“The Adjusted Ferritin Inflammation Index: A Novel Metric for Predicting Mortality in Heart Failure with Reduced and Mildly Reduced Ejection Fraction”

Abstract Aims Iron deficiency (ID) is a prevalent comorbidity in patients with heart failure (HF) and is associated with adverse outcomes. Traditional markers such as ferritin and transferrin saturation (TSAT) may be misleading due to the confounding impact of systemic inflammation. This study aimed to develop and validate the Adjusted Ferritin Inflammation Index (AFII), a novel composite score integrating ferritin/CRP ratio and albumin levels, to improve mortality risk stratification in HF patients. Methods This retrospective cohort study included 322 patients with heart failure and reduced or mildly reduced ejection fraction (HFrEF: LVEF ≤40%; HFmrEF: LVEF 41–49%). Patients were evaluated for iron parameters between January 2017 and September 2023. Laboratory values (ferritin, CRP, albumin) were obtained at admission for inpatients or at the first outpatient evaluation. Baseline characteristics were compared between survivors and deceased patients. AFII was derived using logistic regression and calculated as: AFII = (Albumin × −0.168) + (Ferritin/CRP × −0.012) + 6.958. The score was log-transformed (base 2), and the optimal cutoff (2.1) was determined via ROC curve analysis. Mortality predictors were assessed using Cox regression, and survival differences were analyzed with Kaplan-Meier curves. Results During a median follow-up of 41 months, 106 patients (32.9%) died. In multivariate Cox regression, AFII ≥ 2.1 independently predicted mortality (HR: 2.155; 95% CI: 1.361–3.412; p = 0.001), along with NYHA class, sodium, BNP, and smoking. Ferritin and TSAT were not associated with survival (p = 0.733 and p = 0.790, respectively). The AFII showed superior predictive performance (AUC: 0.713) compared to ferritin/CRP (AUC: 0.438) and albumin (AUC: 0.694). Kaplan-Meier analysis showed significantly reduced survival in patients with AFII ≥ 2.1 across the overall cohort (3-year survival: 54.9% vs. 84.6%); NYHA class I–II (84.5% vs. 94.1%); NYHA class III–IV (35.8% vs. 63.1%); and inpatient group (40% vs. 74.1%) (all p 0.001). Conclusions AFII is a novel inflammation adjusted metric that independently predicts mortality in HFrEF/HFmrEF patients and outperforms traditional iron markers. Its use may enhance risk stratification and inform future strategies for iron deficiency management in HF. It should be considered a complementary prognostic tool rather than a replacement for existing guidelines. Prospective multicenter validation is warranted to determine its potential clinical utility and confirm its applicability in diverse heart failure populations.