Sex differences in response to ferric carboxymaltose in heart failure: molecular insights from AFFIRM-AHF
N Grote Beverborg, R I S Alnuwaysir, M Kutscher, D J Van Veldhuisen, N Bomer, G Voordes, A A Voors, P Van Der MeerAbstract
Background
In patients with heart failure (HF) and iron deficiency (ID), intravenous ferric carboxymaltose (FCM) improves symptoms and reduces hospitalizations. Emerging evidence suggests sex-specific efficacy, with men deriving greater clinical benefit, yet the biological basis for this remains poorly understood. We investigated sex-specific molecular responses to FCM and assessed whether cumulative dose differences could contribute to heterogeneity.
Methods
In an AFFIRM-AHF proteomics substudy, 364 plasma proteins from 4 panels (Cardiovascular III&II, Immune response and Oncology II) in Olink were measured at baseline, week 6 and week 24 in patients randomized to FCM or placebo. Within-arm changes (follow-up vs baseline) were evaluated separately by sex, and sex×treatment interaction was tested. Cumulative FCM dose was compared between women and men.
Results
Among 210 patients (99 women, 111 men), women were slightly older, had higher rates of hypertension, lower rates of smoking and ischaemic aetiology of HF (p<0.05). Baseline ferritin was lower in women (69 ± 48 vs 91 ± 68 ng/mL, p=0.026), while transferrin saturation was similar (both median = 15%). Patients were well balanced between sexes within each arm, with a slight male predominance. Before treatment, women showed a characteristic adipokine-dominant profile, with leptin and FABP4 markedly higher in women than men (FDR < 0.05). At week-6 in the FCM arm, men exhibited a broad, predominantly downward proteomic shift relative to baseline, with suppression of iron-handling and inflammatory/metabolic proteins such as TFRC, FGF23, DECR1, FABP4, PPY, ESM1, and PTX3, alongside markers linked to vascular inflammation (CXCL16, IL6, TNFRSF11A) and lipid/energy metabolism (PCSK9, SOD2). In total, 63 proteins were differentially expressed in men at week-6 (53 unique to week-6 and 10 overlapping with week-24). In contrast, women showed directionally concordant but attenuated changes, with only three proteins reaching significance at week 6 (TFRC, FGF23 and MUC16) and four at week 24. No signal of divergent or maladaptive proteomic response in women was observed. Yet, formal sex×treatment interaction identified only a small subset with significant interaction under FCM such as DECR1, FABP4, IL10 and TFPI. Cumulative FCM dose was 1171mg overall, with no difference between men and women at baseline nor during follow-up (p>0.05).
Conclusions
In patients with ID and HF, FCM modulates largely shared biological programs in women and men, but the magnitude seems lesser in women despite similar doses of FCM received.Figure 1For image description, please refer to the figure legend and surrounding text.Figure 2For image description, please refer to the figure legend and surrounding text.