Clemente-Moragón, AgustínSuárez-Barrientos, AidaGómez Tech, MónicaLópez-Palomar Tech, Lucía PilarCallejas Alejano, SergioMartínez, FernandoFernández, Francisco JoséVega, María CristinaTech, Angela PollánDopazo, AnaSánchez-Cabo, FátimaFuster, ValentínOliver, EduardoIbáñez, Borja2025-12-222025-12-222025-11-25Nat Commun_2025 Nov 25;16(1):10450.https://hdl.handle.net/20.500.12105/27103Acute myocardial infarction remains a leading cause of morbidity and mortality worldwide. Pharmacogenetic and chronotherapeutic approaches are increasingly applied to optimize therapy in chronic cardiovascular diseases. While gene variants are known to influence long-term drug efficacy, their role in modulating drug-induced cardioprotection in acute conditions such as myocardial infarction is unclear. Similarly, the impact of circadian timing on cardioprotective responses remains insufficiently defined. To address these questions, we evaluated metoprolol as a model cardioprotective agent. Here we examine, in a non-pre-specified exploratory analysis of the METOCARD-CNIC trial (NCT01311700), the influence of ADRB1 Arg389Gly polymorphism and the time of AMI onset on metoprolol efficacy. We found that metoprolol reduced infarct size only in patients homozygous for the ADRB1 Arg389 allele, consistent with its genotype-dependent inhibition of neutrophil migration. In-silico docking and binding studies revealed unstable interactions of metoprolol with the Gly389 variant of ADRB1. Moreover, metoprolol was associated with reduced infarct size when AMI onset occurred between 6:00 and 12:00 h. Restricted cardioprotection to the light phase was confirmed in male mice and in neutrophil-specific Adrb1-knockout models. Collectively, these findings highlight the critical roles of genetic background and circadian timing in shaping the efficacy of acute cardioprotective therapies, supporting the rationale for personalized interventions in acute myocardial infarction.This study received funding from the Spanish Ministry of Science, Innovation and Universities (PID2022−140176OB-I00 to B.I.), the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Programme (ERC-Consolidator Grant agreement No. 819775 to B.I.), and the Comunidad de Madrid through the Red Madrileña de Nanomedicina en Imagen Molecular (P2022/BMD-7403 RENIM-CM). E.O. is supported by funding from Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación MCIN/ AEI/10.13039/501100011033 and by “ERDF A way of making Europe” (PID2021-123167OB-I00), and CSIC Talent Attraction program (20222AT010). A.C-M. was supported by a fellowship from the Ministerio de Ciencia e Innovación (MCN) and ISCIII (FPU2017/01932). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MICIU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020- 001041-S funded by MICIU/AEI/10.13039/501100011033).engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 International41290608Nature Communicationsopen access