Abstract Body: Background: Postmenopausal women face an elevated risk of cardiovascular disease (CVD), the leading cause of death among women. Improving the prediction of adverse cardiovascular events (ACE) in this population requires identifying biomarkers that extend beyond traditional risk factors, while being clinically useful and cost-effective. Ferritin, commonly used to assess iron status, is an acute-phase protein implicated in CVD risk. Its role in postmenopausal women remains understudied.

Objective: To investigate the association between serum ferritin and ACE in postmenopausal women from the Women’s Health Initiative (WHI) study.

Methods: A nested case-control study was conducted within the WHI, including 1,382 postmenopausal women (313 adjudicated ACE cases and 1,069 controls). Ferritin concentrations were categorized into quartiles based on the control distribution (≤49, 50-85, 86-146, ≥147 ng/mL). To estimate the association between ferritin and ACE, doubly robust logistic regression was used, adjusting for traditional CVD risk factors and pertinent demographic, clinical, lifestyle, and menopausal variables.

Results: Ferritin levels did not differ significantly between ACE cases and controls (median: 85 ng/mL; p ≥ 0.05). However, cases were older, had greater waist circumference, higher prevalence of diabetes, hypertension, and hyperlipidemia (p < 0.05), but similar AHEI scores. Bilateral oophorectomy was more common among cases, whereas hormone therapy use was more prevalent among controls. Inflammatory markers such as hs-CRP were higher among cases, although IL-6 levels were similar. Compared with women in the lowest ferritin quartile (≤49 ng/mL), women in the second, third, and fourth quartiles had 47% (OR: 0.53; 95% CI: 0.36-0.79), 47% (OR: 0.53; 95% CI: 0.35-0.79), and 40% (OR: 0.60; 95% CI: 0.41-0.88) lower odds of ACE, respectively. The association plateaued across quartiles 2-4 and remained significant in sensitivity analyses, including anemia and sarcopenia.

Conclusions: Low serum ferritin (≤49 ng/mL) was associated with higher odds of ACE in postmenopausal women, while higher levels appeared protective. These results suggest an inverse association with a threshold effect, consistent with prior studies of older women. Our findings provide preliminary support for ferritin as a potential CVD risk marker in postmenopausal women and warrant further study.