Pharmacogenomics and chronotherapy of drug-induced cardioprotection in acute myocardial infarction

Agustín Clemente-Moragón, Aida Suárez-Barrientos, Mónica Gómez Tech, Lucía Pilar López-Palomar Tech, Sergio Callejas Alejano, Fernando Martínez, Francisco José Fernández, María Cristina Vega, Angela Pollán Tech, Ana Dopazo, Fátima Sánchez-Cabo, Valentín Fuster, Eduardo Oliver and Borja Ibáñez ()
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Agustín Clemente-Moragón: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Aida Suárez-Barrientos: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Mónica Gómez Tech: Centro Nacional de Investigaciones Oncológicas (CNIO)
Lucía Pilar López-Palomar Tech: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Sergio Callejas Alejano: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Fernando Martínez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Francisco José Fernández: Abvance Biotech SL
María Cristina Vega: Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC)
Angela Pollán Tech: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Ana Dopazo: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Fátima Sánchez-Cabo: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Valentín Fuster: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Eduardo Oliver: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Borja Ibáñez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65385-9

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