Endometriosis-Associated Cardiovascular Remodeling: Mechanistic Insights and the Modulatory Role of Flavonoids

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Despite this, the connections between endometriosis and alterations in cardiac structure, as well as its relationship with cardiovascular disease, remain inadequately characterized, with underlying mechanisms and potential interventions yet to be clearly defined. Methods We analyzed data from the UK Biobank, including 6,158 women with and 229,453 women without endometriosis, and validated our findings in a hospital-based cohort comprising 612 women with laparoscopically confirmed endometriosis and 612 matched controls. Multivariable-adjusted Cox proportional hazards models were employed to estimate the associations between endometriosis and the incidence of cardiovascular disease. Generalized linear models assessed links with cardiac magnetic resonance (CMR) metrics. Mediation analyses evaluated metabolic, inflammatory, hormonal, and oxidative stress pathways. Finally, we assessed whether flavonoid intake modified these associations. Results Over a median 13-year follow-up, 23,239 CVD events occurred. Endometriosis was found to be associated with an 18% increased risk of composite CVD and a 25% increased risk of coronary heart disease. These findings were validated in an external hospital-based cohort, where similar associations with composite CVD and coronary heart disease were observed. Cardiac magnetic resonance imaging revealed subtle yet significant structural and functional cardiac alterations, including increased interventricular septal thickness and regional wall motion abnormalities, with trends indicating greater left ventricular wall thickness and systolic longitudinal wall thickening. Biomarkers indicative of metabolic, inflammatory, and oxidative stress pathways collectively mediated the association between endometriosis and CVD. Notably, high dietary intakes of specific flavonoid subclasses, particularly flavones and flavanones, were observed to attenuate this association. Conclusions Endometriosis is linked to increased CVD risk and early cardiac remodeling, partly via metabolic, inflammatory, and oxidative stress pathways. Increased flavone and flavanone intake may help reduce cardiovascular risk, highlighting potential dietary interventions. Endometriosis Cardiovascular disease Coronary heart disease Cardiac magnetic resonance imaging Flavonoids Mediation analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Highlights 1. Women with endometriosis face higher risks of cardiovascular disease, especially coronary heart disease. 2. CMR reveals subtle but significant adverse cardiac remodeling in women with endometriosis. 3. Metabolic, inflammatory, and oxidative stress pathways mediate endometriosis’s impact on cardiovascular disease. 4. Higher flavone and flavanone intake attenuates endometriosis-related cardiovascular risk. Introduction Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in women, accounting for approximately 35% of all deaths in women globally [ 1 ]. Beyond traditional risk factors, emerging evidence highlights the importance of female-specific conditions and reproductive history in shaping long-term cardiovascular health [ 2 ]. Endometriosis is a chronic inflammatory gynecologic condition affecting ~ 10% of women of reproductive age, often characterized by delayed diagnosis and inadequate treatment [ 3 – 5 ]. Traditionally viewed as a pelvic disorder, it is now increasingly recognized as a multisystem disease [ 6 ]. Mounting evidence suggests that women with endometriosis may be at greater risk for CVD later in life [ 2 , 4 , 7 – 10 ]. Further, treatments for endometriosis, such as hormonal medications, hysterectomy, and oophorectomy, may modify CVD risk [ 4 , 11 , 12 ]. Despite growing evidence linking endometriosis to CVD, it remains uncertain whether endometriosis independently associates with adverse cardiac structural and functional phenotypes. Prior investigations have primarily targeted isolated cardiovascular outcomes, often lacking comprehensive scope and mechanistic exploration. Addressing this gap is crucial for developing integrated approaches that consider both reproductive and systemic health in women with endometriosis. Flavonoids, a class of (poly)phenolic compounds, are prevalent constituents of the human diet, sourced from a diverse array of foods such as fruits, vegetables, nuts, legumes, wines, and teas [ 13 , 14 ]. These compounds are categorized into several subclasses, including flavonols, anthocyanins, flavan-3-ols, flavanones, and flavones [ 15 ]. Upon ingestion and absorption, flavonoids and their metabolites have the potential to confer health benefits [ 14 ]. Numerous prospective cohort studies have demonstrated that higher habitual intake of various flavonoid subclasses is inversely associated with the risk of CVD [ 13 , 15 – 17 ]. Flavonoids, with their varied structures and metabolic processes, exhibit a range of biological effects, notably anti-inflammatory and antioxidative actions crucial for cardiovascular health [ 18 ]. However, it's unclear if different flavonoids can reduce endometriosis-related CVD risks. In this study, we leveraged the population-based UK Biobank (UKB) and a hospital-based cohort of laparoscopically confirmed cases to investigate the relationship between endometriosis and CVD. Specifically, our aims were to: 1) systematically examine the prospective associations between endometriosis and incident CVD risk; 2) investigate the associations between endometriosis and subclinical cardiac structural alterations as measured by cardiac magnetic resonance (CMR) imaging; 3) elucidate underlying mechanisms by evaluating the potential mediating roles of metabolic dysfunction, systemic inflammation, oxidative stress, and hormonal imbalance in the relationship between endometriosis and CVD; and 4) explore whether flavonoid intake can mitigate the increased risk of CVD associated with endometriosis. Methods Study population UK Biobank cohort The UKB is a prospective cohort study that gathered data from more than 500,000 participants aged 40 to 69, sourced from 22 assessment centers across England, Scotland, and Wales. Participants, from 2006 to 2010, completed a series of questionnaires, underwent diverse physical measurements, and provided biological samples. Participants provided informed consent for linking their data to national records of hospital admissions, cancer diagnoses, and death records. UK Biobank has approval from the North West Multicenter Research Ethics Committee ( https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics ). This study utilizes data from the UK Biobank baseline assessment conducted between 2006 and 2010. Among the 502,128 participants enrolled in the UK Biobank, 273,155 women aged 40 to 69 years with available information on endometriosis were identified. Initially, 36,206 women with a history of coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), or stroke at baseline were excluded. Subsequently, 1,338 women diagnosed with endometriosis during follow-up were excluded. Ultimately, 235,611 women were included in the main and mediation analyses, among whom 6,158 were diagnosed with endometriosis and 229,453 without endometriosis ( Fig. 1 ) . External validation hospital cohort To address potential misclassification of endometriosis in the UK Biobank due to reliance on self-reported and registry-based diagnoses, we conducted an external validation study using a retrospective-prospective hospital-based cohort from the Second Affiliated Hospital of University of South China, a tertiary referral center for gynecologic diseases. This hospital-based cohort included women who underwent laparoscopic surgery for suspected endometriosis between January 2008 and December 2012. Eligibility criteria included: (i) women aged ≥ 20 years at the time of diagnosis, (ii) laparoscopically confirmed endometriosis based on intraoperative visual inspection and histopathological examination, and (iii) absence of clinically evident cardiovascular disease prior to laparoscopic confirmation. Women were excluded if they were pregnant, had pathologically or clinically confirmed leiomyoma, adenomyosis, pelvic inflammatory disease, kidney disease, cancer, or autoimmune disorders, or had previously undergone hysterectomy or oophorectomy. The control group comprised women from the same hospital and time period who had no evidence of endometriosis on transvaginal ultrasound or laparoscopy. Controls were frequency-matched to cases in a 1:1 ratio by age and met the same exclusion criteria as cases. In total, 621 women with laparoscopically confirmed endometriosis were included as cases, and 621 matched controls comprised the comparison group (Figure S1 ) . Participants were followed up through May 2025. Because imaging, biomarker, and dietary data were unavailable in this cohort, validation was limited to the association between endometriosis and incident cardiovascular events. The hospital-based study was approved by the Ethics Committee of the Second Affiliated Hospital of University of South China (Approval No. 2025006), and informed consent was obtained from all participants. Definition of endometriosis To maximize case ascertainment, we defined endometriosis using both UK Biobank electronic health records (EHR) diagnoses and self-reported physician diagnoses. Specifically, EHR diagnoses were based on ICD-10 codes N80.x, while self-reported cases were obtained during a structured, nurse-led interview at baseline assessment [ 19 ]. A total of 6,158 women with endometriosis were identified: 3,627 through health records, 3,384 through self-report, and 853 by both sources. While laparoscopic confirmation with histological verification remains the diagnostic gold standard [ 20 ], such information is not systematically available in population-based cohorts. Previous validation studies have shown that registry- and self-report–based definitions of endometriosis, although less sensitive, have high specificity, and thus are more likely to result in under-ascertainment rather than false-positive misclassification [ 21 ]. To strengthen diagnostic validity, we further conducted an external validation study in the Second Affiliated Hospital of University of South China, where all diagnoses were confirmed by laparoscopy and histopathology. This external dataset not only corroborated the accuracy of our case definition but also enabled a sensitivity analysis restricted to laparoscopically confirmed cases, thereby ensuring the robustness of our findings. Definition of cardiovascular disease The primary outcome in both the UK Biobank and the hospital-based validation cohort was incident CVD, encompassing CHD, MI, HF, AF, and stroke. In the UK Biobank, events were ascertained through linkage to national hospital admission databases in England, Wales, and Scotland, with follow-up from baseline assessment until the first occurrence of a CVD event or October 31, 2022, whichever came first. In the hospital-based cohort, CVD events were identified through electronic medical records and clinical follow-up up to the most recent available date. All events in both cohorts were defined using ICD-10 codes: CHD (I20–I25, including fatal ischemic heart disease and nonfatal MI I21–I23), AF and related arrhythmias (I48–I49), HF (I50), and stroke encompassing all cerebrovascular diseases (I60–I64, I69) ( Table S1 ). CMR outcomes A previously detailed CMR protocol and analysis method were used in a study involving ~ 40,000 participants from the UK Biobank, out of the initial ~ 500,000, who were scanned by August 2023 [ 22 ]. These CMR scans primarily assessed cardiac anatomy and biventricular function, providing comprehensive evaluations of cardiac structure, function, tissue characteristics, and prognostic markers. Details are provided in Supplementary Methods. Peripheral biomarkers In this study, we analyzed 12 metabolic, 11 inflammatory, 4 oxidative stress, and 1 hormonal biomarkers. Detailed information is provided in Supplementary Methods. Dietary flavonoid intake assessment Dietary intake was evaluated using the Oxford WebQ 24-hour recall up to five times from 2009 to 2012 [ 23 ] [ 24 ]. Flavonoid intake was estimated by matching Oxford WebQ food codes with USDA flavonoid databases, using updated nutrient algorithms for individual foods and recipes [ 25 ]. Mean daily intakes (mg/d) were averaged from valid questionnaires. Subclass intakes included flavan-3-ols, flavonols, flavones, anthocyanins, and flavanones. Total flavonoid intake was the sum of all compounds, excluding isoflavones due to low UK consumption. Participants were grouped into low, medium, and high intake based on population-specific tertiles of total flavonoid intake. Descriptive statistics for total and subclass intakes were calculated for all participants (n = 103,108; see Supplementary Table S11 ). Measurement of covariates Covariates were selected based on prior literature [ 4 , 26 ] across four domains: sociodemographic, lifestyle, cardiovascular risk, and reproductive/hormonal factors. UK Biobank cohort (1) Baseline sociodemographic factors such as age, ethnicity, education, and the Townsend Deprivation Index (TDI); (2) Lifestyle factors like alcohol use, smoking, physical activity, and a healthy diet score; (3) Cardiovascular risk factors, including baseline diabetes and hypertension diagnoses, and use of related medications; (4) Reproductive and hormonal factors, such as age at menarche, and use of oral contraceptives and hormone replacement therapy. The TDI measures socioeconomic status, with lower values indicating higher status. Diabetes was defined using UK Biobank algorithms, and hypertension was defined by self-reported diagnosis or antihypertensive medication use [ 27 ]. Information on smoking, alcohol consumption, physical activity, and diet was collected. Smoking was categorized as never, former, or current. Alcohol intake was divided into never, former, < 1 drink/week, 1–2 drinks/week, and ≥ 3 drinks/week [ 28 ]. Physical activity was measured using the International Physical Activity Questionnaire and classified as low (< 600 MET/min per week), moderate (≥ 600 MET/min per week), or high (≥ 3000 MET/min per week) [ 28 ]. A healthy diet score was based on fruit, vegetable, fish, processed meat, and red meat intake, with each favorable factor scored as 1 and unfavorable as 0, resulting in a total score ranging from 0 to 5 [ 29 ]. Additional covariate details are in Table S3. Hospital-based external validation cohort Sociodemographic information was obtained from medical records and patient interviews. Lifestyle factors (smoking, alcohol, physical activity, diet) were collected via standardized questionnaires administered at baseline. Cardiovascular risk factors (diabetes, hypertension, medication use) and reproductive/hormonal factors (age at menarche, contraceptive or hormone therapy use) were abstracted from medical records. Measurement categories were harmonized as closely as possible with the UKB cohort. Statistical analysis Association analysis between endometriosis and CVD incidence Continuous variables were summarized as mean ± SD or median with IQR, and categorical variables as percentages. All continuous variables were log-transformed and standardized (Z-score) to minimize the statistical biases. Moreover, adjustments to the Benjamini-Hochberg method for false discovery rate (FDR) were applied. Multivariable Cox proportional hazards regression models were employed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between endometriosis and incident CVD and other cardiovascular outcomes. A stepwise modeling strategy was adopted: the primary model was adjusted for age. Multivariable models were further adjusted for Townsend deprivation index, race/ethnicity, education level of college, baseline hypertension, baseline diabetes, smoking status, alcohol consumption, physical activity, and healthy diet score. The fully models were further adjusted for reproductive factors (age at menarche, OC and HRT use). The proportional hazards assumption was tested using the Kolmogorov-type supremum test, with no violations detected (all P -values > 0.05). To strengthen our findings, we conducted five sensitivity analyses: 1) excluded participants with less than 5 years of follow-up to avoid reverse causation; 2) limited endometriosis cases to those identified by ICD-10 codes to prevent misclassification; 3) adjusted for menopausal status to control for reproductive aging; 4) excluded women with a history of hysterectomy or oophorectomy to assess the impact of surgically induced hormonal changes; and 5) conducted an analysis in the hospital-based external validation cohort, including only laparoscopically confirmed cases, to verify exposure accuracy and replicate the associations observed in the UK Biobank cohort. Given the positively skewed distributions of CMR metrics, generalized linear models with a gamma distribution and log link were used to investigate the associations between endometriosis as the independent variable and the cardiac phenotype by CMR as the dependent variable. FDR correction was appropriately applied, and Q values were reported across the analyses. Mediation models were used to explore how endometriosis might influence CVD risk through biomarkers. Initially, linear regression identified biomarkers linked to endometriosis. The most significant biomarkers were then tested as mediators using the "mediation" package in R, adjusting for various demographic and health factors. The significance of mediation effects was evaluated with 5000 bootstrap iterations. Finally, we further investigated whether dietary flavonoid intake modified the association between endometriosis and CVD. To formally test for interaction, multiplicative terms between endometriosis status and flavonoid intake were incorporated into the models. In addition, we evaluated the joint associations of endometriosis and flavonoid intake categories with CVD risk, using women without endometriosis and with high flavonoid intake as the reference group. Analyses were performed in R 4.3.3. Results Participant characteristics Tables 1 and S4 summarize the baseline characteristics of women in the UK Biobank and hospital-based cohorts. In the UK Biobank cohort (n = 235,611; mean age 55.7 years), women with endometriosis were younger and less likely to have a college education. Also, they exhibited a slightly elevated prevalence of current smoking, an increase in low to moderate alcohol consumption, and diminished levels of physical activity (all P < 0.05). Moreover, these women experienced menarche at an earlier age and more frequently utilized oral contraceptives and hormone replacement therapy (all P < 0.05). Diabetes was slightly less prevalent among women with endometriosis ( P = 0.017). Figure 1 shows an overview of analyses performed in the study. Table 1 Baseline characteristics of the study population (n = 235,611). Characteristics All Without endometriosis at baseline Endometriosis at baseline P value Number of women 235,611 229,453 6,158 Age (years) 55.68±(7.99) 55.76±(7.98) 52.62±(7.59) < 0.001 Townsend deprivation index -1.41±(3.00) -1.41±(3.00) -1.38±(2.97) 0.150 Race/ethnicity 0.100 White 223,231 (95%) 217,395 (95%) 5,836 (95%) Asian or Asian British 4,588 (2%) 4,487 (2%) 101 (2%) Other or mixed 7,792 (3%) 7,571 (3%) 221 (4%) Education level of college Smoking status < 0.001 Never 142,353 (60%) 138,641 (60%) 3,712 (60%) Former 72,607 (31%) 70,795 (31%) 1,812 (29%) Current 20,651 (9%) 20 017 (9%) 634 (10%) Alcohol consumption < 0.001 Never 12,706 (5%) 12,422 (5%) 284 (5%) Former 7,934 (3%) 7,684 (3%) 250 (4%) Current: < 1 drink/week 33,863 (14%) 32,905 (14%) 958 (16%) Current: 1–2 drinks/week 30,798 (13%) 29,797 (13%) 1,001 (16%) Current: ≥3 drinks/weeks 150,310 (64%) 146,645 (64%) 3,665 (60%) Physical activity 0.006 Low 31,106 (13%) 30,202 (13%) 904 (15%) Moderate 74,916 (32%) 72,994 (32%) 1,922 (31%) High 69,182 (29%) 67,385 (29%) 1,797 (29%) Missing 60,407 (26%) 58,872 (26%) 1,535 (25%) Healthy diet score 2.89 ± 0.97 2.89 ± 0.97 2.87 ± 0.98 0.300 Age at menarche (years) < 0.001 <12 46,240 (20%) 44,841 (20%) 1,399 (23%) 12 44,716 (19%) 43,570 (19%) 1,146 (19%) 13 58,313 (25%) 56,794 (25%) 1,519 (25%) 14 46,866 (20%) 45,751 (20%) 1,115 (18%) ≥15 39,476 (17%) 38,497 (17%) 979 (16%) OC use 193,798 (82%) 188,459 (82%) 5,339 (87%) < 0.001 HRT use 85,091 (36%) 82,028 (36%) 3,063 (50%) < 0.001 Hypertension at baseline 46,815 (20%) 45,618 (20%) 1,197 (19%) 0.400 Diabetes at baseline 5,630 (2%) 5 511 (2%) 119 (2%) 0.017 Data are presented as the means (SDs), medians (interquartile ranges), or percentages. OC: oral contraceptives; HRT: hormone replacement therapy. In the hospital-based cohort (n = 1,224; 612 cases and 612 controls; mean age 42.3 years), women with laparoscopically confirmed endometriosis similarly had lower college education rates (34.6% vs. 40.0%, P = 0.025), engaged in less physical activity (low activity: 49.0% vs. 43.1%, P < 0.001), experienced earlier menarche ( P = 0.004), and more frequently used oral contraceptives (74.7% vs. 66.0%, P = 0.001) and HRT (4.2% vs. 2.0%, P = 0.030). No significant differences were observed in marital status, smoking, alcohol consumption, hypertension, or diabetes ( Table S4 ). Prospective association between endometriosis and CVD risk During a median follow-up of 13.03 years, women with endometriosis had higher risk of CVD than those without endometriosis after fully adjustment for age, ethnicity, education level, Townsend deprivation index, alcohol consumption, smoking status, physical activity, healthy diet score, baseline diabetes, baseline hypertension, age at menarche, OC and HRT use (HR = 1.18, 95% CI: 1.08–1.28, Q < 0.001; Fig. 2 A). With further in-depth analyses examining subtypes of cardiovascular outcomes, endometriosis was associated with an increased risk of CHD (HR = 1.25, 95% CI: 1.11–1.40, Q < 0.001; Fig. 2 A). However, no significant associations were observed for myocardial infarction, atrial fibrillation, heart failure, or stroke after full adjustment (Fig. 2 A). Sensitivity analyses, such as excluding participants with less than 5 years of follow-up, focusing on ICD-10 endometriosis diagnoses, and adjusting for menopausal status, showed no significant change in associations ( Figs. S2-S4 ). Even after excluding women with previous hysterectomy or oophorectomy, endometriosis was still significantly linked to heart failure (HR = 1.47, 95% CI: 1.04–2.09, Q = 0.030; Fig. S5 ). Similarly, in the hospital-based external validation cohort of laparoscopically confirmed cases, endometriosis was associated with higher risks of composite CVD (HR = 1.22, 95% CI: 1.08–1.36, Q < 0.001; Fig. S6 ) and CHD (HR = 1.25, 95% CI: 1.08–1.40, Q = 0.023; Fig. S6 ). While associations with myocardial infarction, atrial fibrillation, and heart failure were not significant, stroke risk remained elevated (HR = 1.19, 95% CI: 1.03–1.40, Q = 0.041; Fig. S6 ), highlighting the consistency of key cardiovascular findings across both cohorts. Interaction analyses support a significant modulating effect of physical activity on the association of endometriosis with CHD risks ( P for interaction = 0.030; Figs. 2 B- 2 C). In stratified analyses, women with endometriosis with low physical activity had a higher CHD risk than those with high physical activity (Fig. 2 C and Figs. S7-S8 ). Associations between endometriosis and the CMR phenotypes To further explore the cardiovascular effects of endometriosis, we used CMR imaging to compare cardiac structure and function. In the fully adjusted model, participants with endometriosis had significantly greater IVST (% difference = 1.07, 95% CI: 0.10–2.04, Q = 0.030; Fig. 3 and Table S5 ) and LV RWM (% difference = 1.07, 95% CI: 0.04 to 2.12, Q = 0.042; Fig. 3 and Table S5 ). In addition, LV \(\:\overline{\text{W}\text{T}}\) (% difference = 0.78, 95% CI: -0.06-1.62, Q = 0.069; Fig. 3 and Table S5 ) and SLWR (% difference = 0.63, 95% CI: -0.01-1.27, Q = 0.052; Fig. 3 and Table S5 ) were marginally elevated in the endometriosis group, suggesting a possible trend toward concentric remodeling. Potential mechanism contributing to the associations between endometriosis and CVD risk A linear regression model revealed significant links between endometriosis and various biomarkers, including ten metabolic, six inflammatory, two oxidative stress, and one hormonal ( Table S6 ). Specifically, higher levels of triglycerides (β: 0.14, Q < 0.001), LDL-C (β: 0.09, Q < 0.001), total cholesterol (β: 0.08, Q < 0.001), TyG indices (β: 0.10–0.13, Q < 0.001), and LAP (β: 0.12, Q < 0.001) were associated with endometriosis, while HDL-C (β: -0.07, Q < 0.001) and total bilirubin (β: -0.05, Q < 0.001) were inversely related. Regarding inflammatory markers, CRP (β: 0.11, Q < 0.001), lymphocyte percentage (β: 0.03, Q = 0.049), lymphocyte count (β: 0.04, Q = 0.006), and INFLA score (β: 0.22, Q = 0.005) were positively linked to endometriosis, whereas monocyte percentage (β: -0.03, Q = 0.031) and platelet count (β: -0.03, Q = 0.045) were negatively associated. For oxidative stress markers, urate (β: 0.06, Q < 0.001) showed a positive association, and DBIL (β: 0.06, Q < 0.001) an inverse one, with endometriosis. In addition, SHBG (β: -0.04, Q = 0.002) levels were inversely related to endometriosis. We further used the Cox proportional hazards model to examine the relationship between peripheral biomarkers and CVD risk ( Tables S7-S8 ). Metabolic markers like triglycerides (CVD: HR: 1.08, Q < 0.001; CHD: HR: 1.18, Q < 0.001), FPG (CVD: HR: 1.03, Q < 0.001; CHD: HR: 1.05, Q < 0.001), TyG indices (CVD: HR: 1.09–1.21, Q < 0.001; CHD: HR: 1.20–1.24, Q < 0.001), and LAP (CVD: HR: 1.13, Q < 0.001; CHD: HR: 0.84, Q < 0.001) were linked to higher CVD and CHD risk, while HDL-C (CVD: HR: 0.89, Q < 0.001; CHD: HR: 1.18, Q < 0.001) was inversely related. LDL-C (CHD: HR: 1.14, Q < 0.001) and total cholesterol (CHD: HR: 1.10, Q < 0.001) were associated with increased CHD risk. Inflammatory markers, including monocyte (HR: 1.02, Q = 0.011) and basophil percentages (HR: 1.02, Q = 0.003), their absolute counts (monocyte: HR: 1.07, Q < 0.001; basophil: HR: 1.03, Q < 0.001), CRP (HR: 1.16, Q < 0.001), NLR (HR: 1.04, Q < 0.001), MLR (HR: 1.04, Q < 0.001), SII (HR: 1.00, Q < 0.001), SIRI (HR: 1.02, Q < 0.001), and the INFLA score (HR: 1.02, Q < 0.001), were positively associated with CVD, and similar markers were linked to CHD (All Q < 0.05). Lymphocyte percentage (CVD: HR: 0.93, Q < 0.001; CHD: HR: 0.95, Q < 0.001) was inversely related to both CVD and CHD. For oxidative stress, urate (HR: 1.11, Q < 0.001) and DBIL (HR: 1.04, Q < 0.001) were positively associated with CVD, but albumin (HR: 0.89, Q < 0.001) was inversely related. Albumin (HR: 0.91, Q < 0.001) and DBIL (HR: 0.97, Q = 0.007) were inversely linked to CHD, while urate (HR: 1.12, Q < 0.001) showed a positive association. SHBG (CVD: HR: 0.97, Q < 0.001; CHD: HR: 0.90, Q < 0.001) was inversely associated with both CVD and CHD. Mediation model was used to explore how endometriosis influences CVD via peripheral biomarkers (Fig. 4 and Tables S9-S10 ). For CVD, metabolic indices like TyG-WC (13.7%), TyG-BMI (13.3%), and others showed the highest mediation, while inflammatory markers like CRP (9.6%) and oxidative stress markers like urate (3.7%) had smaller effects. For CHD, metabolic mediators such as triglycerides (10.8%) and TyG (10.5%) were most significant, with inflammatory markers like CRP (7.7%) also contributing. Oxidative stress markers had minor roles. Joint effect of dietary flavonoid intake and endometriosis on CVD risk Compared with the reference group (women without endometriosis and with high intakes of flavonoid subclasses), women with endometriosis and low intakes of total flavones (luteolin: HR = 1.34; 95% CI: 1.08–1.67) and total flavanones (HR = 1.36; 95% CI: 1.10–1.68), including hesperetin (HR = 1.33; 95% CI: 1.07–1.64) and naringenin (HR = 1.38; 95% CI: 1.11–1.70), had the highest CVD risk. By contrast, women with endometriosis who consumed high amounts of these flavonoid subclasses did not show an elevated CVD risk relative to the reference group. A similar pattern was observed for CHD. Among women with endometriosis, those with low intakes of total flavonols (HR = 1.37; 95% CI: 1.01–1.87) and total flavanones (HR = 1.53; 95% CI: 1.15–2.04), including hesperetin (HR = 1.51; 95% CI: 1.13–2.01) and naringenin (HR = 1.62; 95% CI: 1.23–2.15), exhibited the highest CHD risk, whereas high intakes of these flavonoid subclasses were not associated with excess risk. Among women with endometriosis, moderate intakes of total anthocyanidins (HR = 1.29; 95% CI: 1.02–1.61) were associated with an increased CVD risk, while neither low nor high intakes were linked to significant associations. Likewise, moderate intakes of total flavones (HR = 1.41; 95% CI: 1.03–1.92) and apigenin (HR = 1.48; 95% CI: 1.10–1.99) were associated with significantly higher CHD risk (Fig. 5 and Tables S11-S13 ). Discussion Principal findings In this large cohort study, we explored the link between endometriosis and increased long-term CVD risk, especially CHD. CMR imaging showed significant cardiac changes, such as increased interventricular septal thickness and regional wall motion abnormalities, suggesting early concentric remodeling. Mediation analyses revealed that metabolic, inflammatory, and oxidative stress biomarkers partly explained these associations, particularly for CHD. Furthermore, a low dietary intake of specific flavonoid subclasses—particularly flavones and flavanones—was associated with the highest risks of CVD and CHD among women with endometriosis, whereas higher intakes appeared to confer a protective effect. Interpretation of study findings and comparison with existing literature To date, a limited number of observational studies have examined the relationship between endometriosis and CVD, often constrained by small sample sizes, inconsistent definitions of CVD, and inadequate adjustment for key confounding variables. For example, Mu et al. (2016) identified an increased risk of CHD, primarily mediated by hysterectomy and oophorectomy; however, their analysis did not account for comorbidities and hormone therapy [ 12 ]. Subsequent studies associated endometriosis with stroke and arrhythmias, but their findings were limited by heterogeneous definitions of CVD and insufficient control of confounding factors [ 30 ]. A recent study corroborated increased risks of myocardial infarction, stroke, arrhythmia, and heart failure, yet was limited by its focus on a predominantly Danish population [ 2 , 4 ]. Our study addressed previous research gaps by leveraging both a large, population-based cohort (UK Biobank) and a hospital-based cohort with laparoscopically confirmed cases, while adjusting for sociodemographic, lifestyle, and reproductive factors. Across both cohorts, endometriosis independently increases the risk of CVD and CHD, with cardiovascular medications mitigating this risk. The observed cardiac changes provide imaging evidence of early myocardial remodeling in women with endometriosis, a phenomenon not well-documented before. These changes include increased interventricular septal thickness, regional wall motion abnormalities, and trends toward greater left ventricular wall thickness and systolic longitudinal wall thickening. This suggests that women with endometriosis may undergo subtle yet significant myocardial adaptations, possibly due to chronic inflammation or metabolic issues. Although endometriosis is linked to CVD, the exact mechanisms are rarely studied. This study explores four potential pathways, metabolism, inflammation, hormonal factors, and oxidative stress, that might mediate this relationship. Our initial findings suggest that metabolic biomarkers like triglycerides, LDL-C, TyG indices, and LAP may play a role in connecting endometriosis to CVD. There is growing evidence that endometriosis is linked to negative metabolic profiles, including a higher risk of type 2 diabetes and metabolic syndrome [ 31 – 33 ]. It is also associated with increased waist circumference, hypercholesterolemia, and hypertension [ 34 , 35 ]. Secondly, inflammation and oxidative stress are key pathways linking endometriosis to CVD risk. Endometriosis involves systemic chronic inflammation, which can lead to endothelial dysfunction, atherogenesis, and cardiac arrhythmias [ 36 – 38 ]. Additionally, oxidative damage can impair vascular and cardiac function, contributing to arrhythmias and cardiac remodeling [ 39 , 40 ]. Collectively, our findings offer preliminary insights into the potential underlying mechanisms by which endometriosis may contribute to increased CVD risk. Metabolic disturbances, chronic inflammation, and oxidative stress link endometriosis to higher CVD risk, suggesting dietary interventions could help. Flavonoids, plant-based compounds with anti-inflammatory and antioxidant properties, show promise. Studies indicate high flavonoid intake may lower risks of atherosclerosis [ 41 ], stroke [ 42 ], and coronary artery disease [ 43 ], and some research suggests it reduces CVD mortality [ 16 ]. However, evidence on specific flavonoid types like anthocyanins and isoflavones is inconsistent, and no clear benefits are seen for other subclasses [ 16 , 41 , 44 ]. Our research indicates that dietary intake of flavonoids may influence cardiovascular risk in women diagnosed with endometriosis. Specifically, lower consumption of total flavones and flavanones, including compounds such as hesperetin and naringenin, was correlated with an elevated risk of CVD and CHD, whereas higher consumption appeared to confer a protective effect. This suggests potential cardiometabolic benefits associated with these flavonoid subclasses. A comparable yet more complex pattern emerged for other flavonoid subclasses, such as anthocyanidins and apigenin, where moderate intake—but not low or high—was associated with increased risk, indicating possible non-linear or threshold effects. These findings highlight the significance of diet as a modifiable factor that may help mitigate the heightened cardiovascular risk in women with endometriosis and emphasize the necessity of considering specific flavonoid subclasses in the formulation of dietary interventions for this high-risk group. Clinical and research implications Our findings highlight the importance of managing and preventing CVD in women with endometriosis. The connection between endometriosis and increased CVD risk, particularly CHD, calls for enhanced cardiovascular monitoring. Early risk assessments using metabolic, inflammatory, and oxidative stress markers can identify high-risk individuals for targeted prevention. Subtle myocardial changes seen in CMR imaging suggest early cardiac alterations, underscoring the value of non-invasive cardiac imaging. Additionally, increasing flavone and flavanone intake through dietary changes may effectively reduce cardiovascular risk in these women. Strengths and limitations This study combines a large population-based cohort with an external hospital-based validation cohort, integrating cardiac magnetic resonance imaging, peripheral biomarkers, and dietary data to comprehensively evaluate associations and potential mechanisms linking endometriosis with cardiovascular remodeling and disease risk. Nevertheless, several limitations should be acknowledged. First, despite using both self-reported and registry-based diagnoses in the UK Biobank, misclassification of endometriosis remains possible, potentially attenuating observed associations; we mitigated this concern by conducting external validation with laparoscopically confirmed cases. Second, the hospital-based validation cohort only included clinical cardiovascular outcomes and lacked imaging, biomarker, and detailed dietary data, limiting validation to the association between endometriosis and incident cardiovascular events. Additionally, this cohort was smaller, which reduced statistical power for some cardiovascular outcomes and subgroup analyses. Third, although multiple sociodemographic, lifestyle, reproductive, and cardiovascular risk factors were adjusted for, residual confounding cannot be fully excluded, particularly for unmeasured factors such as disease severity, long-term medication adherence, or other dietary components beyond flavonoids. Fourth, dietary flavonoid intake was assessed using self-reported 24-hour recalls [ 23 , 45 ], which are subject to recall bias and potential misclassification, limiting causal interpretation. Finally, the generalizability of our findings may be restricted to populations similar to those in the UK Biobank or the hospital-based cohort, given differences in age, ethnicity, and healthcare access. Conclusions This study found that endometriosis is linked to a higher long-term risk of cardiovascular disease, especially CHD. Early heart changes, such as increased interventricular septal thickness and left ventricular hypertrophy, were observed in affected women. Metabolic, inflammatory, and oxidative stress pathways partly explain these links, while certain flavonoids in the diet may reduce cardiovascular risk. These results underscore endometriosis as a female-specific cardiovascular risk factor and suggest targeted prevention strategies, including biomarker-based risk assessment, lifestyle changes, and dietary interventions, to enhance cardiovascular outcomes in this high-risk group. Declarations Acknowledgments We thank the UK Biobank (Application Number: 529233) and its participants, as well as the patients, clinicians, and staff at the Second Affiliated Hospital of University of South China for their important contributions to this study. Author contributions Conceptualization: W.S.X. and F.Y.Z; Data curation: F.Y.Z., N.K.B., and X.M.L; Formal analysis: F.Y.Z., Z.J.J., and X.M.L; Methodology: F.Y.Z. and X.M.L; Validation: F.Y.Z.; Writing original draft: F.Y.Z., W.T., and Z.J.J; Writing review and editing: W.S.X., Z.J.J., W.T., and L.X.Y; Funding acquisition: W.S.X., and Z.J.J. All authors reviewed and approved the submitted version of the manuscript. Funding This research was funded by the National Key Research and Development Program of China, grant number 2022YFC2704100 and the National Natural Science Foundation of China, grant number 82371648. Data availability The UK Biobank resource can be accessed by researchers on application (Application Number: 529233). Data are available from the UK Biobank (https://www.ukbiobank.ac.uk/, accessed on 1 January 2024). The hospital validation cohort data are available upon reasonable request. Access requires submission of a research proposal and approval by the institutional ethics committee. Ethics approval and consent to participate The UK Biobank was approved by the North West Research Ethics Committee in 22 August 2006 (06/MRE08/65) and has been renewed every five years since then. The hospital-based study was approved by the Ethics Committee of the Second Affiliated Hospital of University of South China (No. 2025006), with informed consent obtained from all participants. Consent for publication Not appliable. Clinical trial number Not appliable. Competing interests All authors declare no disclosure of interest. Appendix A. Supplementary data The online version contains supplementary material available at https://orcid.org/0000-0002-8610-952X. References Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Barone Gibbs B, Beaton AZ, Boehme AK, et al: 2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 2024, 149: e347-e913. Pabon MA, Wang X, Rexrode KM: Beyond reproductive health: the cardiovascular risks of endometriosis. Eur Heart J 2024, 45: 4744-4746. Shafrir AL, Farland LV, Shah DK, Harris HR, Kvaskoff M, Zondervan K, Missmer SA: Risk for and consequences of endometriosis: A critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol 2018, 51: 1-15. Havers-Borgersen E, Hartwell D, Ekelund C, Butt JH, Østergaard L, Holgersson C, Schou M, Køber L, Fosbøl EL: Endometriosis and long-term cardiovascular risk: a nationwide Danish study. Eur Heart J 2024, 45: 4734-4743. Zondervan KT, Becker CM, Missmer SA: Endometriosis. N Engl J Med 2020, 382: 1244-1256. Giudice LC: Clinical practice. Endometriosis. N Engl J Med 2010, 362: 2389-2398. Poeta do Couto C, Policiano C, Pinto FJ, Brito D, Caldeira D: Endometriosis and cardiovascular disease: A systematic review and meta-analysis. Maturitas 2023, 171: 45-52. Vercellini P, Viganò P, Somigliana E, Fedele L: Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014, 10: 261-275. Marchandot B, Curtiaud A, Matsushita K, Trimaille A, Host A, Faller E, Garbin O, Akladios C, Jesel L, Morel O: Endometriosis and cardiovascular disease. Eur Heart J Open 2022, 2: oeac001. Santoro L, D'Onofrio F, Campo S, Ferraro PM, Flex A, Angelini F, Forni F, Nicolardi E, Campo V, Mascilini F, et al: Regression of endothelial dysfunction in patients with endometriosis after surgical treatment: a 2-year follow-up study. Hum Reprod 2014, 29: 1205-1210. Farland LV, Degnan WJ, 3rd, Bell ML, Kasner SE, Liberman AL, Shah DK, Rexrode KM, Missmer SA: Laparoscopically Confirmed Endometriosis and Risk of Incident Stroke: A Prospective Cohort Study. Stroke 2022, 53: 3116-3122. Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA: Endometriosis and Risk of Coronary Heart Disease. Circ Cardiovasc Qual Outcomes 2016, 9: 257-264. Parmenter BH, Croft KD, Hodgson JM, Dalgaard F, Bondonno CP, Lewis JR, Cassidy A, Scalbert A, Bondonno NP: An overview and update on the epidemiology of flavonoid intake and cardiovascular disease risk. Food Funct 2020, 11: 6777-6806. Del Rio D, Rodriguez-Mateos A, Spencer JP, Tognolini M, Borges G, Crozier A: Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid Redox Signal 2013, 18: 1818-1892. Hu Q, Ma X, Cai T, Li Y: Flavonoid intake, inflammation, and atherosclerotic cardiovascular disease risk in U.S. adults: a cross-sectional study. Nutr Metab (Lond) 2025, 22: 24. Grosso G, Micek A, Godos J, Pajak A, Sciacca S, Galvano F, Giovannucci EL: Dietary Flavonoid and Lignan Intake and Mortality in Prospective Cohort Studies: Systematic Review and Dose-Response Meta-Analysis. Am J Epidemiol 2017, 185: 1304-1316. Cassidy A, Mukamal KJ, Liu L, Franz M, Eliassen AH, Rimm EB: High anthocyanin intake is associated with a reduced risk of myocardial infarction in young and middle-aged women. Circulation 2013, 127: 188-196. Williamson G, Kay CD, Crozier A: The Bioavailability, Transport, and Bioactivity of Dietary Flavonoids: A Review from a Historical Perspective. Compr Rev Food Sci Food Saf 2018, 17: 1054-1112. Koller D, Løkhammer S, Goroshchuk O, Denner V, Stiltner B, Mitjans M, He J, Taylor HS, Lawn RB, Koenen KC, Polimanti R: Observational and Genetic Analyses of Traumatic Experiences and Endometriosis. JAMA Psychiatry 2025, 82: 386-394. Horne AW, Missmer SA: Pathophysiology, diagnosis, and management of endometriosis. Bmj 2022, 379: e070750. Gete DG, Dobson AJ, Mortlock S, Montgomery GW, Hockey R, Doust J, Mishra GD: Validation of self-reported endometriosis. Maturitas 2025, 199: 108642. Topriceanu CC, Gong X, Shah M, Shiwani H, Eminson K, Atilola GO, Jephcote C, Adams K, Blangiardo M, Moon JC, et al: Higher Aircraft Noise Exposure Is Linked to Worse Heart Structure and Function by Cardiovascular MRI. J Am Coll Cardiol 2025, 85: 454-469. Liu B, Young H, Crowe FL, Benson VS, Spencer EA, Key TJ, Appleby PN, Beral V: Development and evaluation of the Oxford WebQ, a low-cost, web-based method for assessment of previous 24 h dietary intakes in large-scale prospective studies. Public Health Nutr 2011, 14: 1998-2005. Bradbury KE, Young HJ, Guo W, Key TJ: Dietary assessment in UK Biobank: an evaluation of the performance of the touchscreen dietary questionnaire. J Nutr Sci 2018, 7: e6. Parmenter BH, Thompson AS, Bondonno NP, Jennings A, Murray K, Perez-Cornago A, Hodgson JM, Tresserra-Rimbau A, Kühn T, Cassidy A: High diversity of dietary flavonoid intake is associated with a lower risk of all-cause mortality and major chronic diseases. Nat Food 2025, 6: 668-680. Wang YX, Farland LV, Gaskins AJ, Wang S, Terry KL, Rexrode KM, Rich-Edwards JW, Tamimi R, Chavarro JE, Missmer SA: Endometriosis and uterine fibroids and risk of premature mortality: prospective cohort study. Bmj 2024, 387: e078797. Eastwood SV, Mathur R, Atkinson M, Brophy S, Sudlow C, Flaig R, de Lusignan S, Allen N, Chaturvedi N: Algorithms for the Capture and Adjudication of Prevalent and Incident Diabetes in UK Biobank. PLoS One 2016, 11: e0162388. Huang C, Lin B, Yuan Y, Li K, Xu B, Zhang P, Wei X, Wang W, Liu W, Deng Y, et al: Associations of Menstrual Cycle Regularity and Length With Cardiovascular Diseases: A Prospective Study From UK Biobank. J Am Heart Assoc 2023, 12: e029020. Hu Y, Tang R, Li X, Wang X, Ma H, Heianza Y, Qi L, Liang Z: Spontaneous miscarriage and social support in predicting risks of depression and anxiety: a cohort study in UK Biobank. Am J Obstet Gynecol 2024, 231: 655.e651-655.e659. Okoth K, Wang J, Zemedikun D, Thomas GN, Nirantharakumar K, Adderley NJ: Risk of cardiovascular outcomes among women with endometriosis in the United Kingdom: a retrospective matched cohort study. Bjog 2021, 128: 1598-1609. Farland LV, Degnan WJ, Harris HR, Tobias DK, Missmer SA: A prospective study of endometriosis and risk of type 2 diabetes. Diabetologia 2021, 64: 552-560. Li B, Zhang Y, Zhang L, Zhang L: Association between endometriosis and metabolic syndrome: a cross-sectional study based on the National Health and Nutrition Examination Survey data. Gynecol Endocrinol 2023, 39: 2254844. Grassi D, Desideri G, Di Giosia P, De Feo M, Fellini E, Cheli P, Ferri L, Ferri C: Tea, flavonoids, and cardiovascular health: endothelial protection. Am J Clin Nutr 2013, 98: 1660s-1666s. Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Forman JP, Missmer SA: Association Between Endometriosis and Hypercholesterolemia or Hypertension. Hypertension 2017, 70: 59-65. Melo AS, Rosa-e-Silva JC, Rosa-e-Silva AC, Poli-Neto OB, Ferriani RA, Vieira CS: Unfavorable lipid profile in women with endometriosis. Fertil Steril 2010, 93: 2433-2436. Du WW, Rafiq M, Yuan H, Li X, Wang S, Wu J, Wei J, Li RK, Guo H, Yang BB: A Novel Protein NAB1-356 Encoded by circRNA circNAB1 Mitigates Atrial Fibrillation by Reducing Inflammation and Fibrosis. Adv Sci (Weinh) 2025, 12: e2411959. Parent S, Vaka R, St Amant J, Kahn S, Van Remortel S, Bi C, Courtman D, Stewart DJ, Davis DR: Inactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation. Theranostics 2024, 14: 608-621. Bock JM, Shraffi Venkatesh V, Somers VK: Sex Differences in Atherosclerotic Cardiovascular Disease Risk in Obstructive Sleep Apnea. Curr Atheroscler Rep 2025, 27: 64. Gupta S, Agarwal A, Krajcir N, Alvarez JG: Role of oxidative stress in endometriosis. Reprod Biomed Online 2006, 13: 126-134. Sovari AA: Cellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress. Cardiol Res Pract 2016, 2016: 9656078. Garcia C, Blesso CN: Antioxidant properties of anthocyanins and their mechanism of action in atherosclerosis. Free Radic Biol Med 2021, 172: 152-166. Zhuo S, Zhang B, Zhang J, Yang M, Yu Z: Effects of dietary inflammatory index, blood lead levels, and flavonoid intake on stroke risk in older Americans: A cross-sectional study. J Stroke Cerebrovasc Dis 2023, 32: 107336. Dalgaard F, Bondonno NP, Murray K, Bondonno CP, Lewis JR, Croft KD, Kyrø C, Gislason G, Scalbert A, Cassidy A, et al: Associations between habitual flavonoid intake and hospital admissions for atherosclerotic cardiovascular disease: a prospective cohort study. Lancet Planet Health 2019, 3: e450-e459. Guo Q, Wang L, Qu Q, Cheang I, Li X, Pang H, Liao S: Association of flavonoid intake with coronary artery disease risk in the older population based on the National Health and Nutrition Examination Survey. Environ Sci Pollut Res Int 2024, 31: 3815-3827. Greenwood DC, Hardie LJ, Frost GS, Alwan NA, Bradbury KE, Carter M, Elliott P, Evans CEL, Ford HE, Hancock N, et al: Validation of the Oxford WebQ Online 24-Hour Dietary Questionnaire Using Biomarkers. Am J Epidemiol 2019, 188: 1858-1867. Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials.docx Graphicabstract.pdf Cite Share Download PDF Status: Published Journal Publication published 02 May, 2026 Read the published version in Reproductive Biology and Endocrinology → Version 1 posted Editorial decision: Revision requested 05 Mar, 2026 Reviews received at journal 24 Nov, 2025 Reviewers agreed at journal 23 Oct, 2025 Reviewers agreed at journal 23 Oct, 2025 Reviewers invited by journal 16 Oct, 2025 Editor assigned by journal 08 Oct, 2025 Submission checks completed at journal 08 Oct, 2025 First submitted to journal 06 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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07:05:12","extension":"xml","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":146127,"visible":true,"origin":"","legend":"","description":"","filename":"ceea8b4502e3459e91ce33ace469a0421structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/9e4ed57ef9be8e1df8ae998e.xml"},{"id":94709869,"identity":"76ff2c55-2678-4667-8e4f-618edd5812e2","added_by":"auto","created_at":"2025-10-30 01:08:34","extension":"html","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":158676,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/4792055c8816777131d9e6f1.html"},{"id":94709875,"identity":"6a5d610a-199d-4bfb-9e37-9d049a276de3","added_by":"auto","created_at":"2025-10-30 01:08:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1253292,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/663bf1bc962089b7e964b96e.png"},{"id":94709876,"identity":"165902d6-5c23-440d-bef1-21df3e472e2d","added_by":"auto","created_at":"2025-10-30 01:08:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":854349,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of cardiovascular outcomes according to the occurrence of endometriosis among 235,611 women. (A) Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cardiovascular outcomes in women with versus without endometriosis. Age-adjusted models included age only, multivariable models additionally adjusted for socioeconomic and lifestyle factors (Townsend deprivation index, race/ethnicity, education, hypertension, diabetes, smoking, alcohol consumption, physical activity, and healthy diet score), and fully adjusted models further accounted for reproductive factors (age at menarche, oral contraceptive use, and hormone replacement therapy); (B) Interaction analyses between endometriosis and overall cardiovascular disease (CVD); (C) Interaction analyses between endometriosis and coronary heart disease (CHD). All covariates the same as the full model were adjusted.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/17db3d1f87455ea1f6bf0003.png"},{"id":94709871,"identity":"2c47c69a-f11d-4121-a7b6-e1d2c3a19067","added_by":"auto","created_at":"2025-10-30 01:08:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":326268,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u0026nbsp;\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/50e2dd60086e8d6ded17016c.png"},{"id":94729806,"identity":"7481c6bd-1d21-42ad-b070-e44aa366e15c","added_by":"auto","created_at":"2025-10-30 07:05:25","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":694477,"visible":true,"origin":"","legend":"\u003cp\u003ePotential mechanisms linking endometriosis to cardiovascular outcomes. Mediation models were applied to evaluate the indirect effects of peripheral biomarkers on the associations between endometriosis and cardiovascular outcomes. (A) Mediation analysis for cardiovascular disease (CVD). (B) Mediation analysis for coronary heart disease (CHD). All models were adjusted for the same covariates as in the fully adjusted model. β\u003csub\u003eDE\u003c/sub\u003e represents the direct effect of endometriosis, and β\u003csub\u003eIE\u003c/sub\u003e represents the indirect effect mediated through biomarkers. **\u003cem\u003eP \u003c/em\u003e\u0026lt; 0.01, ***\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001.\u003c/p\u003e\n\u003cp\u003eTBIL: total bilirubin; LDL: low-density lipoprotein; HDL: high-density lipoprotein; TyG: triglyceride-glucose index; BMI: body mass Index; WC: waist circumference; WtHR: waist-to-height ratio; LAP: lipid accumulation product; CRP: C-reactive protein; INDLA score: low-grade inflammation score; DBIL: direct bilirubin; TC: total cholesterol.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/85e0b929a9b6f23f2eeb8270.png"},{"id":94709879,"identity":"040be883-ca58-4c4a-8143-a40016460aac","added_by":"auto","created_at":"2025-10-30 01:08:35","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":845031,"visible":true,"origin":"","legend":"\u003cp\u003eJoint associations of endometriosis and dietary flavonoid intake with cardiovascular disease. (A) Combined associations of endometriosis with total flavonoid and major flavonoid subclasses. (B) Further stratified analyses of specific flavonoid subclasses. All models were adjusted for the same covariates as in the fully adjusted model. * \u003cem\u003eP \u003c/em\u003e\u0026lt;0.05, **\u003cem\u003eP \u003c/em\u003e\u0026lt; 0.01, ***\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/0793581847f34fcce03d9207.png"},{"id":108804346,"identity":"262ba8c8-46c5-4cd1-a19d-18389859f61b","added_by":"auto","created_at":"2026-05-08 15:19:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3569674,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/1e065953-84a9-4eb1-9626-5ce3fd82dd0e.pdf"},{"id":94709887,"identity":"bb112505-e0fc-4e4d-9ba4-9decb9bbb5aa","added_by":"auto","created_at":"2025-10-30 01:08:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":26837303,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/f6abef7c6d9ebb0f09d95833.docx"},{"id":94709878,"identity":"fa64b776-b8ab-4b89-97e0-6e7c4a666751","added_by":"auto","created_at":"2025-10-30 01:08:35","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":155648,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicabstract.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7789511/v1/c30bdbef5386db02fa7fdadd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Endometriosis-Associated Cardiovascular Remodeling: Mechanistic Insights and the Modulatory Role of Flavonoids","fulltext":[{"header":"Highlights","content":"\u003cp\u003e1. Women with endometriosis face higher risks of cardiovascular disease, especially coronary heart disease.\u003c/p\u003e\u003cp\u003e2. CMR reveals subtle but significant adverse cardiac remodeling in women with endometriosis.\u003c/p\u003e\u003cp\u003e3. Metabolic, inflammatory, and oxidative stress pathways mediate endometriosis\u0026rsquo;s impact on cardiovascular disease.\u003c/p\u003e\u003cp\u003e4. Higher flavone and flavanone intake attenuates endometriosis-related cardiovascular risk.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eCardiovascular disease (CVD) remains a leading cause of morbidity and mortality in women, accounting for approximately 35% of all deaths in women globally [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Beyond traditional risk factors, emerging evidence highlights the importance of female-specific conditions and reproductive history in shaping long-term cardiovascular health [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEndometriosis is a chronic inflammatory gynecologic condition affecting\u0026thinsp;~\u0026thinsp;10% of women of reproductive age, often characterized by delayed diagnosis and inadequate treatment [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Traditionally viewed as a pelvic disorder, it is now increasingly recognized as a multisystem disease [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Mounting evidence suggests that women with endometriosis may be at greater risk for CVD later in life [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Further, treatments for endometriosis, such as hormonal medications, hysterectomy, and oophorectomy, may modify CVD risk [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Despite growing evidence linking endometriosis to CVD, it remains uncertain whether endometriosis independently associates with adverse cardiac structural and functional phenotypes. Prior investigations have primarily targeted isolated cardiovascular outcomes, often lacking comprehensive scope and mechanistic exploration. Addressing this gap is crucial for developing integrated approaches that consider both reproductive and systemic health in women with endometriosis.\u003c/p\u003e\u003cp\u003eFlavonoids, a class of (poly)phenolic compounds, are prevalent constituents of the human diet, sourced from a diverse array of foods such as fruits, vegetables, nuts, legumes, wines, and teas [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These compounds are categorized into several subclasses, including flavonols, anthocyanins, flavan-3-ols, flavanones, and flavones [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Upon ingestion and absorption, flavonoids and their metabolites have the potential to confer health benefits [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Numerous prospective cohort studies have demonstrated that higher habitual intake of various flavonoid subclasses is inversely associated with the risk of CVD [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Flavonoids, with their varied structures and metabolic processes, exhibit a range of biological effects, notably anti-inflammatory and antioxidative actions crucial for cardiovascular health [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, it's unclear if different flavonoids can reduce endometriosis-related CVD risks.\u003c/p\u003e\u003cp\u003eIn this study, we leveraged the population-based UK Biobank (UKB) and a hospital-based cohort of laparoscopically confirmed cases to investigate the relationship between endometriosis and CVD. Specifically, our aims were to: 1) systematically examine the prospective associations between endometriosis and incident CVD risk; 2) investigate the associations between endometriosis and subclinical cardiac structural alterations as measured by cardiac magnetic resonance (CMR) imaging; 3) elucidate underlying mechanisms by evaluating the potential mediating roles of metabolic dysfunction, systemic inflammation, oxidative stress, and hormonal imbalance in the relationship between endometriosis and CVD; and 4) explore whether flavonoid intake can mitigate the increased risk of CVD associated with endometriosis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003eUK Biobank cohort\u003c/h2\u003e\u003cp\u003eThe UKB is a prospective cohort study that gathered data from more than 500,000 participants aged 40 to 69, sourced from 22 assessment centers across England, Scotland, and Wales. Participants, from 2006 to 2010, completed a series of questionnaires, underwent diverse physical measurements, and provided biological samples. Participants provided informed consent for linking their data to national records of hospital admissions, cancer diagnoses, and death records. UK Biobank has approval from the North West Multicenter Research Ethics Committee (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics\u003c/span\u003e\u003cspan address=\"https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). This study utilizes data from the UK Biobank baseline assessment conducted between 2006 and 2010. Among the 502,128 participants enrolled in the UK Biobank, 273,155 women aged 40 to 69 years with available information on endometriosis were identified. Initially, 36,206 women with a history of coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), or stroke at baseline were excluded. Subsequently, 1,338 women diagnosed with endometriosis during follow-up were excluded. Ultimately, 235,611 women were included in the main and mediation analyses, among whom 6,158 were diagnosed with endometriosis and 229,453 without endometriosis \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eExternal validation hospital cohort\u003c/h3\u003e\n\u003cp\u003eTo address potential misclassification of endometriosis in the UK Biobank due to reliance on self-reported and registry-based diagnoses, we conducted an external validation study using a retrospective-prospective hospital-based cohort from the Second Affiliated Hospital of University of South China, a tertiary referral center for gynecologic diseases. This hospital-based cohort included women who underwent laparoscopic surgery for suspected endometriosis between January 2008 and December 2012. Eligibility criteria included: (i) women aged\u0026thinsp;\u0026ge;\u0026thinsp;20 years at the time of diagnosis, (ii) laparoscopically confirmed endometriosis based on intraoperative visual inspection and histopathological examination, and (iii) absence of clinically evident cardiovascular disease prior to laparoscopic confirmation. Women were excluded if they were pregnant, had pathologically or clinically confirmed leiomyoma, adenomyosis, pelvic inflammatory disease, kidney disease, cancer, or autoimmune disorders, or had previously undergone hysterectomy or oophorectomy. The control group comprised women from the same hospital and time period who had no evidence of endometriosis on transvaginal ultrasound or laparoscopy. Controls were frequency-matched to cases in a 1:1 ratio by age and met the same exclusion criteria as cases. In total, 621 women with laparoscopically confirmed endometriosis were included as cases, and 621 matched controls comprised the comparison group \u003cb\u003e(Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/b\u003e. Participants were followed up through May 2025. Because imaging, biomarker, and dietary data were unavailable in this cohort, validation was limited to the association between endometriosis and incident cardiovascular events. The hospital-based study was approved by the Ethics Committee of the Second Affiliated Hospital of University of South China (Approval No. 2025006), and informed consent was obtained from all participants.\u003c/p\u003e\n\u003ch3\u003eDefinition of endometriosis\u003c/h3\u003e\n\u003cp\u003eTo maximize case ascertainment, we defined endometriosis using both UK Biobank electronic health records (EHR) diagnoses and self-reported physician diagnoses. Specifically, EHR diagnoses were based on ICD-10 codes N80.x, while self-reported cases were obtained during a structured, nurse-led interview at baseline assessment [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A total of 6,158 women with endometriosis were identified: 3,627 through health records, 3,384 through self-report, and 853 by both sources.\u003c/p\u003e\u003cp\u003eWhile laparoscopic confirmation with histological verification remains the diagnostic gold standard [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], such information is not systematically available in population-based cohorts. Previous validation studies have shown that registry- and self-report\u0026ndash;based definitions of endometriosis, although less sensitive, have high specificity, and thus are more likely to result in under-ascertainment rather than false-positive misclassification [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. To strengthen diagnostic validity, we further conducted an external validation study in the Second Affiliated Hospital of University of South China, where all diagnoses were confirmed by laparoscopy and histopathology. This external dataset not only corroborated the accuracy of our case definition but also enabled a sensitivity analysis restricted to laparoscopically confirmed cases, thereby ensuring the robustness of our findings.\u003c/p\u003e\n\u003ch3\u003eDefinition of cardiovascular disease\u003c/h3\u003e\n\u003cp\u003eThe primary outcome in both the UK Biobank and the hospital-based validation cohort was incident CVD, encompassing CHD, MI, HF, AF, and stroke. In the UK Biobank, events were ascertained through linkage to national hospital admission databases in England, Wales, and Scotland, with follow-up from baseline assessment until the first occurrence of a CVD event or October 31, 2022, whichever came first. In the hospital-based cohort, CVD events were identified through electronic medical records and clinical follow-up up to the most recent available date. All events in both cohorts were defined using ICD-10 codes: CHD (I20\u0026ndash;I25, including fatal ischemic heart disease and nonfatal MI I21\u0026ndash;I23), AF and related arrhythmias (I48\u0026ndash;I49), HF (I50), and stroke encompassing all cerebrovascular diseases (I60\u0026ndash;I64, I69) (\u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eCMR outcomes\u003c/h2\u003e\u003cp\u003eA previously detailed CMR protocol and analysis method were used in a study involving\u0026thinsp;~\u0026thinsp;40,000 participants from the UK Biobank, out of the initial\u0026thinsp;~\u0026thinsp;500,000, who were scanned by August 2023 [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. These CMR scans primarily assessed cardiac anatomy and biventricular function, providing comprehensive evaluations of cardiac structure, function, tissue characteristics, and prognostic markers. Details are provided in Supplementary Methods.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePeripheral biomarkers\u003c/h3\u003e\n\u003cp\u003eIn this study, we analyzed 12 metabolic, 11 inflammatory, 4 oxidative stress, and 1 hormonal biomarkers. Detailed information is provided in Supplementary Methods.\u003c/p\u003e\n\u003ch3\u003eDietary flavonoid intake assessment\u003c/h3\u003e\n\u003cp\u003eDietary intake was evaluated using the Oxford WebQ 24-hour recall up to five times from 2009 to 2012 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Flavonoid intake was estimated by matching Oxford WebQ food codes with USDA flavonoid databases, using updated nutrient algorithms for individual foods and recipes [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Mean daily intakes (mg/d) were averaged from valid questionnaires. Subclass intakes included flavan-3-ols, flavonols, flavones, anthocyanins, and flavanones. Total flavonoid intake was the sum of all compounds, excluding isoflavones due to low UK consumption. Participants were grouped into low, medium, and high intake based on population-specific tertiles of total flavonoid intake. Descriptive statistics for total and subclass intakes were calculated for all participants (n\u0026thinsp;=\u0026thinsp;103,108; see \u003cb\u003eSupplementary Table S11\u003c/b\u003e).\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eMeasurement of covariates\u003c/h2\u003e\u003cp\u003eCovariates were selected based on prior literature [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] across four domains: sociodemographic, lifestyle, cardiovascular risk, and reproductive/hormonal factors.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eUK Biobank cohort\u003c/h2\u003e\u003cp\u003e(1) Baseline sociodemographic factors such as age, ethnicity, education, and the Townsend Deprivation Index (TDI); (2) Lifestyle factors like alcohol use, smoking, physical activity, and a healthy diet score; (3) Cardiovascular risk factors, including baseline diabetes and hypertension diagnoses, and use of related medications; (4) Reproductive and hormonal factors, such as age at menarche, and use of oral contraceptives and hormone replacement therapy. The TDI measures socioeconomic status, with lower values indicating higher status. Diabetes was defined using UK Biobank algorithms, and hypertension was defined by self-reported diagnosis or antihypertensive medication use [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Information on smoking, alcohol consumption, physical activity, and diet was collected. Smoking was categorized as never, former, or current. Alcohol intake was divided into never, former, \u0026lt;\u0026thinsp;1 drink/week, 1\u0026ndash;2 drinks/week, and \u0026ge;\u0026thinsp;3 drinks/week [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Physical activity was measured using the International Physical Activity Questionnaire and classified as low (\u0026lt;\u0026thinsp;600 MET/min per week), moderate (\u0026ge;\u0026thinsp;600 MET/min per week), or high (\u0026ge;\u0026thinsp;3000 MET/min per week) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. A healthy diet score was based on fruit, vegetable, fish, processed meat, and red meat intake, with each favorable factor scored as 1 and unfavorable as 0, resulting in a total score ranging from 0 to 5 [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Additional covariate details are in \u003cb\u003eTable S3.\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eHospital-based external validation cohort\u003c/h2\u003e\u003cp\u003e Sociodemographic information was obtained from medical records and patient interviews. Lifestyle factors (smoking, alcohol, physical activity, diet) were collected via standardized questionnaires administered at baseline. Cardiovascular risk factors (diabetes, hypertension, medication use) and reproductive/hormonal factors (age at menarche, contraceptive or hormone therapy use) were abstracted from medical records. Measurement categories were harmonized as closely as possible with the UKB cohort.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003eAssociation analysis between endometriosis and CVD incidence\u003c/h2\u003e\u003cp\u003eContinuous variables were summarized as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median with IQR, and categorical variables as percentages. All continuous variables were log-transformed and standardized (Z-score) to minimize the statistical biases. Moreover, adjustments to the Benjamini-Hochberg method for false discovery rate (FDR) were applied. Multivariable Cox proportional hazards regression models were employed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between endometriosis and incident CVD and other cardiovascular outcomes. A stepwise modeling strategy was adopted: the primary model was adjusted for age. Multivariable models were further adjusted for Townsend deprivation index, race/ethnicity, education level of college, baseline hypertension, baseline diabetes, smoking status, alcohol consumption, physical activity, and healthy diet score. The fully models were further adjusted for reproductive factors (age at menarche, OC and HRT use). The proportional hazards assumption was tested using the Kolmogorov-type supremum test, with no violations detected (all \u003cem\u003eP\u003c/em\u003e-values\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e To strengthen our findings, we conducted five sensitivity analyses: 1) excluded participants with less than 5 years of follow-up to avoid reverse causation; 2) limited endometriosis cases to those identified by ICD-10 codes to prevent misclassification; 3) adjusted for menopausal status to control for reproductive aging; 4) excluded women with a history of hysterectomy or oophorectomy to assess the impact of surgically induced hormonal changes; and 5) conducted an analysis in the hospital-based external validation cohort, including only laparoscopically confirmed cases, to verify exposure accuracy and replicate the associations observed in the UK Biobank cohort.\u003c/p\u003e\u003cp\u003eGiven the positively skewed distributions of CMR metrics, generalized linear models with a gamma distribution and log link were used to investigate the associations between endometriosis as the independent variable and the cardiac phenotype by CMR as the dependent variable. FDR correction was appropriately applied, and Q values were reported across the analyses.\u003c/p\u003e\u003cp\u003eMediation models were used to explore how endometriosis might influence CVD risk through biomarkers. Initially, linear regression identified biomarkers linked to endometriosis. The most significant biomarkers were then tested as mediators using the \"mediation\" package in R, adjusting for various demographic and health factors. The significance of mediation effects was evaluated with 5000 bootstrap iterations.\u003c/p\u003e\u003cp\u003eFinally, we further investigated whether dietary flavonoid intake modified the association between endometriosis and CVD. To formally test for interaction, multiplicative terms between endometriosis status and flavonoid intake were incorporated into the models. In addition, we evaluated the joint associations of endometriosis and flavonoid intake categories with CVD risk, using women without endometriosis and with high flavonoid intake as the reference group. Analyses were performed in R 4.3.3.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eParticipant characteristics\u003c/h2\u003e\u003cp\u003eTables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and S4 summarize the baseline characteristics of women in the UK Biobank and hospital-based cohorts. In the UK Biobank cohort (n\u0026thinsp;=\u0026thinsp;235,611; mean age 55.7 years), women with endometriosis were younger and less likely to have a college education. Also, they exhibited a slightly elevated prevalence of current smoking, an increase in low to moderate alcohol consumption, and diminished levels of physical activity (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Moreover, these women experienced menarche at an earlier age and more frequently utilized oral contraceptives and hormone replacement therapy (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Diabetes was slightly less prevalent among women with endometriosis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows an overview of analyses performed in the study.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics of the study population (n\u0026thinsp;=\u0026thinsp;235,611).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWithout endometriosis at baseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEndometriosis at baseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of women\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e235,611\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e229,453\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,158\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55.68\u0026plusmn;(7.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55.76\u0026plusmn;(7.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e52.62\u0026plusmn;(7.59)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTownsend deprivation index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-1.41\u0026plusmn;(3.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1.41\u0026plusmn;(3.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-1.38\u0026plusmn;(2.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.150\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRace/ethnicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.100\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhite\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e223,231 (95%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e217,395 (95%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5,836 (95%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAsian or Asian British\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4,588 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4,487 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e101 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther or mixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7,792 (3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7,571 (3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e221 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEducation level of college\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmoking status\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNever\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e142,353 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e138,641 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3,712 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFormer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72,607 (31%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70,795 (31%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,812 (29%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCurrent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20,651 (9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 017 (9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e634 (10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlcohol consumption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNever\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12,706 (5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12,422 (5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e284 (5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFormer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7,934 (3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7,684 (3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e250 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCurrent: \u0026lt; 1 drink/week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33,863 (14%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32,905 (14%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e958 (16%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCurrent: 1\u0026ndash;2 drinks/week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30,798 (13%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29,797 (13%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,001 (16%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCurrent: \u0026ge;3 drinks/weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e150,310 (64%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e146,645 (64%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3,665 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhysical activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31,106 (13%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30,202 (13%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e904 (15%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e74,916 (32%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72,994 (32%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,922 (31%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e69,182 (29%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e67,385 (29%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,797 (29%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60,407 (26%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58,872 (26%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,535 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHealthy diet score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.300\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at menarche (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46,240 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44,841 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,399 (23%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44,716 (19%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43,570 (19%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,146 (19%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e58,313 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56,794 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,519 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46,866 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45,751 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,115 (18%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39,476 (17%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38,497 (17%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e979 (16%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOC use\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e193,798 (82%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e188,459 (82%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5,339 (87%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHRT use\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85,091 (36%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e82,028 (36%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3,063 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension at baseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46,815 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45,618 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,197 (19%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.400\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes at baseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5,630 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 511 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e119 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are presented as the means (SDs), medians (interquartile ranges), or percentages. OC: oral contraceptives; HRT: hormone replacement therapy.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIn the hospital-based cohort (n\u0026thinsp;=\u0026thinsp;1,224; 612 cases and 612 controls; mean age 42.3 years), women with laparoscopically confirmed endometriosis similarly had lower college education rates (34.6% vs. 40.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025), engaged in less physical activity (low activity: 49.0% vs. 43.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), experienced earlier menarche (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), and more frequently used oral contraceptives (74.7% vs. 66.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and HRT (4.2% vs. 2.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030). No significant differences were observed in marital status, smoking, alcohol consumption, hypertension, or diabetes (\u003cb\u003eTable S4\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eProspective association between endometriosis and CVD risk\u003c/h2\u003e\u003cp\u003eDuring a median follow-up of 13.03 years, women with endometriosis had higher risk of CVD than those without endometriosis after fully adjustment for age, ethnicity, education level, Townsend deprivation index, alcohol consumption, smoking status, physical activity, healthy diet score, baseline diabetes, baseline hypertension, age at menarche, OC and HRT use (HR\u0026thinsp;=\u0026thinsp;1.18, 95% CI: 1.08\u0026ndash;1.28, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). With further in-depth analyses examining subtypes of cardiovascular outcomes, endometriosis was associated with an increased risk of CHD (HR\u0026thinsp;=\u0026thinsp;1.25, 95% CI: 1.11\u0026ndash;1.40, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). However, no significant associations were observed for myocardial infarction, atrial fibrillation, heart failure, or stroke after full adjustment (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Sensitivity analyses, such as excluding participants with less than 5 years of follow-up, focusing on ICD-10 endometriosis diagnoses, and adjusting for menopausal status, showed no significant change in associations (\u003cb\u003eFigs. S2-S4\u003c/b\u003e). Even after excluding women with previous hysterectomy or oophorectomy, endometriosis was still significantly linked to heart failure (HR\u0026thinsp;=\u0026thinsp;1.47, 95% CI: 1.04\u0026ndash;2.09, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030; \u003cb\u003eFig. S5\u003c/b\u003e). Similarly, in the hospital-based external validation cohort of laparoscopically confirmed cases, endometriosis was associated with higher risks of composite CVD (HR\u0026thinsp;=\u0026thinsp;1.22, 95% CI: 1.08\u0026ndash;1.36, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; \u003cb\u003eFig. S6\u003c/b\u003e) and CHD (HR\u0026thinsp;=\u0026thinsp;1.25, 95% CI: 1.08\u0026ndash;1.40, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023; \u003cb\u003eFig. S6\u003c/b\u003e). While associations with myocardial infarction, atrial fibrillation, and heart failure were not significant, stroke risk remained elevated (HR\u0026thinsp;=\u0026thinsp;1.19, 95% CI: 1.03\u0026ndash;1.40, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041; \u003cb\u003eFig. S6\u003c/b\u003e), highlighting the consistency of key cardiovascular findings across both cohorts.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eInteraction analyses support a significant modulating effect of physical activity on the association of endometriosis with CHD risks (\u003cem\u003eP\u003c/em\u003e for interaction\u0026thinsp;=\u0026thinsp;0.030; Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB-\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). In stratified analyses, women with endometriosis with low physical activity had a higher CHD risk than those with high physical activity (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC \u003cb\u003eand Figs. S7-S8\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eAssociations between endometriosis and the CMR phenotypes\u003c/h2\u003e\u003cp\u003eTo further explore the cardiovascular effects of endometriosis, we used CMR imaging to compare cardiac structure and function. In the fully adjusted model, participants with endometriosis had significantly greater IVST (% difference\u0026thinsp;=\u0026thinsp;1.07, 95% CI: 0.10\u0026ndash;2.04, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003eand Table S5\u003c/b\u003e) and LV RWM (% difference\u0026thinsp;=\u0026thinsp;1.07, 95% CI: 0.04 to 2.12, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003eand Table S5\u003c/b\u003e). In addition, LV \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\overline{\\text{W}\\text{T}}\\)\u003c/span\u003e\u003c/span\u003e (% difference\u0026thinsp;=\u0026thinsp;0.78, 95% CI: -0.06-1.62, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.069; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003eand Table S5\u003c/b\u003e) and SLWR (% difference\u0026thinsp;=\u0026thinsp;0.63, 95% CI: -0.01-1.27, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.052; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003eand Table S5\u003c/b\u003e) were marginally elevated in the endometriosis group, suggesting a possible trend toward concentric remodeling.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003ePotential mechanism contributing to the associations between endometriosis and CVD risk\u003c/h2\u003e\u003cp\u003eA linear regression model revealed significant links between endometriosis and various biomarkers, including ten metabolic, six inflammatory, two oxidative stress, and one hormonal (\u003cb\u003eTable S6\u003c/b\u003e). Specifically, higher levels of triglycerides (β: 0.14, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), LDL-C (β: 0.09, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), total cholesterol (β: 0.08, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), TyG indices (β: 0.10\u0026ndash;0.13, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and LAP (β: 0.12, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were associated with endometriosis, while HDL-C (β: -0.07, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and total bilirubin (β: -0.05, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were inversely related. Regarding inflammatory markers, CRP (β: 0.11, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), lymphocyte percentage (β: 0.03, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049), lymphocyte count (β: 0.04, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006), and INFLA score (β: 0.22, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005) were positively linked to endometriosis, whereas monocyte percentage (β: -0.03, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031) and platelet count (β: -0.03, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045) were negatively associated. For oxidative stress markers, urate (β: 0.06, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) showed a positive association, and DBIL (β: 0.06, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) an inverse one, with endometriosis. In addition, SHBG (β: -0.04, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) levels were inversely related to endometriosis. We further used the Cox proportional hazards model to examine the relationship between peripheral biomarkers and CVD risk (\u003cb\u003eTables S7-S8\u003c/b\u003e). Metabolic markers like triglycerides (CVD: HR: 1.08, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CHD: HR: 1.18, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), FPG (CVD: HR: 1.03, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CHD: HR: 1.05, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), TyG indices (CVD: HR: 1.09\u0026ndash;1.21, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CHD: HR: 1.20\u0026ndash;1.24, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and LAP (CVD: HR: 1.13, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CHD: HR: 0.84, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were linked to higher CVD and CHD risk, while HDL-C (CVD: HR: 0.89, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CHD: HR: 1.18, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was inversely related. LDL-C (CHD: HR: 1.14, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and total cholesterol (CHD: HR: 1.10, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were associated with increased CHD risk. Inflammatory markers, including monocyte (HR: 1.02, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) and basophil percentages (HR: 1.02, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), their absolute counts (monocyte: HR: 1.07, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; basophil: HR: 1.03, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), CRP (HR: 1.16, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), NLR (HR: 1.04, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), MLR (HR: 1.04, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), SII (HR: 1.00, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), SIRI (HR: 1.02, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the INFLA score (HR: 1.02, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), were positively associated with CVD, and similar markers were linked to CHD (All \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Lymphocyte percentage (CVD: HR: 0.93, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CHD: HR: 0.95, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was inversely related to both CVD and CHD. For oxidative stress, urate (HR: 1.11, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and DBIL (HR: 1.04, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were positively associated with CVD, but albumin (HR: 0.89, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was inversely related. Albumin (HR: 0.91, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and DBIL (HR: 0.97, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007) were inversely linked to CHD, while urate (HR: 1.12, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) showed a positive association. SHBG (CVD: HR: 0.97, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CHD: HR: 0.90, \u003cem\u003eQ\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was inversely associated with both CVD and CHD.\u003c/p\u003e\u003cp\u003eMediation model was used to explore how endometriosis influences CVD via peripheral biomarkers (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e \u003cb\u003eand Tables S9-S10\u003c/b\u003e). For CVD, metabolic indices like TyG-WC (13.7%), TyG-BMI (13.3%), and others showed the highest mediation, while inflammatory markers like CRP (9.6%) and oxidative stress markers like urate (3.7%) had smaller effects. For CHD, metabolic mediators such as triglycerides (10.8%) and TyG (10.5%) were most significant, with inflammatory markers like CRP (7.7%) also contributing. Oxidative stress markers had minor roles.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003eJoint effect of dietary flavonoid intake and endometriosis on CVD risk\u003c/h2\u003e\u003cp\u003eCompared with the reference group (women without endometriosis and with high intakes of flavonoid subclasses), women with endometriosis and low intakes of total flavones (luteolin: HR\u0026thinsp;=\u0026thinsp;1.34; 95% CI: 1.08\u0026ndash;1.67) and total flavanones (HR\u0026thinsp;=\u0026thinsp;1.36; 95% CI: 1.10\u0026ndash;1.68), including hesperetin (HR\u0026thinsp;=\u0026thinsp;1.33; 95% CI: 1.07\u0026ndash;1.64) and naringenin (HR\u0026thinsp;=\u0026thinsp;1.38; 95% CI: 1.11\u0026ndash;1.70), had the highest CVD risk. By contrast, women with endometriosis who consumed high amounts of these flavonoid subclasses did not show an elevated CVD risk relative to the reference group. A similar pattern was observed for CHD. Among women with endometriosis, those with low intakes of total flavonols (HR\u0026thinsp;=\u0026thinsp;1.37; 95% CI: 1.01\u0026ndash;1.87) and total flavanones (HR\u0026thinsp;=\u0026thinsp;1.53; 95% CI: 1.15\u0026ndash;2.04), including hesperetin (HR\u0026thinsp;=\u0026thinsp;1.51; 95% CI: 1.13\u0026ndash;2.01) and naringenin (HR\u0026thinsp;=\u0026thinsp;1.62; 95% CI: 1.23\u0026ndash;2.15), exhibited the highest CHD risk, whereas high intakes of these flavonoid subclasses were not associated with excess risk. Among women with endometriosis, moderate intakes of total anthocyanidins (HR\u0026thinsp;=\u0026thinsp;1.29; 95% CI: 1.02\u0026ndash;1.61) were associated with an increased CVD risk, while neither low nor high intakes were linked to significant associations. Likewise, moderate intakes of total flavones (HR\u0026thinsp;=\u0026thinsp;1.41; 95% CI: 1.03\u0026ndash;1.92) and apigenin (HR\u0026thinsp;=\u0026thinsp;1.48; 95% CI: 1.10\u0026ndash;1.99) were associated with significantly higher CHD risk (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e \u003cb\u003eand Tables S11-S13\u003c/b\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e\u003ch2\u003ePrincipal findings\u003c/h2\u003e\u003cp\u003eIn this large cohort study, we explored the link between endometriosis and increased long-term CVD risk, especially CHD. CMR imaging showed significant cardiac changes, such as increased interventricular septal thickness and regional wall motion abnormalities, suggesting early concentric remodeling. Mediation analyses revealed that metabolic, inflammatory, and oxidative stress biomarkers partly explained these associations, particularly for CHD. Furthermore, a low dietary intake of specific flavonoid subclasses\u0026mdash;particularly flavones and flavanones\u0026mdash;was associated with the highest risks of CVD and CHD among women with endometriosis, whereas higher intakes appeared to confer a protective effect.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003eInterpretation of study findings and comparison with existing literature\u003c/h2\u003e\u003cp\u003eTo date, a limited number of observational studies have examined the relationship between endometriosis and CVD, often constrained by small sample sizes, inconsistent definitions of CVD, and inadequate adjustment for key confounding variables. For example, Mu et al. (2016) identified an increased risk of CHD, primarily mediated by hysterectomy and oophorectomy; however, their analysis did not account for comorbidities and hormone therapy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Subsequent studies associated endometriosis with stroke and arrhythmias, but their findings were limited by heterogeneous definitions of CVD and insufficient control of confounding factors [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. A recent study corroborated increased risks of myocardial infarction, stroke, arrhythmia, and heart failure, yet was limited by its focus on a predominantly Danish population [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur study addressed previous research gaps by leveraging both a large, population-based cohort (UK Biobank) and a hospital-based cohort with laparoscopically confirmed cases, while adjusting for sociodemographic, lifestyle, and reproductive factors. Across both cohorts, endometriosis independently increases the risk of CVD and CHD, with cardiovascular medications mitigating this risk. The observed cardiac changes provide imaging evidence of early myocardial remodeling in women with endometriosis, a phenomenon not well-documented before. These changes include increased interventricular septal thickness, regional wall motion abnormalities, and trends toward greater left ventricular wall thickness and systolic longitudinal wall thickening. This suggests that women with endometriosis may undergo subtle yet significant myocardial adaptations, possibly due to chronic inflammation or metabolic issues.\u003c/p\u003e\u003cp\u003eAlthough endometriosis is linked to CVD, the exact mechanisms are rarely studied. This study explores four potential pathways, metabolism, inflammation, hormonal factors, and oxidative stress, that might mediate this relationship. Our initial findings suggest that metabolic biomarkers like triglycerides, LDL-C, TyG indices, and LAP may play a role in connecting endometriosis to CVD. There is growing evidence that endometriosis is linked to negative metabolic profiles, including a higher risk of type 2 diabetes and metabolic syndrome [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. It is also associated with increased waist circumference, hypercholesterolemia, and hypertension [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Secondly, inflammation and oxidative stress are key pathways linking endometriosis to CVD risk. Endometriosis involves systemic chronic inflammation, which can lead to endothelial dysfunction, atherogenesis, and cardiac arrhythmias [\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Additionally, oxidative damage can impair vascular and cardiac function, contributing to arrhythmias and cardiac remodeling [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Collectively, our findings offer preliminary insights into the potential underlying mechanisms by which endometriosis may contribute to increased CVD risk.\u003c/p\u003e\u003cp\u003eMetabolic disturbances, chronic inflammation, and oxidative stress link endometriosis to higher CVD risk, suggesting dietary interventions could help. Flavonoids, plant-based compounds with anti-inflammatory and antioxidant properties, show promise. Studies indicate high flavonoid intake may lower risks of atherosclerosis [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], stroke [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], and coronary artery disease [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], and some research suggests it reduces CVD mortality [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, evidence on specific flavonoid types like anthocyanins and isoflavones is inconsistent, and no clear benefits are seen for other subclasses [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Our research indicates that dietary intake of flavonoids may influence cardiovascular risk in women diagnosed with endometriosis. Specifically, lower consumption of total flavones and flavanones, including compounds such as hesperetin and naringenin, was correlated with an elevated risk of CVD and CHD, whereas higher consumption appeared to confer a protective effect. This suggests potential cardiometabolic benefits associated with these flavonoid subclasses. A comparable yet more complex pattern emerged for other flavonoid subclasses, such as anthocyanidins and apigenin, where moderate intake\u0026mdash;but not low or high\u0026mdash;was associated with increased risk, indicating possible non-linear or threshold effects. These findings highlight the significance of diet as a modifiable factor that may help mitigate the heightened cardiovascular risk in women with endometriosis and emphasize the necessity of considering specific flavonoid subclasses in the formulation of dietary interventions for this high-risk group.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\u003ch2\u003eClinical and research implications\u003c/h2\u003e\u003cp\u003eOur findings highlight the importance of managing and preventing CVD in women with endometriosis. The connection between endometriosis and increased CVD risk, particularly CHD, calls for enhanced cardiovascular monitoring. Early risk assessments using metabolic, inflammatory, and oxidative stress markers can identify high-risk individuals for targeted prevention. Subtle myocardial changes seen in CMR imaging suggest early cardiac alterations, underscoring the value of non-invasive cardiac imaging. Additionally, increasing flavone and flavanone intake through dietary changes may effectively reduce cardiovascular risk in these women.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\u003ch2\u003eStrengths and limitations\u003c/h2\u003e\u003cp\u003eThis study combines a large population-based cohort with an external hospital-based validation cohort, integrating cardiac magnetic resonance imaging, peripheral biomarkers, and dietary data to comprehensively evaluate associations and potential mechanisms linking endometriosis with cardiovascular remodeling and disease risk. Nevertheless, several limitations should be acknowledged. First, despite using both self-reported and registry-based diagnoses in the UK Biobank, misclassification of endometriosis remains possible, potentially attenuating observed associations; we mitigated this concern by conducting external validation with laparoscopically confirmed cases. Second, the hospital-based validation cohort only included clinical cardiovascular outcomes and lacked imaging, biomarker, and detailed dietary data, limiting validation to the association between endometriosis and incident cardiovascular events. Additionally, this cohort was smaller, which reduced statistical power for some cardiovascular outcomes and subgroup analyses. Third, although multiple sociodemographic, lifestyle, reproductive, and cardiovascular risk factors were adjusted for, residual confounding cannot be fully excluded, particularly for unmeasured factors such as disease severity, long-term medication adherence, or other dietary components beyond flavonoids. Fourth, dietary flavonoid intake was assessed using self-reported 24-hour recalls [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], which are subject to recall bias and potential misclassification, limiting causal interpretation. Finally, the generalizability of our findings may be restricted to populations similar to those in the UK Biobank or the hospital-based cohort, given differences in age, ethnicity, and healthcare access.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study found that endometriosis is linked to a higher long-term risk of cardiovascular disease, especially CHD. Early heart changes, such as increased interventricular septal thickness and left ventricular hypertrophy, were observed in affected women. Metabolic, inflammatory, and oxidative stress pathways partly explain these links, while certain flavonoids in the diet may reduce cardiovascular risk. These results underscore endometriosis as a female-specific cardiovascular risk factor and suggest targeted prevention strategies, including biomarker-based risk assessment, lifestyle changes, and dietary interventions, to enhance cardiovascular outcomes in this high-risk group.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the UK Biobank (Application Number: 529233) and its participants, as well as the patients, clinicians, and staff at the Second Affiliated Hospital of University of South China for their important contributions to this study.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eConceptualization: W.S.X. and F.Y.Z; Data curation: F.Y.Z., N.K.B., and X.M.L; Formal analysis: F.Y.Z., Z.J.J., and X.M.L; Methodology: F.Y.Z. and X.M.L; Validation: F.Y.Z.; Writing original draft: F.Y.Z., W.T., and Z.J.J; Writing review and editing: W.S.X., Z.J.J., W.T., and L.X.Y; Funding acquisition: W.S.X., and Z.J.J. All authors reviewed and approved the submitted version of the manuscript.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis research was funded by the National Key Research and Development Program of China, grant number 2022YFC2704100 and the National Natural Science Foundation of China, grant number 82371648.\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eThe UK Biobank resource can be accessed by researchers on application (Application Number: 529233). Data are available from the UK Biobank (https://www.ukbiobank.ac.uk/, accessed on 1 January 2024). The hospital validation cohort data are available upon reasonable request. Access requires submission of a research proposal and approval by the institutional ethics committee.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe UK Biobank was approved by the North West Research Ethics Committee in 22 August 2006 (06/MRE08/65) and has been renewed every five years since then. The hospital-based study was approved by the Ethics Committee of the Second Affiliated Hospital of University of South China (No. 2025006), with informed consent obtained from all participants.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot appliable.\u003c/p\u003e\n\u003cp\u003eClinical trial number\u003c/p\u003e\n\u003cp\u003eNot appliable.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eAll authors declare no disclosure of interest.\u003c/p\u003e\n\u003cp\u003eAppendix A. Supplementary data\u003c/p\u003e\n\u003cp\u003eThe online version contains supplementary material available at https://orcid.org/0000-0002-8610-952X.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMartin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Barone Gibbs B, Beaton AZ, Boehme AK, et al: \u003cstrong\u003e2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.\u003c/strong\u003e \u003cem\u003eCirculation \u003c/em\u003e2024, \u003cstrong\u003e149:\u003c/strong\u003ee347-e913.\u003c/li\u003e\n\u003cli\u003ePabon MA, Wang X, Rexrode KM: \u003cstrong\u003eBeyond reproductive health: the cardiovascular risks of endometriosis.\u003c/strong\u003e \u003cem\u003eEur Heart J \u003c/em\u003e2024, \u003cstrong\u003e45:\u003c/strong\u003e4744-4746.\u003c/li\u003e\n\u003cli\u003eShafrir AL, Farland LV, Shah DK, Harris HR, Kvaskoff M, Zondervan K, Missmer SA: \u003cstrong\u003eRisk for and consequences of endometriosis: A critical epidemiologic review.\u003c/strong\u003e \u003cem\u003eBest Pract Res Clin Obstet Gynaecol \u003c/em\u003e2018, \u003cstrong\u003e51:\u003c/strong\u003e1-15.\u003c/li\u003e\n\u003cli\u003eHavers-Borgersen E, Hartwell D, Ekelund C, Butt JH, \u0026Oslash;stergaard L, Holgersson C, Schou M, K\u0026oslash;ber L, Fosb\u0026oslash;l EL: \u003cstrong\u003eEndometriosis and long-term cardiovascular risk: a nationwide Danish study.\u003c/strong\u003e \u003cem\u003eEur Heart J \u003c/em\u003e2024, \u003cstrong\u003e45:\u003c/strong\u003e4734-4743.\u003c/li\u003e\n\u003cli\u003eZondervan KT, Becker CM, Missmer SA: \u003cstrong\u003eEndometriosis.\u003c/strong\u003e \u003cem\u003eN Engl J Med \u003c/em\u003e2020, \u003cstrong\u003e382:\u003c/strong\u003e1244-1256.\u003c/li\u003e\n\u003cli\u003eGiudice LC: \u003cstrong\u003eClinical practice. Endometriosis.\u003c/strong\u003e \u003cem\u003eN Engl J Med \u003c/em\u003e2010, \u003cstrong\u003e362:\u003c/strong\u003e2389-2398.\u003c/li\u003e\n\u003cli\u003ePoeta do Couto C, Policiano C, Pinto FJ, Brito D, Caldeira D: \u003cstrong\u003eEndometriosis and cardiovascular disease: A systematic review and meta-analysis.\u003c/strong\u003e \u003cem\u003eMaturitas \u003c/em\u003e2023, \u003cstrong\u003e171:\u003c/strong\u003e45-52.\u003c/li\u003e\n\u003cli\u003eVercellini P, Vigan\u0026ograve; P, Somigliana E, Fedele L: \u003cstrong\u003eEndometriosis: pathogenesis and treatment.\u003c/strong\u003e \u003cem\u003eNat Rev Endocrinol \u003c/em\u003e2014, \u003cstrong\u003e10:\u003c/strong\u003e261-275.\u003c/li\u003e\n\u003cli\u003eMarchandot B, Curtiaud A, Matsushita K, Trimaille A, Host A, Faller E, Garbin O, Akladios C, Jesel L, Morel O: \u003cstrong\u003eEndometriosis and cardiovascular disease.\u003c/strong\u003e \u003cem\u003eEur Heart J Open \u003c/em\u003e2022, \u003cstrong\u003e2:\u003c/strong\u003eoeac001.\u003c/li\u003e\n\u003cli\u003eSantoro L, D\u0026apos;Onofrio F, Campo S, Ferraro PM, Flex A, Angelini F, Forni F, Nicolardi E, Campo V, Mascilini F, et al: \u003cstrong\u003eRegression of endothelial dysfunction in patients with endometriosis after surgical treatment: a 2-year follow-up study.\u003c/strong\u003e \u003cem\u003eHum Reprod \u003c/em\u003e2014, \u003cstrong\u003e29:\u003c/strong\u003e1205-1210.\u003c/li\u003e\n\u003cli\u003eFarland LV, Degnan WJ, 3rd, Bell ML, Kasner SE, Liberman AL, Shah DK, Rexrode KM, Missmer SA: \u003cstrong\u003eLaparoscopically Confirmed Endometriosis and Risk of Incident Stroke: A Prospective Cohort Study.\u003c/strong\u003e \u003cem\u003eStroke \u003c/em\u003e2022, \u003cstrong\u003e53:\u003c/strong\u003e3116-3122.\u003c/li\u003e\n\u003cli\u003eMu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA: \u003cstrong\u003eEndometriosis and Risk of Coronary Heart Disease.\u003c/strong\u003e \u003cem\u003eCirc Cardiovasc Qual Outcomes \u003c/em\u003e2016, \u003cstrong\u003e9:\u003c/strong\u003e257-264.\u003c/li\u003e\n\u003cli\u003eParmenter BH, Croft KD, Hodgson JM, Dalgaard F, Bondonno CP, Lewis JR, Cassidy A, Scalbert A, Bondonno NP: \u003cstrong\u003eAn overview and update on the epidemiology of flavonoid intake and cardiovascular disease risk.\u003c/strong\u003e \u003cem\u003eFood Funct \u003c/em\u003e2020, \u003cstrong\u003e11:\u003c/strong\u003e6777-6806.\u003c/li\u003e\n\u003cli\u003eDel Rio D, Rodriguez-Mateos A, Spencer JP, Tognolini M, Borges G, Crozier A: \u003cstrong\u003eDietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases.\u003c/strong\u003e \u003cem\u003eAntioxid Redox Signal \u003c/em\u003e2013, \u003cstrong\u003e18:\u003c/strong\u003e1818-1892.\u003c/li\u003e\n\u003cli\u003eHu Q, Ma X, Cai T, Li Y: \u003cstrong\u003eFlavonoid intake, inflammation, and atherosclerotic cardiovascular disease risk in U.S. adults: a cross-sectional study.\u003c/strong\u003e \u003cem\u003eNutr Metab (Lond) \u003c/em\u003e2025, \u003cstrong\u003e22:\u003c/strong\u003e24.\u003c/li\u003e\n\u003cli\u003eGrosso G, Micek A, Godos J, Pajak A, Sciacca S, Galvano F, Giovannucci EL: \u003cstrong\u003eDietary Flavonoid and Lignan Intake and Mortality in Prospective Cohort Studies: Systematic Review and Dose-Response Meta-Analysis.\u003c/strong\u003e \u003cem\u003eAm J Epidemiol \u003c/em\u003e2017, \u003cstrong\u003e185:\u003c/strong\u003e1304-1316.\u003c/li\u003e\n\u003cli\u003eCassidy A, Mukamal KJ, Liu L, Franz M, Eliassen AH, Rimm EB: \u003cstrong\u003eHigh anthocyanin intake is associated with a reduced risk of myocardial infarction in young and middle-aged women.\u003c/strong\u003e \u003cem\u003eCirculation \u003c/em\u003e2013, \u003cstrong\u003e127:\u003c/strong\u003e188-196.\u003c/li\u003e\n\u003cli\u003eWilliamson G, Kay CD, Crozier A: \u003cstrong\u003eThe Bioavailability, Transport, and Bioactivity of Dietary Flavonoids: A Review from a Historical Perspective.\u003c/strong\u003e \u003cem\u003eCompr Rev Food Sci Food Saf \u003c/em\u003e2018, \u003cstrong\u003e17:\u003c/strong\u003e1054-1112.\u003c/li\u003e\n\u003cli\u003eKoller D, L\u0026oslash;khammer S, Goroshchuk O, Denner V, Stiltner B, Mitjans M, He J, Taylor HS, Lawn RB, Koenen KC, Polimanti R: \u003cstrong\u003eObservational and Genetic Analyses of Traumatic Experiences and Endometriosis.\u003c/strong\u003e \u003cem\u003eJAMA Psychiatry \u003c/em\u003e2025, \u003cstrong\u003e82:\u003c/strong\u003e386-394.\u003c/li\u003e\n\u003cli\u003eHorne AW, Missmer SA: \u003cstrong\u003ePathophysiology, diagnosis, and management of endometriosis.\u003c/strong\u003e \u003cem\u003eBmj \u003c/em\u003e2022, \u003cstrong\u003e379:\u003c/strong\u003ee070750.\u003c/li\u003e\n\u003cli\u003eGete DG, Dobson AJ, Mortlock S, Montgomery GW, Hockey R, Doust J, Mishra GD: \u003cstrong\u003eValidation of self-reported endometriosis.\u003c/strong\u003e \u003cem\u003eMaturitas \u003c/em\u003e2025, \u003cstrong\u003e199:\u003c/strong\u003e108642.\u003c/li\u003e\n\u003cli\u003eTopriceanu CC, Gong X, Shah M, Shiwani H, Eminson K, Atilola GO, Jephcote C, Adams K, Blangiardo M, Moon JC, et al: \u003cstrong\u003eHigher Aircraft Noise Exposure Is Linked to Worse Heart Structure and Function by Cardiovascular MRI.\u003c/strong\u003e \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2025, \u003cstrong\u003e85:\u003c/strong\u003e454-469.\u003c/li\u003e\n\u003cli\u003eLiu B, Young H, Crowe FL, Benson VS, Spencer EA, Key TJ, Appleby PN, Beral V: \u003cstrong\u003eDevelopment and evaluation of the Oxford WebQ, a low-cost, web-based method for assessment of previous 24 h dietary intakes in large-scale prospective studies.\u003c/strong\u003e \u003cem\u003ePublic Health Nutr \u003c/em\u003e2011, \u003cstrong\u003e14:\u003c/strong\u003e1998-2005.\u003c/li\u003e\n\u003cli\u003eBradbury KE, Young HJ, Guo W, Key TJ: \u003cstrong\u003eDietary assessment in UK Biobank: an evaluation of the performance of the touchscreen dietary questionnaire.\u003c/strong\u003e \u003cem\u003eJ Nutr Sci \u003c/em\u003e2018, \u003cstrong\u003e7:\u003c/strong\u003ee6.\u003c/li\u003e\n\u003cli\u003eParmenter BH, Thompson AS, Bondonno NP, Jennings A, Murray K, Perez-Cornago A, Hodgson JM, Tresserra-Rimbau A, K\u0026uuml;hn T, Cassidy A: \u003cstrong\u003eHigh diversity of dietary flavonoid intake is associated with a lower risk of all-cause mortality and major chronic diseases.\u003c/strong\u003e \u003cem\u003eNat Food \u003c/em\u003e2025, \u003cstrong\u003e6:\u003c/strong\u003e668-680.\u003c/li\u003e\n\u003cli\u003eWang YX, Farland LV, Gaskins AJ, Wang S, Terry KL, Rexrode KM, Rich-Edwards JW, Tamimi R, Chavarro JE, Missmer SA: \u003cstrong\u003eEndometriosis and uterine fibroids and risk of premature mortality: prospective cohort study.\u003c/strong\u003e \u003cem\u003eBmj \u003c/em\u003e2024, \u003cstrong\u003e387:\u003c/strong\u003ee078797.\u003c/li\u003e\n\u003cli\u003eEastwood SV, Mathur R, Atkinson M, Brophy S, Sudlow C, Flaig R, de Lusignan S, Allen N, Chaturvedi N: \u003cstrong\u003eAlgorithms for the Capture and Adjudication of Prevalent and Incident Diabetes in UK Biobank.\u003c/strong\u003e \u003cem\u003ePLoS One \u003c/em\u003e2016, \u003cstrong\u003e11:\u003c/strong\u003ee0162388.\u003c/li\u003e\n\u003cli\u003eHuang C, Lin B, Yuan Y, Li K, Xu B, Zhang P, Wei X, Wang W, Liu W, Deng Y, et al: \u003cstrong\u003eAssociations of Menstrual Cycle Regularity and Length With Cardiovascular Diseases: A Prospective Study From UK Biobank.\u003c/strong\u003e \u003cem\u003eJ Am Heart Assoc \u003c/em\u003e2023, \u003cstrong\u003e12:\u003c/strong\u003ee029020.\u003c/li\u003e\n\u003cli\u003eHu Y, Tang R, Li X, Wang X, Ma H, Heianza Y, Qi L, Liang Z: \u003cstrong\u003eSpontaneous miscarriage and social support in predicting risks of depression and anxiety: a cohort study in UK Biobank.\u003c/strong\u003e \u003cem\u003eAm J Obstet Gynecol \u003c/em\u003e2024, \u003cstrong\u003e231:\u003c/strong\u003e655.e651-655.e659.\u003c/li\u003e\n\u003cli\u003eOkoth K, Wang J, Zemedikun D, Thomas GN, Nirantharakumar K, Adderley NJ: \u003cstrong\u003eRisk of cardiovascular outcomes among women with endometriosis in the United Kingdom: a retrospective matched cohort study.\u003c/strong\u003e \u003cem\u003eBjog \u003c/em\u003e2021, \u003cstrong\u003e128:\u003c/strong\u003e1598-1609.\u003c/li\u003e\n\u003cli\u003eFarland LV, Degnan WJ, Harris HR, Tobias DK, Missmer SA: \u003cstrong\u003eA prospective study of endometriosis and risk of type 2 diabetes.\u003c/strong\u003e \u003cem\u003eDiabetologia \u003c/em\u003e2021, \u003cstrong\u003e64:\u003c/strong\u003e552-560.\u003c/li\u003e\n\u003cli\u003eLi B, Zhang Y, Zhang L, Zhang L: \u003cstrong\u003eAssociation between endometriosis and metabolic syndrome: a cross-sectional study based on the National Health and Nutrition Examination Survey data.\u003c/strong\u003e \u003cem\u003eGynecol Endocrinol \u003c/em\u003e2023, \u003cstrong\u003e39:\u003c/strong\u003e2254844.\u003c/li\u003e\n\u003cli\u003eGrassi D, Desideri G, Di Giosia P, De Feo M, Fellini E, Cheli P, Ferri L, Ferri C: \u003cstrong\u003eTea, flavonoids, and cardiovascular health: endothelial protection.\u003c/strong\u003e \u003cem\u003eAm J Clin Nutr \u003c/em\u003e2013, \u003cstrong\u003e98:\u003c/strong\u003e1660s-1666s.\u003c/li\u003e\n\u003cli\u003eMu F, Rich-Edwards J, Rimm EB, Spiegelman D, Forman JP, Missmer SA: \u003cstrong\u003eAssociation Between Endometriosis and Hypercholesterolemia or Hypertension.\u003c/strong\u003e \u003cem\u003eHypertension \u003c/em\u003e2017, \u003cstrong\u003e70:\u003c/strong\u003e59-65.\u003c/li\u003e\n\u003cli\u003eMelo AS, Rosa-e-Silva JC, Rosa-e-Silva AC, Poli-Neto OB, Ferriani RA, Vieira CS: \u003cstrong\u003eUnfavorable lipid profile in women with endometriosis.\u003c/strong\u003e \u003cem\u003eFertil Steril \u003c/em\u003e2010, \u003cstrong\u003e93:\u003c/strong\u003e2433-2436.\u003c/li\u003e\n\u003cli\u003eDu WW, Rafiq M, Yuan H, Li X, Wang S, Wu J, Wei J, Li RK, Guo H, Yang BB: \u003cstrong\u003eA Novel Protein NAB1-356 Encoded by circRNA circNAB1 Mitigates Atrial Fibrillation by Reducing Inflammation and Fibrosis.\u003c/strong\u003e \u003cem\u003eAdv Sci (Weinh) \u003c/em\u003e2025, \u003cstrong\u003e12:\u003c/strong\u003ee2411959.\u003c/li\u003e\n\u003cli\u003eParent S, Vaka R, St Amant J, Kahn S, Van Remortel S, Bi C, Courtman D, Stewart DJ, Davis DR: \u003cstrong\u003eInactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation.\u003c/strong\u003e \u003cem\u003eTheranostics \u003c/em\u003e2024, \u003cstrong\u003e14:\u003c/strong\u003e608-621.\u003c/li\u003e\n\u003cli\u003eBock JM, Shraffi Venkatesh V, Somers VK: \u003cstrong\u003eSex Differences in Atherosclerotic Cardiovascular Disease Risk in Obstructive Sleep Apnea.\u003c/strong\u003e \u003cem\u003eCurr Atheroscler Rep \u003c/em\u003e2025, \u003cstrong\u003e27:\u003c/strong\u003e64.\u003c/li\u003e\n\u003cli\u003eGupta S, Agarwal A, Krajcir N, Alvarez JG: \u003cstrong\u003eRole of oxidative stress in endometriosis.\u003c/strong\u003e \u003cem\u003eReprod Biomed Online \u003c/em\u003e2006, \u003cstrong\u003e13:\u003c/strong\u003e126-134.\u003c/li\u003e\n\u003cli\u003eSovari AA: \u003cstrong\u003eCellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress.\u003c/strong\u003e \u003cem\u003eCardiol Res Pract \u003c/em\u003e2016, \u003cstrong\u003e2016:\u003c/strong\u003e9656078.\u003c/li\u003e\n\u003cli\u003eGarcia C, Blesso CN: \u003cstrong\u003eAntioxidant properties of anthocyanins and their mechanism of action in atherosclerosis.\u003c/strong\u003e \u003cem\u003eFree Radic Biol Med \u003c/em\u003e2021, \u003cstrong\u003e172:\u003c/strong\u003e152-166.\u003c/li\u003e\n\u003cli\u003eZhuo S, Zhang B, Zhang J, Yang M, Yu Z: \u003cstrong\u003eEffects of dietary inflammatory index, blood lead levels, and flavonoid intake on stroke risk in older Americans: A cross-sectional study.\u003c/strong\u003e \u003cem\u003eJ Stroke Cerebrovasc Dis \u003c/em\u003e2023, \u003cstrong\u003e32:\u003c/strong\u003e107336.\u003c/li\u003e\n\u003cli\u003eDalgaard F, Bondonno NP, Murray K, Bondonno CP, Lewis JR, Croft KD, Kyr\u0026oslash; C, Gislason G, Scalbert A, Cassidy A, et al: \u003cstrong\u003eAssociations between habitual flavonoid intake and hospital admissions for atherosclerotic cardiovascular disease: a prospective cohort study.\u003c/strong\u003e \u003cem\u003eLancet Planet Health \u003c/em\u003e2019, \u003cstrong\u003e3:\u003c/strong\u003ee450-e459.\u003c/li\u003e\n\u003cli\u003eGuo Q, Wang L, Qu Q, Cheang I, Li X, Pang H, Liao S: \u003cstrong\u003eAssociation of flavonoid intake with coronary artery disease risk in the older population based on the National Health and Nutrition Examination Survey.\u003c/strong\u003e \u003cem\u003eEnviron Sci Pollut Res Int \u003c/em\u003e2024, \u003cstrong\u003e31:\u003c/strong\u003e3815-3827.\u003c/li\u003e\n\u003cli\u003eGreenwood DC, Hardie LJ, Frost GS, Alwan NA, Bradbury KE, Carter M, Elliott P, Evans CEL, Ford HE, Hancock N, et al: \u003cstrong\u003eValidation of the Oxford WebQ Online 24-Hour Dietary Questionnaire Using Biomarkers.\u003c/strong\u003e \u003cem\u003eAm J Epidemiol \u003c/em\u003e2019, \u003cstrong\u003e188:\u003c/strong\u003e1858-1867.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"reproductive-biology-and-endocrinology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rbej","sideBox":"Learn more about [Reproductive Biology and Endocrinology](http://rbej.biomedcentral.com)","snPcode":"12958","submissionUrl":"https://submission.nature.com/new-submission/12958/3","title":"Reproductive Biology and Endocrinology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Endometriosis, Cardiovascular disease, Coronary heart disease, Cardiac magnetic resonance imaging, Flavonoids, Mediation analysis","lastPublishedDoi":"10.21203/rs.3.rs-7789511/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7789511/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eEndometriosis is a systemic gynecological disorder that affects approximately 10% of women of reproductive age and shares certain pathophysiological features with cardiovascular disease (CVD). Despite this, the connections between endometriosis and alterations in cardiac structure, as well as its relationship with cardiovascular disease, remain inadequately characterized, with underlying mechanisms and potential interventions yet to be clearly defined.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe analyzed data from the UK Biobank, including 6,158 women with and 229,453 women without endometriosis, and validated our findings in a hospital-based cohort comprising 612 women with laparoscopically confirmed endometriosis and 612 matched controls. Multivariable-adjusted Cox proportional hazards models were employed to estimate the associations between endometriosis and the incidence of cardiovascular disease. Generalized linear models assessed links with cardiac magnetic resonance (CMR) metrics. Mediation analyses evaluated metabolic, inflammatory, hormonal, and oxidative stress pathways. Finally, we assessed whether flavonoid intake modified these associations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOver a median 13-year follow-up, 23,239 CVD events occurred. Endometriosis was found to be associated with an 18% increased risk of composite CVD and a 25% increased risk of coronary heart disease. These findings were validated in an external hospital-based cohort, where similar associations with composite CVD and coronary heart disease were observed. Cardiac magnetic resonance imaging revealed subtle yet significant structural and functional cardiac alterations, including increased interventricular septal thickness and regional wall motion abnormalities, with trends indicating greater left ventricular wall thickness and systolic longitudinal wall thickening. Biomarkers indicative of metabolic, inflammatory, and oxidative stress pathways collectively mediated the association between endometriosis and CVD. Notably, high dietary intakes of specific flavonoid subclasses, particularly flavones and flavanones, were observed to attenuate this association.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eEndometriosis is linked to increased CVD risk and early cardiac remodeling, partly via metabolic, inflammatory, and oxidative stress pathways. Increased flavone and flavanone intake may help reduce cardiovascular risk, highlighting potential dietary interventions.\u003c/p\u003e","manuscriptTitle":"Endometriosis-Associated Cardiovascular Remodeling: Mechanistic Insights and the Modulatory Role of Flavonoids","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-30 01:08:21","doi":"10.21203/rs.3.rs-7789511/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-05T06:29:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-25T00:07:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"50742480966963621325178513921910784935","date":"2025-10-23T17:45:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"108358448355120134055358562707923297216","date":"2025-10-23T09:18:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-16T05:24:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-08T07:49:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-08T07:47:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Reproductive Biology and Endocrinology","date":"2025-10-06T08:28:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"reproductive-biology-and-endocrinology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rbej","sideBox":"Learn more about [Reproductive Biology and Endocrinology](http://rbej.biomedcentral.com)","snPcode":"12958","submissionUrl":"https://submission.nature.com/new-submission/12958/3","title":"Reproductive Biology and Endocrinology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ad11c47a-a589-4359-a414-fb26dac36172","owner":[],"postedDate":"October 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-05T09:59:21+00:00","versionOfRecord":{"articleIdentity":"rs-7789511","link":"https://doi.org/10.1186/s12958-026-01564-7","journal":{"identity":"reproductive-biology-and-endocrinology","isVorOnly":false,"title":"Reproductive Biology and Endocrinology"},"publishedOn":"2026-05-02 15:58:13","publishedOnDateReadable":"May 2nd, 2026"},"versionCreatedAt":"2025-10-30 01:08:21","video":"","vorDoi":"10.1186/s12958-026-01564-7","vorDoiUrl":"https://doi.org/10.1186/s12958-026-01564-7","workflowStages":[]},"version":"v1","identity":"rs-7789511","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7789511","identity":"rs-7789511","version":["v1"]},"buildId":"0U-iFTyB6qxOgVj8rjrZV","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}