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Background: It is commonly assumed that high oestradiol levels in women are cardioprotective. We assessed the association between oestradiol and the risk of incident myocardial infarction (MI) in women.Methods: We used data from 263 295 female UK Biobank participants [mean age 56.2; standard deviation (SD) 8.0 years] without previous cardiovascular disease (CVD). Associations of oestradiol with age and other cardiovascular risk factors were assessed. Cox proportional hazards models estimated crude, ag- and multiple-adjusted hazard ratios (HR) for MI associated with oestradiol levels.Results: After a mean follow-up of 9 years, 2206 incident cases of MI had been recorded, including 230 events among the 57 204 women (mean age 48) with detectable oestradiol levels. In the unadjusted analyses, a unit higher in log-transformed oestradiol was associated with an HR [95% confidence interval (CI) for MI of 0.73 (0.58; 0.92)]. After adjusting for age, this HR became 0.94 (0.75; 1.17), and after further adjusting for classical CVD risk factors, it was 1.05 (0.83; 1.31. Results were similar in subgroup analyses defined by age, menopausal status, socioeconomic status, contraceptive pill use and the use of hormone replacement therapy. The multivariable-adjusted HR for the 171 431 women (mean age 59) with undetectable levels of oestradiol, compared with those with detectable levels, was 0.97 (0.92; 1.02).Conclusions: Higher levels of oestradiol were not associated with a decreased risk of MI. The presumed cardioprotective effects of oestradiol seem to be largely confounded by age and further confounded by other cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Objective: Diabetes has shown to be a stronger risk factor for myocardial infarction (MI) in women than men. Whether sex differences exist across the glycemic spectrum is unknown. We investigated sex differences in the associations of diabetes status and glycated hemoglobin (HbA1c) with the risk of MI.Research Design and Methods: Data were used from 471,399 (56% women) individuals without cardiovascular disease (CVD) included in the UK Biobank. Sex-specific incidence rates were calculated by diabetes status and across levels of HbA1c using Poisson regression. Cox proportional hazards analyses estimated sex-specific hazard ratios (HRs) and women-to-men ratios by diabetes status and HbA1c for MI during a mean follow-up of 9 years.Results: Women had lower incidence rates of MI than men, regardless of diabetes status or HbA1c level. Compared with individuals without diabetes, prediabetes, undiagnosed diabetes, and previously diagnosed diabetes were associated with an increased risk of MI in both sexes. Previously diagnosed diabetes was more strongly associated with MI in women (HR 2.33 [95% CI 1.96; 2.78]) than men (1.81 [1.63; 2.02]), with a women-to-men ratio of HRs of 1.29 (1.05; 1.58). Each 1% higher HbA1c, independent of diabetes status, was associated with an 18% greater risk of MI in both women and men.Conclusions: Although the incidence of MI was higher in men than women, the presence of diabetes is associated with a greater excess relative risk of MI in women. However, each 1% higher HbA1c was associated with an 18% greater risk of MI in both women and men. [ABSTRACT FROM AUTHOR]

Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1β expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk.Methods: We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with DNMT3A or TET2 CHIP. We used the IL6R p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by IL6R p.Asp358Ala.Results: We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 [95% CI, 1.04-1.56], P=0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21-2.09], P<0.001). IL6R p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 [95% CI, 0.29-0.73], P<0.001) but not in individuals without CHIP (hazard ratio, 0.95 [95% CI, 0.89-1.01], P=0.08; Pinteraction=0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by IL6R p.Asp358Ala (Pinteraction=0.036).Conclusions: CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk. [ABSTRACT FROM AUTHOR]