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oai:repisalud.isciii.es:20.500.12105/271032025-12-23T01:20:27Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud author Clemente-Moragón, Agustín author Suárez-Barrientos, Aida author Gómez Tech, Mónica author López-Palomar Tech, Lucía Pilar author Callejas Alejano, Sergio author Martínez, Fernando author Fernández, Francisco José author Vega, María Cristina author Tech, Angela Pollán author Dopazo, Ana author Sánchez-Cabo, Fátima author Fuster, Valentín author Oliver, Eduardo author Ibáñez, Borja funder Unión Europea. Comisión Europea. European Research Council (ERC) funder Unión Europea. Comisión Europea. H2020 funder Comunidad de Madrid (España) funder Red Madrileña de Nanomedicina en Imagen Molecular funder Ministerio de Ciencia e Innovación (España) funder Agencia Estatal de Investigación (España) funder Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) funder Instituto de Salud Carlos III funder Ministerio de Ciencia, Innovación y Universidades (España) funder Fundación ProCNIC funder Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) 2025-12-22T11:40:31Z 2025-12-22T11:40:31Z 2025-11-25 Nat Commun_2025 Nov 25;16(1):10450. Nature Communications 41290608 https://hdl.handle.net/20.500.12105/27103 Acute 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. eng Pharmacogenomics and chronotherapy of drug-induced cardioprotection in acute myocardial infarction. research article 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 URL https://repisalud.isciii.es/bitstreams/d6f55389-3b40-4922-a85f-0e018ee35a58/download File MD5 09a179de9ed235699bbc09be0d0e36a0 2058560 application/pdf Pharmacogenomics and chronotherapy_Nat Commun_2025.pdf