Pharmacogenomics and chronotherapy of drug-induced cardioprotection in acute myocardial infarction
Year: 2025
Type: article
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. It remains uncertain whether genetic variants and day–night cycles affect the efficacy of drugs in acute disease settings. Here, the authors show that metoprolol reduces risk only in patients who carry two Arg389 alleles of the beta-1 adrenoceptor, and specifically when myocardial infarction occurs at the beginning of the light cycle.
Source: Nature Communications
Institutions: Spanish National Centre for Cardiovascular Research, Centro de Investigación en Red en Enfermedades Cardiovasculares, Centro de Investigación Biomédica en Red, Universidad Alfonso X el Sabio, Spanish National Cancer Research Centre, Consejo Superior de Investigaciones Científicas, Centro de Investigaciones Biológicas Margarita Salas, Icahn School of Medicine at Mount Sinai, Hospital Universitario Fundación Jiménez Díaz, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: 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
Awards: G1105844351, G1175115578, G121809054, G1220040391, G1602493886, G1728342668, G1855990336, G210041235, G2152959462, G2262748287, G2309174360, G2601397997, G2660406951, G2672435700, G279363373, G288011245, G300979063, G34346518, G3480869486, G3681454997, G4042783231, G410571670, G425668148, G430777504, G434337789, G451917667, G47790720, G488842982, G491712853, G4936363825, G5080475149, G5195188938, G5421974903, G5539308778, G5967599077, G6033112984, G7084143925, G7805626310, G7863371703, G7941032108, G8497050386, G8696694383, G8920660035, G926782147, G929308097, G99296377
OpenAlex ID: W4416631568