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

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.

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Journal
Nature Communications
Published
2025-11-25
DOI
https://doi.org/10.1038/s41467-025-65385-9
Primary Topic
Cardiac Ischemia and Reperfusion
Type
article
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article

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

Agustín Clemente‐Moragón, Fátima Sánchez‐Cabo, Borja Ibáñez, Ana Dopazo et al.
Nature Communications
Cardiac Ischemia and Reperfusion
article

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

Agustín Clemente‐Moragón, Fátima Sánchez‐Cabo, Borja Ibáñez, Ana Dopazo, M. Cristina Vega, Aida Suárez-Barrientos, Sergio Callejas, Valentı́n Fuster, Eduardo Oliver, M. Tech, Fernando Martínez, Francisco José Fernández, Angela Pollán Tech, Lucía Pilar López-Palomar Tech
article en

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.

Nature CommunicationsVol. 16(1)
Spanish National Centre for Cardiovascular Research (ES), Spanish National Cancer Research Centre (ES), Centro de Investigación en Red en Enfermedades Cardiovasculares (ES), Centro Nacional de Epidemiología (ES), Centro de Investigación Biomédica en Red (ES), Hospital Universitario Fundación Jiménez Díaz (ES), Spanish National Centre for Cardiovascular Research (ES), Universidad Alfonso X el Sabio (ES), Centro de Investigaciones Biológicas Margarita Salas (ES), Universidad Autónoma de Madrid (ES), Icahn School of Medicine at Mount Sinai (US)
University of Texas Southwestern Medical Center, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades, European Commission, Ministerio de Ciencia e Innovación, Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación
Openalex Percentile: Top 50%
Cardiac Ischemia and Reperfusion
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