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Menopausal age is established as a strong marker of adverse cardiovascular risk. Earlier age of menopause has been related to increased myocardial infarction, stroke, heart failure and cardiovascular mortality. It would stand to reason, then, that menopausal age would similarly be associated with increased likelihood of atrial fibrillation (AF). AF is most commonly a disease of cardiovascular ageing, and multiple factors—cardiovascular events, increased inflammation and thrombosis and hormonal dysregulation—could be expected to link earlier onset of menopause with increased risk of AF.
Several cohort studies have now examined the association of earlier menopausal age and AF. In their Heart manuscript, Wong et al have elucidated the relation between age of menopause and incident AF.1 In a cohort of over 30 000 women from the Women’s Health Study—the largest cohort to examine this question to date—the authors followed cohort participants for a median of 20.5 years. The primary outcome was the onset of AF, self-reported and confirmed by physician review of medical records. In this cohort of 30 034 women, there were 1350 confirmed cases of AF. Wong et al determined that earlier age of menopause was not associated with risk of AF when compared with women with older onset of menopause (<45 years: HR 0.82, 95% CI 0.67 to 1.02; 45–49 years: HR 0.90, 95% CI 0.74 to 1.08; 50–54 years: HR 0.89, 95% CI 0.75 to 1.06; compared with age of menopause >54 years as the referent).
This study by Wong et al confirms and extends findings from previous literature with the strengths of a larger cohort, longer follow-up time and greater number of AF events. One of us (JWM) participated in a smaller study in the Framingham Heart Study which also did not identify an association between menopausal age and AF.2 Adjustment for interim cardiovascular events did not change the results, suggesting that cardiovascular events are not intermediate mechanisms that mediate the association of menopausal age and AF. Additional strengths of the work presented by Wong et al are the reliable ascertainment of AF, large cohort size and median follow-up duration exceeding 20 years. Table 1 situates this contribution in the literature that we identified addressing the association of menopausal age and AF.
The authors conducted a secondary analysis of participants taking postmenopausal hormone replacement therapy (PHT). Interestingly, oestrogen-only PHT, but not combined oestrogen and progesterone, was associated with 1.2-fold increased risk of AF (HR 1.22, 95% CI 1.02 to 1.45). This effect size confirms findings from previous, smaller studies.3 4 Oestrogen has been associated with QT-prolongation, increased inflammatory markers and alteration of cardiac ion channel dynamics, which may contribute to AF pathogenesis. However, the association in the study by Wong et al was small and the number of participants with oestrogen exposure limited. Further, oestrogen was examined as a dichotomous exposure, making the interpretation of cumulative exposure difficult to interpret. As PHT is not a standard of care for postmenopausal women, we consider this finding as minimally informative about AF risk in postmenopausal women.
We would note that the work of Wong et al does have some important limitations. The cohort comprised health professionals, and it is possible that such individuals are more likely to have increased access to healthcare and adequate health literacy, factors that may influence AF ascertainment and awareness. There is also potential for misclassification of AF status, as AF events may not have been recognised in some cohort participants. Finally, the study did not include recognition of hot flashes, associated with important changes in reproductive hormones, and that may be associated with cardiovascular dysregulation. Whether women with increased premenopausal hot flashes have increased risk for AF has not been examined to our knowledge.
The interaction of AF, sex, menopausal age and postmenopausal hormone therapy is complex with multiple potential contributing mechanisms.5 Earlier menopausal age has a number of cardiovascular associations that may also affect risk for AF. After menopause, women have differential cardiovascular risk, increased inflammatory markers, increased sympathetic tone and increased risk for thrombosis. While there are multiple mechanisms impacting cardiovascular and AF risks, the present study confirms no increased risk of AF with an earlier age of menopause. We present a hypothesised pathway linking menopause to cardiovascular outcomes, but not AF, in figure 1.
While there remain unanswered questions about why menopausal age is associated with cardiovascular risk, we consider it unlikely that further studies will find an association with AF. In our opinion, with the publication of this work by Wong et al, the question has been definitively answered. And, studies that claim an association between age of menopause and AF need to be examined closely for biased ascertainment of AF. Menopause and AF? For now, not something else for our patients with early menopause to worry about.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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