Examining the Role of Serum Ferritin Levels and the Risk of Adverse Cardiac Events Among Postmenopausal Women: Insights from the Women's Health Initiative Study

Abstract

Background: Postmenopausal women have a heightened risk of cardiovascular diseases (CVD), the primary cause of mortality among women in the United States. While premenopausal women are believed to have relative protection against heart disease compared to men, these benefits diminish after menopause, leading to increased cardiovascular risk. The mechanisms behind this progression are unclear, underscoring the need to evaluate additional sex-specific risk factors and biomarkers for accurate prediction of women's risk for adverse cardiovascular events (ACE). Ferritin, an acute-phase protein involved in iron storage and linked to CVD, may serve as a potential biomarker, but its role in the cardiovascular health of postmenopausal women has been understudied. Objective: This study investigates the association between serum ferritin levels and ACE in postmenopausal women using data from the Women's Health Initiative (WHI) study. Methods: A case-control study was conducted using data from the WHI, which consists of 161,808 postmenopausal women aged 50-79 from 40 U.S. clinical centers. This analysis included 313 incident cases of ACE and 1,069 controls from an ancillary study of 2,855 women with and without sarcopenia. Propensity score matching combined with inverse probability weighting was used to control for potential confounding factors and selection bias. Multivariate logistic regression analyses were conducted to examine the association between serum ferritin levels and ACE, adjusting for established cardiovascular risk factors. 6 Results: Low ferritin levels were associated with an increased odds of cardiovascular events in postmenopausal women, compared to higher levels. Women in the three highest ferritin quartiles (50-85 ng/mL, 86-146 ng/mL, and ≥147 ng/mL) had 48% (OR:0.52, 95% CI: 0.35-0.77), 48% (OR:0.52, 95% CI: 0.35-0.79), and 42% (OR:0.58, 95% CI: 0.40-0.85) lower odds of experiencing ACE compared to women in the lowest quartile (≤49 ng/mL), respectively. This suggests a threshold effect for serum ferritin, where the odds of ACE increase below a certain level and plateau at 42-48% lower in women within the three higher quartiles compared to those in the lowest quartile. Conclusion: In our study, low ferritin levels (<50 ng/mL) were associated with increased odds of experiencing ACE among postmenopausal women, while higher levels above this threshold were associated with 42-48% lower odds indicating a threshold effect. Whether targeted treatments to increase ferritin levels among those with low levels will reduce CVD risk remains unknown and warrants further study