Letter: FGF-23 as a Potential Prognostic Biomarker in Peripheral Artery Disease

Dear Editor,

We commend Zierfuss et al ¹ for their article titled “FGF-23 and Long-term Outcome in Peripheral Artery Disease.” This study enrolled 298 patients with stable peripheral artery disease (PAD; Fontaine stage I-II). Over a median follow-up of 8.06 years, elevated fibroblast growth factor 23 (FGF-23) remained significantly associated with all-cause mortality (hazard ratio, 1.35; 95% confidence interval, 1.05-1.74), even after adjustment for traditional cardiovascular risk factors and renal excretory function. Patients in the highest FGF-23 tertile exhibited the poorest long-term all-cause mortality.

Although this study was well-designed, we would like to make several suggestions. First, future studies should investigate whether the prognostic value of FGF-23 differs across PAD subtypes (e.g., intermittent claudication vs chronic limb-threatening ischemia). Second, a serial sampling strategy (e.g., at admission, 24 hours post-revascularization, at discharge, and at 3, 6, and 12 months of follow-up) is recommended to dynamically monitor FGF-23 levels, thereby evaluating its potential as a treatment-responsive biomarker and identifying patients with residual cardiovascular risk.

In addition to the mechanisms mentioned in this study, FGF-23 may also increase mortality risk through direct myocardial toxicity and endothelial dysfunction. Preclinical studies have demonstrated that FGF-23 binds directly to fibroblast growth factor receptor 4 on cardiomyocytes, activating the phospholipase C gamma/nuclear factor of activated T-cells pathway to induce left ventricular hypertrophy, ² and promotes myocardial fibrosis through the β-catenin/transforming growth factor-beta axis. ³ With respect to endothelial function, FGF-23 activates nicotinamide adenine dinucleotide phosphate oxidase to increase superoxide generation, which reacts with nitric oxide to form peroxynitrite, thereby impairing endothelium-dependent vasodilation; this injury is reversible by the superoxide scavenger tiron. ⁴ Furthermore, Klotho expression is downregulated under pathological conditions such as aging and diabetes, ⁵ which amplifies the cardiovascular toxic effects of FGF-23, consistent with the superior predictive performance of the FGF-23/Klotho ratio reported by Biscetti et al. ⁶

In conclusion, FGF-23 demonstrates potential for prognostic stratification in PAD; future studies should validate its differential value across PAD subtypes and explore serial sampling to evaluate treatment responsiveness and identify residual cardiovascular risk.