Ferric carboxymaltose modulates metabolic and inflammatory pathways alongside erythropoiesis in heart failure: mechanistic insights from the 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
While intravenous ferric carboxymaltose (FCM) therapy improves functional status and reduces heart failure (HF) hospitalizations in patients with iron deficiency (ID), the molecular mechanisms underlying these clinical benefits remain incompletely understood. We aimed to explore the molecular effects of FCM and identify key pathophysiological pathways modulated by iron repletion in patients with HF and ID.
Methods
We conducted targeted proteomic profiling in 210 patients from the AFFIRM-AHF trial (FCM n=111, placebo n=99), measuring 364 circulating proteins (Olink® Explore platform) at baseline, week 6, and week 24. Within-arm (follow-up vs baseline) and between-arm (FCM vs placebo) proteomic changes and subsequent pathway enrichment were assessed. Associations between changes in biomarkers or pathways and clinical outcomes were analyzed. Studied outcomes included cardiovascular (CV) death, first HF hospitalizations, their composite and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. An external sensibility analysis compared the FCM-induced proteomic signature with the pattern linked to ID in BIOSTAT-CHF, a large independent cohort of HF patients.
Results
Baseline characteristics were comparable to the total trial population and balanced by treatment arm. At week 6, in total, 81 proteins were differentially expressed compared to baseline, with 67 proteins uniquely altered in the FCM arm and none unique to placebo. The week-6 FCM effect was characterized predominantly by protein downregulation. Suppressed proteins included FGF23, TFRC, IL-6, IL1RN, FABP4, SOD2, DECR1 and PCSK9. By week 24, effect sizes attenuated, with 25 markers (e.g., TFRC, FGF23) remaining significantly altered. Pathway analysis revealed dampening of inflammatory, hypoxia and coagulation/vascular pathways alongside shifts in lipid/energy metabolism, while enhancing haematopoiesis and iron related pathways. In the sensitivity analysis, 53 of the 67 FCM specific biomarkers overlapped with ID in the independent BIOSTAT-CHF cohort. Downregulation of multiple FCM specific biomarkers (e.g. TFRC and IGFBP2, GDF15) and their associated pathways, correlated with improvements in KCCQ-scores as well as a reduced risk of HF hospitalizations or CV death.
Conclusions
FCM induces remodeling of the circulating proteome in patients with HF and ID by attenuating inflammatory and oxidative-stress signalling and shifting lipid/energy-metabolic programs beyond its erythropoietic effects. This molecular signature parallels improvements in health-status and clinical outcomes, supporting anti-inflammatory and metabolic pathway modulation as key mechanisms underlying FCM benefit.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.