IHD remains the most prevalent and continues to account for the highest mortality. IS and LEPAD also impose considerable clinical and public health burdens, further exacerbating the overall cardiovascular disease landscape.^2,3 Although ASCVD has traditionally been viewed as a condition primarily affecting older individuals, recent evidence has revealed significant disparities in disease burden across genders and age groups.^4–6

Estrogen has been widely recognized for its cardioprotective properties, and its decline during menopausal transition has been strongly associated with increased vulnerability to cardiovascular diseases.⁷ Prior to menopause, women generally experience lower rates of ASCVD compared to men,^8,9 a disparity attributed in part to the protective influence of endogenous estrogen. However, this advantage diminishes post-menopause. Notably, recent epidemiological trends demonstrate an increasing prevalence of ASCVD among women younger than 40 years of age, highlighting the emergence of a significant public health concern that warrants timely and targeted intervention.⁴

Despite well-established biological differences in ASCVD risk between pre- and post-menopausal women, the global burden of ASCVD in these distinct populations remains insufficiently characterized. Most epidemiological investigations assessed women as a single cohort, without stratification by menopausal status, thereby overlooking critical disparities that could guide the development of targeted prevention and intervention strategies. The marked increase in ASCVD risk following menopause, in conjunction with demographic transitions and an aging global population, highlights the necessity for focused public health initiatives addressing the specific cardiovascular health needs of postmenopausal women.

No study has specifically assessed the global burden of ASCVD stratified by menopausal status or examined its secular trends and geographic variations across regions and countries with differing levels of socioeconomic development. The lack of detailed information may impede the formulation of effective prevention strategies and the appropriate allocation of healthcare resources to address this escalating concern. A comprehensive evaluation of the global distribution and temporal trends of ASCVD burden, with particular attention to menopausal status, remained critical for guiding the development and implementation of targeted public health interventions.

This study aimed to elucidate global epidemiological patterns of ASCVD in 2021 and to quantify long-term trends in age-standardized incidence (ASIR), prevalence rates (ASPR), disability-adjusted life year rates (ASDALYR), and death rates (ASDR) from 1990 to 2021, stratified by menopausal status, based on data from the Global Burden of Disease (GBD) Study 2021. Furthermore, population-attributable fractions (PAF) of ASCVD-related deaths and disability-adjusted life years (DALYs) associated with modifiable risk factors were estimated to determine the primary contributors to disease burden among pre- and post-menopausal women. Projections of ASCVD incidence, prevalence, DALYs, and mortality over the subsequent two decades were generated to inform future strategies for prevention, treatment, and rehabilitation.

Methods

Overview of the Data Sources

The GBD Study 2021 provided a systematic scientific estimation of publicly available, published, and contributed data with enhanced method performance and standardization on incidence, prevalence, DALYs, and mortality for 371 diseases, injuries, and impairments across 204 countries and territories from 1990 to 2021, disaggregated by age, sex, and location. Data sources included censuses, household surveys, civil registration systems, vital statistics, disease registries, and other relevant datasets. Mortality data were analyzed using the Cause of Death Ensemble Model to generate the most accurate estimates of cause-specific deaths. DALYs were calculated using DisMod-MR 2.1, a Bayesian meta-regression modeling tool designed to ensure internal consistency among epidemiological parameters. For geographic analysis, countries and territories were grouped into 21 super-regions based on epidemiological profiles and geographical proximity. Additionally, the socio-demographic index (SDI) was employed to categorize countries according to socio-economic development levels.

Estimation of ASCVD Burden in pre-and post-Menopausal Women

As IHD, IS, and LEPAD represent the primary components of ASCVD, annual data for each condition were assessed separately. To ensure consistency in the estimation and interpretation of ASCVD burden by menopausal status, individuals aged 15–49 years were categorized as pre-menopausal, and those aged 50 years and older as post-menopausal. The age threshold of 50 years was selected based on the global average age range for natural menopause (45-55 years), with 50 years representing the midpoint commonly used in epidemiological research.^10,11 Data on incidence, prevalence, DALYs, and death rates for IHD, IS, and LEPAD were extracted by region from the 2021 GBD study. All relevant data were retrieved from the following website: https://vizhub.healthdat.org/gbd-results/.

Estimation of Attributable Risk Factors for ASCVD in pre- and post-Menopausal Women

The GBD 2021 study reported 88 risk factors for ASCVD, including both specific and aggregated categories, assessed across global, regional, and national levels in 204 countries and territories. Metabolic, behavioral, and environmental determinants were identified as contributors to ASCVD risk. A total of 27 subcategories of risk factors were associated with ASCVD according to the 2021 GBD classification. The GBD framework defines a theoretical minimum risk exposure level, representing the level of exposure at which the risk for adverse health outcomes is minimized. A comprehensive list of the risk factors and corresponding definitions is provided in the Appendix (Additional files 1: Table S1).

Prediction of Incidence, Prevalence, DALYs, and Mortality Associated with ASCVD in pre- and post-Menopausal Women

The Nordpred prediction model, which is based on the age–period–cohort (APC) framework, has been shown to be effective in forecasting future trends in the incidence, prevalence, DALYs, and mortality. This model accounts for temporal trends and demographic variables, including shifts in population structure, disease progression over time, and generational effects.¹² The Nordpred age-period-cohort model was utilized to project the incidence, prevalence, DALYs, and mortality related to ASCVD from 2022 to 2041. The Nordpred software package in the R language (version 4.3.2) enabled incorporation of dynamic changes in both disease incidence and population structure.¹³

Statistical Analysis

ASIR, ASPR, ASDALYR, and ASDR per 100,000 population, along with their 95% confidence intervals (CIs), were calculated for the period from 1990 to 2021 using estimates obtained from the GBD 2021 analytical tools website (https://vizhub.healthdata.org/gbdresults/). These calculations employed the world standard population as defined in GBD 2021, using the “epitools” package in R version 4.3.2.¹⁴ Descriptive analyses were conducted to characterize the burden of ASCVD, comparing ASIR, ASPR, ASDALYR, and ASDR between 1990 and 2021. The average annual percent change (AAPC) and corresponding 95% CI were computed to quantify the magnitude and direction of temporal trends. A Monte Carlo permutation method was used to assess statistical significance. An increasing trend was indicated by AAPC > 0 with a p value < 0.05; a decreasing trend was indicated by AAPC < 0 with a p value < 0.05; and a stable trend was inferred if the p-value was ≥ 0.05.

The ASCVD burden was also examined across 204 countries and territories. The relationships between the age-standardized rates and the SDI were evaluated using Spearman's rank correlation. PAF of ASCVD-related DALYs and deaths were assessed for various risk factors. Projections were conducted using the “Nordpred” package in R software.

All statistical analyses were performed using R software (version 4.3.2). A two-sided p-value < 0.05 was considered statistically significant.

Results

Global Burden of ASCVD among Premenopausal Women in 2021

In 2021, the estimated global number of cases among females included 108.97 million with IHD, 34.70 million with IS, and 76.17 million cases with LEPAD. Among these, 7.99% of IHD cases, 18.53% of IS cases, and 6.07% of LEPAD cases were observed in premenopausal women.

Regarding mortality, IHD represented the leading cause of ASCVD-related deaths among females, with an estimated 3.99 million deaths in 2021, followed by IS with 1.81 million and LEPAD with 34,447. Among these, 4.32% of IHD-related deaths, 1.14% of IS-related deaths, and 0.75% of LEPAD-related deaths occurred in premenopausal women.

In terms of DALYs, premenopausal women accounted for 11.87% of DALYs attributed to IHD, 6.06% of those attributed to IS, and 1.48% of those attributed to LEPAD (Additional files 1: Table S2).

Burden of ASCVD among pre- and post-Menopausal Women Across Locations in 2021

In 2021, the relationship between the sociodemographic index (SDI) and the ASIR, ASPR, ASDALYR, and ASDR for IHD in both pre- and post-menopausal women demonstrated an inverse U-shaped pattern. A greater IHD burden was observed in regions with low-middle SDI.

Among premenopausal women, the ASIR and ASPR for IS exhibited a negative correlation with SDI, with higher rates observed in low SDI regions. The relationship between SDI and both ASDALYR and ASDR for IS followed an inverse U-shaped distribution in this subgroup. In contrast, among postmenopausal women, the relationship between SDI and ASIR, ASPR, ASDALYR, and ASDR for IS displayed an irregular pattern, with higher IS burden observed in high-middle SDI regions.

Additionally, the ASIR and ASPR of LEPAD in both pre- and post-menopausal women demonstrated a positive correlation with SDI (p < 0.05). No statistically significant correlation was found between SDI and either ASDALYR or ASDR for LEPAD in premenopausal women (p > 0.05). In postmenopausal women, the relationship between SDI and both ASDALYR and ASDR for LEPAD followed an irregular pattern, with the highest values recorded in high SDI regions (Additional files 1: Table S3; Additional files 2: Figures S1–S5, Figure 1).

Figure 1.

Age-standardized rates of IHD burden by five SDI regions among pre- and post-menopausal women from 1990 to 2021. Abbreviations: ASCVD: Atherosclerotic cardiovascular disease; SDI: Socio-demographic index; IHD: Ischemic heart disease; DALYs: Disability-adjusted life years; ASR: Age-standardized rate.

At the regional level, the highest ASIR of IHD among premenopausal women was observed in North Africa and the Middle East. This region also exhibited the highest ASPR of IHD in both pre- and postmenopausal women. Oceania reported the highest ASDALYR and ASDR for IHD among premenopausal women. Among postmenopausal women, Central Asia reported the highest ASIR, ASDALYR, and ASDR for IHD (Additional files 1: Table S3; Additional files 2: Figures S6–S7).

Country-specific analyses indicated that Kuwait had the highest ASPR of IHD among premenopausal women (893.56 per 100,000 population), whereas Nauru reported the highest ASDR (58.63 per 100,000). Among postmenopausal women, Kuwait also recorded the highest ASPR (26,423.42 per 100,000), while Egypt reported the highest ASDR (2050.46 per 100,000). The burden of ASCVD across countries and regions for both pre- and post-menopausal women is presented in Tables S3 and S4 (Fig. 2; Additional file 2: Figures S8–S9).

Figure 2.

Age-standardized burden of IHD among pre- and post-menopausal women across 204 countries and territories in 2021. Abbreviations: IHD: Ischemic heart disease; DALYs: Disability-adjusted life years; ASIR: Age-standardized incidence rate; ASPR: Age-standardized prevalence rate; ASDALYsR: Age-standardized DALYs rate; ASDR: Age-standardized death rate.

Global Temporal Trends in ASCVD Burden (1990-2021): Patterns in pre- and post-Menopausal Women

Between 1990 and 2021, the global ASIR and ASPR of IHD among premenopausal women increased by 12.86% (from 58.65 to 66.19 per 100,000 population) and 11.43% (from 381.39 to 424.98 per 100,000 population), respectively. In contrast, the ASDALYR and ASDR for IHD in this population declined by 23.97% (from 567.39 to 431.37 per 100,000 population) and 24.35% (from 11.21 to 8.48 per 100,000 population), respectively.

Among postmenopausal women, the global ASPR of IHD increased by 4.14% (from 9451.00 to 9842.65 per 100,000 population). However, the ASIR, ASDALYR, and ASDR decreased by 10.61%, 34.99%, and 37.09%, respectively, over the same period. Despite this overall decline, a recent upward trend in ASIR was observed (Additional file 1: Table S3; Figure 3).

Figure 3.

Global burden of ASCVD among pre- and post-menopausal women from 1990 to 2021. Abbreviations: ASCVD: Atherosclerotic cardiovascular disease; IHD: Ischemic heart disease; IS: Ischemic stroke; LEPAD: Lower extremity peripheral artery disease; DALYs: Disability-adjusted life years; ASR: Age-standardized rate.

Notably, although global ASIR, ASPR, ASDALYR, and ASDR for IS and LEPAD demonstrated an overall decreasing trend among both pre- and post-menopausal women, a recent increase was observed in specific indicators among premenopausal women. This included a marked rise in ASDALYR and ASDR for LEPAD, as well as in ASIR and ASPR for IS (Additional files 1: Table S3; Figure 3).

Regional Temporal Trends in ASCVD Burden (1990-2021): Patterns among pre- and Postmenopausal Women

From 1990 to 2021, ASIR and ASPR of IHD among premenopausal women increased across all SDI regions, from 1990 to 2021, with the exception of high SDI regions. The highest ASIR was reported in high-middle SDI regions (average annual percent change [AAPC]: 0.50; 95% CI: 0.47-0.54), while the most pronounced increase in ASPR occurred in middle SDI regions (AAPC: 0.36; 95% CI: 0.32-0.41).

Among postmenopausal women, ASIR of IHD declined in high, high-middle, low-middle, and low SDI regions. In both pre- and postmenopausal groups, ASDALYR and ASDR for IHD and IS decreased across all SDI regions.

However, over the three decades, an upward trend in ASDALYR and ASDR related to LEPAD was observed in both premenopausal and postmenopausal women in low and low-middle SDI regions (Additional files 1: Table S3; Additional file 2: Figures S5).

Regionally, East Asia demonstrated the most rapid increase in the ASIR of IHD among premenopausal women (AAPC: 0.69; 95% CI: 0.63-0.75) and recorded the highest increase in the ASPR among postmenopausal women (AAPC: 0.62; 95% CI: 0.59-0.66). Central Asia exhibited the fastest growth in ASIR of IHD among postmenopausal women (AAPC: 0.87; 95% CI: 0.80-0.93), while Eastern Europe showed the steepest rise in ASPR of IHD among premenopausal women (AAPC: 0.53; 95% CI: 0.49-0.58).

For IS, East Asia reported the most rapid rise in ASIR in both pre- and postmenopausal women. Tropical Latin America experienced the greatest reduction in ASPR of IS among premenopausal women, whereas the most substantial decline among postmenopausal women was observed in the high-income Asia Pacific region. Regarding LEPAD, North Africa and the Middle East recorded the highest increase in ASPR in both groups (Table S3; Figures S6–S7).

Temporal trends in the burden of ASCVD among pre- and post-menopausal women, stratified by country and territory, are presented in Additional files 1: Tables S5 and S6.

Age-specific analyses conducted at the global level and across sub-SDI regions revealed that the incidence, prevalence, DALYs rates, and mortality rates for all three types of ASCVDs consistently increased with advancing age. (Additional file 2: Figures S10–S13).

Attributable Risk Factors for ASCVD-Related Death and DALYs in pre-and post-Menopausal Women

Between 1990 and 2021, elevated LDL cholesterol and high systolic blood pressure were the principal risk factors contributing to the burden of IHD and IS in both pre- and post-menopausal women. In premenopausal women, smoking and high body mass index (BMI) were the predominant contributors to the burden of LEPAD. In contrast, kidney dysfunction and high fasting plasma glucose were responsible for the increased LEPAD burden among postmenopausal women (Additional files 2: Figures S14–S19).

The majority of risk factors had a stronger impact on premenopausal women compared to their postmenopausal counterparts. Exceptions included high systolic blood pressure, ambient particulate matter pollution, a diet high in sodium, elevated fasting plasma glucose, kidney dysfunction, lead exposure, insufficient physical activity, alcohol use, and low ambient temperature, which demonstrated a greater influence in postmenopausal women (Figure 4, Additional files 2: Figures S20).

Figure 4.

PAF of risk factors contributing to IHD DALYs and mortality among pre- and post-menopausal women. A. PAF of risk factors for IHD-related DALYs. B. PAF of risk factors for IHD-related mortality. Abbreviations: DALYs: Disability-adjusted life years; PAF: Population attribution fractions; IHD: Ischemic heart disease.

Trend analysis over the past 32 years demonstrated a substantial decline in the ASDR and ASDALYR associated with most ASCVD risk factors in both premenopausal and postmenopausal women. However, among premenopausal women, the burden of IHD and IS due to ambient particulate matter pollution, high BMI, high temperature, and elevated fasting blood glucose showed an upward trend.

Furthermore, the burden of LEPAD attributable to high BMI and elevated fasting blood glucose increased in premenopausal women. In postmenopausal women, a marked rise in LEPAD burden attributable to elevated fasting blood glucose was also observed (Additional files 1: Table S7; Additional files 2: Figures S14–S19).

Global Projections of ASCVD Burden in pre- and post-Menopausal Women (2022 to 2041)

Projections from 2022 to 2041 indicated that the ASIR of IHD in premenopausal women is expected to remain relatively stable. In contrast, the ASIR of IHD in postmenopausal women is projected to increase from 1223.9 per 100,000 population in 2022 to 1274.3 per 100,000 in 2041.

Globally, the ASPR of IHD in both premenopausal and postmenopausal women is anticipated to rise during this period. Conversely, the ASDALYR and ASDR associated with IHD in both groups are projected to decline (Figure 5).

Figure 5.

Predicted global trends in ASCVD burden among premenopausal and postmenopausal women from 2022 to 2041. A. Predicted number of cases and ASR of IHD in premenopausal women. B. Predicted number of cases and ASR of IS in premenopausal women. C. Predicted number of cases and ASR of IHD in postmenopausal women. D. Predicted number of cases and ASR of IS in postmenopausal women. E. Predicted number of cases and ASR of LEPAD in postmenopausal women. Abbreviations: ASCVD: Atherosclerotic cardiovascular disease; ASR: Age-standardized rate; IHD: Ischemic heart disease; IS: Ischemic stroke; LEPAD: Lower extremity peripheral artery disease; DALYs: Disability-adjusted life years.

Additionally, the ASIR of IS in both pre- and post-menopausal women is projected to increase globally from 2022 to 2041, reaching 23.1 and 361.7 cases per 100,000 population, respectively, by 2041. The ASPR of IS in both groups is expected to remain relatively stable during this period. However, the ASDALYR and ASDR for IS in both pre- and post-menopausal women are projected to decline.

For LEPD in postmenopausal women, the ASIR, ASPR, ASDALYR, and ASDR are projected to decrease from 2022 to 2041, reaching 573.2, 7009.2, 72.3, and 2.9 cases per 100,000 population, respectively, by 2041 (Figure 5).

In terms of absolute numbers, the incidence and prevalence of IHD among premenopausal women are projected to increase by 15.9% and 18.4%, respectively, over the next 20 years. However, DALYs and death due to IHD in this group are projected to decrease by 6.4% and 4.9%, respectively.

Among postmenopausal women, incidence, prevalence, DALYs, and death related to IHD are projected to increase by 79.5%, 79.1%, 56.8%, and 71.8%, respectively, over the same period. For IS, the projected increases in incidence, prevalence, DALYs, and deaths among premenopausal women are projected to increase by 23.2%, 11.5%, 5.5%, and 3.9%, respectively, while the corresponding increases in postmenopausal women are 100.8%, 68.2%, 73.8%, and 85.3%, respectively.

In postmenopausal women, the burden of LEPAD is projected to increase, with incidence, prevalence, DALYs, and deaths increasing by 62.9%, 71.6%, 75.3%, and 82.1%, respectively, over the next two decades (Figure 5).

Discussion

Previous research on the burden of ASCVD has primarily emphasized sex- and age-related differences, with limited detailed investigation focusing specifically on females.^4,5,15 Existing evidence remains insufficient in delineating disease patterns by menopausal status. To date, this study represents the first comprehensive global assessment of ASCVD burden stratified by menopausal status.

Between 1990 and 2021, both the prevalence and incidence of ASCVD among females demonstrated a consistent upward trend, with projections indicating further escalation over the next two decades. Postmenopausal women accounted for a substantially greater absolute burden of ASCVD compared to premenopausal women. However, the proportional burden attributable to premenopausal women across different ASCVD subtypes—particularly in IHD and IS—was also considerable, as reflected in case numbers, mortality, and DALYs.

Population aging has remained a significant driver of the increasing global burden of ASCVD, as previously reported in the literature.^16,17 This association was further substantiated in the present study. In alignment with earlier findings^5,15,18 high LDL cholesterol and high systolic blood pressure remain the primary factors contributing to the burden of IHD and IS in females.

Trend analysis revealed a significant decline in ASCVD-related ASDR and ASDALYR attributable to most risk factors, suggesting measurable progress in cardiovascular health outcomes following public health interventions. However, among premenopausal women, ASCVD burden has increased, primarily due to emerging risk factors such as ambient particulate matter pollution, high BMI, high temperatures, and elevated fasting plasma glucose. These findings highlight emerging public health challenges linked to environmental degradation and lifestyle-related factors.

Despite global initiatives to promote green energy and facilitate energy transitions, assessments as of early 2023 indicated that the current emission trajectories of the world's 20 largest oil and gas companies are projected to exceed the Paris Agreement targets by 173% by the year 2040, a 61% increase from 2022 levels.¹⁹

Furthermore, the influence of individual risk factors on ASCVD differs significantly between premenopausal and postmenopausal women. Although the majority of risk factors exerted a greater impact on premenopausal women, exceptions include elevated systolic blood pressure, ambient particulate matter pollution, high dietary sodium intake, elevated fasting plasma glucose, impaired kidney function, lead exposure, insufficient physical activity, alcohol consumption, and low temperatures, which pose a greater burden among postmenopausal women.

IHD and Menopausal status

IHD remains the primary contributor to premature mortality among women in more than half of all countries worldwide.²⁰ In 2021, premenopausal women accounted for 4.32% of IHD-related deaths and 11.87% of IHD-related DALYs within the global female population—proportions significantly higher than those observed for IS and LEPAD. These findings indicate that premenopausal women represent an increasingly important subgroup contributing to the global IHD burden.

While the ASIR of IHD demonstrated a declining trend among postmenopausal women, premenopausal women experienced a significant rise in ASIR, accompanied by slower reductions in ASDR and ASDALYR. This divergence from expected trends warrants further investigation.

Prior to menopause, females generally experience cardioprotective effects associated with elevated estrogen levels.^7,21,22 However, findings from the current study suggest that most modifiable risk factors exert a greater impact on premenopausal women, potentially diminishing estrogen-related protection. Increased exposure to traditional cardiovascular risk factors such as elevated LDL cholesterol and obesity, along with behavioral and environmental factors, including unhealthy dietary patterns, tobacco use, and exposure to solid fuel, may contribute to this elevated burden.

Further analysis indicated that, with the exception of high-SDI regions, both the ASIR and ASPR of IHD among premenopausal women demonstrated an upward trend. The rate of ASIR increase positively correlated with SDI levels. This trend may reflect the increasing exposure to Westernized dietary habits and lifestyle risk factors in regions undergoing socioeconomic transition, where healthcare infrastructure and preventive measures may not have kept pace with these rapid changes, thereby contributing to a marked increase in IHD incidence.

In low- to middle-income settings, a notable shift toward Westernized dietary patterns has been observed among adolescent girls.²³ Similarly, in these countries, children from socioeconomically advantaged backgrounds exhibit a higher risk of obesity, whereas this trend is reversed in high-income countries.²⁴ Enhancements in diagnostic capabilities and disease surveillance in middle- and high-SDI regions may have also contributed, at least in part, to the observed increases in ASIR.

In contrast, the ASIR of IHD among postmenopausal women exhibited a declining trend across all SDI regions, with the exception of middle-SDI regions. The most substantial reduction was observed in high-SDI regions. This decline may be attributed to higher educational attainment and the sustained implementation of cardiovascular risk mitigation strategies, including early screening, pharmacological interventions such as statin therapy, and lifestyle modifications.²⁵ Furthermore, the appropriate use of hormone replacement therapy in some countries may have contributed to improved cardiovascular outcomes among postmenopausal women.^26,27

In low-SDI regions, the implementation of ASCVD prevention strategies and efforts aligned with Sustainable Development Goal target 3.4^20,28 have contributed to increased awareness and facilitated targeted interventions for postmenopausal women, despite constrained healthcare resources. However, these measures have not adequately addressed the growing burden of IHD among premenopausal women, highlighting a critical need for tailored public health strategies to mitigate their escalating risk.

IS and Menopausal status

In 2021, approximately 34.7 million women globally were living with IS, with premenopausal women accounting for 18.53% of cases. Although the overall ASIR, ASPR, ASDR, and ASDALYR for stroke among women demonstrated a general decline, two notable concerns emerged.

First, the burden of IS in premenopausal women remained predominantly concentrated in low- to lower-middle SDI regions, whereas the highest burden in postmenopausal women was observed in upper-middle- to high-SDI regions. This geographic disparity underscores the ongoing influence of adverse lifestyle and environmental risk factors in lower-SDI regions for premenopausal women and the continuing need for enhanced management of IS among postmenopausal women in higher-SDI areas.

Second, the pace of decline in ASDR and ASDALYR for IS among women globally has slowed over the past decade. In contrast, both ASPR and ASIR have demonstrated an upward trend. Notably, the increase in ASPR between 2020 and 2021 exceeded the cumulative increase observed from 2010 to 2019. This trend may reflect increased exposure to stroke-related risk factors such as elevated blood pressure, increased BMI, and elevated fasting plasma glucose as well as a potential reduction in the effectiveness or coverage of public health interventions targeting these modifiable risks.²⁹ For example, in the United States, the proportion of women with hypertension who achieved blood pressure control, declined significantly from 53.2% in 2015–2016 to 43.9% in 2017–2018.³⁰

Furthermore, the onset of the COVID-19 pandemic in 2019 exerted considerable pressure on global healthcare systems. During the early phases of the pandemic, routine medical care for non-COVID-related conditions was frequently delayed or disrupted, adversely affecting the management of chronic cardiovascular and cerebrovascular diseases. These disruptions may have contributed to shifts in the burden of both IS and IHD.^31,32

LEPAD and Menopausal status

In 2021, both the ASIR and ASPR of LEPAD among premenopausal and postmenopausal women in high-SDI regions exceeded the corresponding rates for IHD and IS. Trend analysis indicated that the burden of LEPAD remained highest in high-SDI regions across both menopausal groups.

Since 2017, a distinct global increase in the ASDALYR and ASDR of LEPAD has been observed among premenopausal women, primarily driven by rising rates in high-middle, middle, and low-SDI regions. This trend highlights a widespread lack of awareness regarding LEPAD among women, irrespective of socioeconomic status. Prior research involving 328 postmenopausal women aged ≥ 65 years with confirmed LEPAD revealed that only one in six were aware of their diagnosis.³³

Further analysis indicated that smoking and elevated BMI were the primary drivers of LEPAD burden among premenopausal women. The impact of elevated BMI and increased fasting plasma glucose demonstrated a continued upward trend in this group. Among postmenopausal women, impaired kidney function and high fasting plasma glucose were identified as the predominant risk factors, with the latter showing a persistent upward trend. These risk exposures, compounded by suboptimal therapeutic management, have contributed to rising ASDR and ASDALYR.^34–36

Despite advancements in healthcare, treatment rates remain inadequate, even in high-income settings. Statin therapy was administered to only 33.9% of patients with LEPAD, with merely 15.6% receiving high-intensity statins, substantially lower than the corresponding treatment rates for coronary artery disease and cerebrovascular disease.³⁷ Furthermore, the use of antiplatelet agents, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) remained suboptimal, with evidence indicating less intensive treatment in females compared to males.³⁸ Notably, women diagnosed with early-onset LEPAD (≤ 55 years or ≤ 40 years) were even less likely to receive these guideline-recommended therapies.³⁹

Limitations

This study presented several limitations. First, the Global Burden of Disease (GBD) 2021 dataset incorporated information from countries with heterogeneous data quality, which may have introduced analytical bias. Second, the absence of specific menopausal status indicators in the GBD database necessitated the use of standard age thresholds and previously published literature to approximate menopausal status, which may have resulted in misclassification. GBD PAFs quantify population-level attributable burdens under theoretical-minimum-risk counterfactuals, not intervention effects; residual confounding and exposure measurement error remain, what's more，The 2041 projections are purely Nordpred APC extrapolations of 1990–2021 rates and embed no exogenous adjustment for future policies, lipid-lowering innovations, PM₂.₅ legislation or COVID-19 sequelae. Consequently they represent a “business-as-usual” scenario; sensitivity tests show that a ± 5% one-time shift in the latest input rate widens the 2041 case window by ±6%–7%, underscoring that real-world trajectories could diverge markedly if major structural changes occur. Finally, the limited research focus on LEPAD among premenopausal women, combined with insufficient data availability, restricted the feasibility of conducting predictive analysis, thereby narrowing the overall scope of the investigation.

Conclusions

ASCVD continued to pose a significant global public health challenge, with substantial regional and demographic disparities in disease burden based on menopausal status. Although global ASDALYR and ASDR associated with ASCVD have declined between 1990 and 2021, the ASIR and ASPR of IHD increased among premenopausal women. Projections indicated a continued rise in the number of ASCVD cases, particularly among postmenopausal women. These trends underscored the need for policymakers and healthcare professionals to implement age-specific and regionally tailored screening strategies and allocate healthcare resources accordingly to mitigate the ASCVD burden.

Supplemental Material

sj-pdf-1-cat-10.1177_10760296251414114 - Supplemental material for Global, Regional, and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study

Supplemental material, sj-pdf-1-cat-10.1177_10760296251414114 for Global, Regional, and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study by Jie Tan, Zhiyu Zhang, Shouying Xiang, Fei Zhang, Heng Zhu, Li Xu and Jing Huang in Clinical and Applied Thrombosis/Hemostasis

Supplemental Material

sj-pdf-2-cat-10.1177_10760296251414114 - Supplemental material for Global, Regional, and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study

Supplemental material, sj-pdf-2-cat-10.1177_10760296251414114 for Global, Regional, and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study by Jie Tan, Zhiyu Zhang, Shouying Xiang, Fei Zhang, Heng Zhu, Li Xu and Jing Huang in Clinical and Applied Thrombosis/Hemostasis

Supplemental Material

sj-7z-3-cat-10.1177_10760296251414114 - Supplemental material for Global, Regional, and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study

Supplemental material, sj-7z-3-cat-10.1177_10760296251414114 for Global, Regional, and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study by Jie Tan, Zhiyu Zhang, Shouying Xiang, Fei Zhang, Heng Zhu, Li Xu and Jing Huang in Clinical and Applied Thrombosis/Hemostasis

Footnotes

List of Abbreviations

Acknowledgements

We are grateful to the Institute of Health Metrology and Evaluation for sharing valuable GBD data.

ORCID iD

Jing Huang

Ethics Approval and Consent to Participate

For the GBD is publicly available and no identifable information was included in the analyses, the ‘Ethical approval and consent to participate’ was not applicable.

Consent for Publication

Not applicable.

Authors’ Contributions

LX and JH conceived the study. JT designed the protocol. JT, ZYZ, SYX, FZ and HZ analysed the GBD data. ZYZ contributed to the statistical analysis and interpretation of data. JT, ZYZ, SYX, FZ and HZ drafted the manuscript, and other authors critically revised the manuscript. JT, LX and JH accessed and verified the underlying data. JH obtained the funding. All authors have read and approved the final version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82170445), the Major Scientific Instrument Development Project of the National Natural Science Foundation of China (No. 32127802) and the Medical technology innovation “Unveiling Command Project” of the Second Affiliated Hospital of Chongqing Medical University (No. 2023IIT094).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Availability of Data and Materials

Relevant data can be retrieved through the available website ().

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

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Global,Regional,and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Overview of the Data Sources

Estimation of ASCVD Burden in pre-and post-Menopausal Women

Estimation of Attributable Risk Factors for ASCVD in pre- and post-Menopausal Women

Prediction of Incidence, Prevalence, DALYs, and Mortality Associated with ASCVD in pre- and post-Menopausal Women

Statistical Analysis

Results

Global Burden of ASCVD among Premenopausal Women in 2021

Burden of ASCVD among pre- and post-Menopausal Women Across Locations in 2021

Global Temporal Trends in ASCVD Burden (1990-2021): Patterns in pre- and post-Menopausal Women

Regional Temporal Trends in ASCVD Burden (1990-2021): Patterns among pre- and Postmenopausal Women

Attributable Risk Factors for ASCVD-Related Death and DALYs in pre-and post-Menopausal Women

Global Projections of ASCVD Burden in pre- and post-Menopausal Women (2022 to 2041)

Discussion

IHD and Menopausal status

IS and Menopausal status

LEPAD and Menopausal status

Limitations

Conclusions

Supplemental Material

sj-pdf-1-cat-10.1177_10760296251414114 - Supplemental material for Global, Regional, and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study

Supplemental Material

sj-pdf-2-cat-10.1177_10760296251414114 - Supplemental material for Global, Regional, and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study

Supplemental Material

sj-7z-3-cat-10.1177_10760296251414114 - Supplemental material for Global, Regional, and National Burden of Atherosclerotic Cardiovascular Disease in Pre- and Post-Menopausal Women: 1990-2021 Trends and 2041 Projections from the Global Burden of Disease Study

Footnotes

List of Abbreviations

Acknowledgements

ORCID iD

Ethics Approval and Consent to Participate

Consent for Publication

Authors’ Contributions

Funding

Declaration of Conflicting Interests

Availability of Data and Materials

Supplemental Material

References

Supplementary Material