Low Transferrin Saturation and Elevated C-Terminal FGF23 Define a High-Risk Phenotype for the Occurrence of Major Adverse Cardiovascular Events in Patients with Coronary Artery Disease.

<title>Abstract</title> <p> Background Fibroblast growth factor 23 (FGF23) is a bone-derived mineral-regulating hormone linked to adverse cardiovascular outcomes. FGF23 production and cleavage are influenced by iron availability and inflammation. Low transferrin saturation (TS) reflects reduced circulating iron availability and may identify functional iron restriction, an emerging cardiovascular risk factor. Whether the combination of elevated FGF23 and low TS identifies a particularly vulnerable subgroup of patients with coronary artery disease (CAD) remains unknown. Methods We investigated the association of C-terminal FGF23 (cFGF23) with an iron-restricted and anemia-associated phenotype, and evaluated whether the combination of elevated cFGF23 with TS &lt; 20% predicts major adverse cardiovascular events (MACE) in 374 patients with preserved renal function and angiographically confirmed significant CAD at study inclusion. Baseline cFGF23, TS, iron-related biomarkers, inflammatory markers and clinical covariates were assessed at angiography. Patients were stratified by cFGF23 tertiles and combined TS/cFGF23 phenotypes. The primary endpoint was 3-year MACE, defined as cardiovascular death, coronary event or stroke. A 5-year sensitivity analysis was also performed. The incremental prognostic value of the combined TS/cFGF23 phenotype was assessed using Harrell’s C-statistic, net reclassification improvement and integrated discrimination improvement. Results Higher cFGF23 tertiles were associated with lower serum iron, lower TS, more frequent TS &lt; 20%, lower hemoglobin and a higher prevalence of anemia. During 3 years, 48 patients (12.8%) experienced MACE. Patients with MACE had lower TS, higher ferritin and a higher prevalence of anemia. Although cFGF23 T3 was associated with 3-year MACE in univariable analysis, this association was attenuated after adjustment for TS, whereas the combined TS/cFGF23 phenotype identified a marked risk gradient. The highest 3-year MACE incidence was observed in patients with TS &lt; 20% + cFGF23 T3 (42.9%), who showed the highest adjusted risk compared with those with TS ≥ 20% + cFGF23 T1/T2 (HR 6.67, 95% CI 3.22–13.80; <italic>P</italic>  &lt; 0.001). In the 5-year sensitivity analysis, this phenotype again showed the highest MACE incidence and remained strongly associated with outcome after extended adjustment (HR 6.54, 95% CI 3.27–13.1; <italic>P</italic>  &lt; 0.001). Addition of the combined TS/cFGF23 phenotype improved model discrimination and risk reclassification for both 3-year and 5-year MACE. Conclusions In patients with preserved renal function and angiographically confirmed significant CAD, the combination of TS &lt; 20% and high cFGF23 identified a subgroup with markedly increased 3-year and 5-year MACE risk and provided incremental prognostic information, suggesting that the FGF23–iron axis may refine residual cardiovascular risk stratification in CAD. </p>