Vázquez-Sánchez, SaraBlasco, AnaPolo-Salguero, MarinaMourino-Álvarez, LauraGil-Fernández, MartaCorbacho-Alonso, NereaNavarro-García, José AlbertoMercado-García, ElisaGonzález-Lafuente, LauraRodríguez-Sánchez, ElenaGonzález-Moreno, DanielPérez-Gómez, AlbertoMatutano, AndreaVázquez, JesúsLópez, Juan AntonioFernández-Velasco, MaríaBarderas, María GRuiz-Hurtado, Gema2026-07-162026-07-162026-02-17J Am Heart Assoc. 2026 Feb 17;15(4):e045175.https://hdl.handle.net/20.500.12105/27592Elevation of FGF23 (fibroblast growth factor 23) and decreased Klotho levels have been associated with various cardiovascular and renal diseases. However, the combined study of the FGF23-Klotho axis in ischemic heart disease remains elusive. We analyzed the associations between circulating FGF23 and Klotho levels with cardiac and renal parameters, as well as mortality outcomes following myocardial infarction (MI). Cardiac tissue from patients with ischemic heart disease and a post-MI mouse model were analyzed to assess myocardial FGF23 expression. Proteomic analysis was performed to examine myocardial pathways activated by FGF23 and regulated by Klotho. We observed an inverse correlation between circulating levels of FGF23 and Klotho in patients after MI. Elevated plasma FGF23 levels were particularly associated with ST-segment-elevation MI and cardiac dysfunction, including reduced left ventricular ejection fraction, prolonged corrected interval, and higher Killip-Kimball classification of cardiac risk, identifying FGF23 as a potential prognostic marker of overall and cardiac-related mortality. In contrast, systemic Klotho levels were reduced in patients with ST-segment-elevation MI but did not correlate with mortality. In cardiac tissue, ischemic injury significantly upregulated FGF23 expression. Although Klotho prevented FGF23-induced proteomic alterations, it did not inhibit cardiac FGF23 overexpression in the post-MI model. FGF23 represents a promising biomarker for mortality and cardiac dysfunction in patients with MI. Although Klotho does not appear to be a reliable predictor of mortality after MI, its cardioprotective properties suggest a role in modulating FGF23-driven metabolic, structural, and proliferative processes in the myocardium.The study was supported mainly by projects from the Instituto de Salud Carlos III (PI20/00763, PI21/00384, CPII20/00022, FI18/00261, FI21/00212, CD19/00029, CD24/00202, IFEQ21/00012, PI23/00182, PI23/01014, RD24/0004/0018, AC22/00022), cofunded by the European Union, Ministerio de Universidades (FPU20/03005), and the Ministerio de Ciencia, Innovación y Universidades, and Agencia Estatal de Investigación (CNS2023‐144891, CNS2023‐145161). This study was partially supported by the Biomedicine Network Comunidad de Madrid (P2022/BMD‐7223 CIFRA_COR‐CM), the Spanish Network (RED2022–134 511‐T), the Spanish Society of Nephrology SEN/2024SENEFRO Foundation, the Spanish Society of Cardiology/Spanish Foundation of Heart (SEC/FEC‐INV‐BAS 23), the Junta de Comunidades de Castilla‐La Mancha (SBPLY/21/180501/000078), cofunded by the European Regional Development Fund, and the collaborative projects CIBERCV and CIBERNED 2024. The Centro Nacional de Investigaciones Cardiovasculares is supported by the Instituto de Salud Carlos III, the Ministerio de Ciencia, Innovación y Universidades, and the Pro Centro Nacional de Investigaciones Cardiovasculares Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020‐001041‐S funded by MICIU/AEI/https://doi.org/10.13039/501100011033). These results are aligned with the Spanish initiative of the Human Proteome Project. Dr Navarro‐García is funded by American Heart Association (25CDA1452048).engVoRFGF23Klothoischemic heart diseasemortalitymyocardial infarction41676927JOURNAL OF THE AMERICAN HEART ASSOCIATIONopen access