Molecular Mechanism of Diurnal Effects in Myocardial Infarction

The severity of myocardial infarction injury varies depending on the time of day; now, researchers have begun to uncover the molecular mechanism behind the circadian pattern. Larger infarcts and poorer outcomes are seen in patients with morning-onset events because of the core circadian transcription factor basic helix-loop-helix ARNT-like protein 1 (BMAL1), “by forming a transcriptionally active heterodimer with a non-canonical partner—hypoxia-inducible factor 2 alpha (HIF2A) —in a diurnal manner,” according to the research team.

Results were published in Nature.

The research team investigated transcriptional pathways during myocardial infarctions at different times by examining left ventricle biopsy samples from 73 patients receiving elective aortic valve replacement surgery (56 samples from morning infarctions and 17 samples from afternoon infarctions).

The samples were collected before and after approximately 80 minutes of ischemia induced by aortic clamping. RNA sequence analysis of pre-clamping samples showed significant circadian modulation of BMAL1 expression, which was identified as the most downregulated gene in the morning cohort.

Using the Human Reference Interactome, the researchers identified HIF2A as the most abundantly expressed BMAL1 interactor. Considering the occurrence of severe hypoxia during myocardial infarction, the researchers examined the BMAL1-HIF2A interaction under hypoxic conditions, which revealed “robust BMAL1-HIF2A nuclear interactions under ambient hypoxia.”

In addition to their findings on the downregulated expression of BMAL1, enabling crosstalk between circadian rhythm and hypoxia signaling, the researchers also identified amphiregulin (AREG) as the “rhythmic target of the BMAL1-HIF2A complex, critical for regulating daytime variations of myocardial injury.”

AREG’s role in circadian variations was analyzed using genetic deletion models in mice, with increased heart cell apoptosis observed in AREG-/- mice, suggesting that AREG plays a key role in regulating time-dependent cardiac injury and protection.

“Given the feasibility of integrating circadian timing into clinical practice, prospective trials are needed to evaluate whether aligning treatments with circadian phases or directly targeting circadian rhythms can improve outcomes in patients with MI. Beyond MI, circadian modulation of hypoxic responses may have broader implications for other hypoxia- and inflammation-related diseases with circadian characteristics, potentially paving the way for clock-based therapeutic innovations,” the researchers concluded.

Reference

Ruan W, et al. Nature. 2025. Published online April 23, 2025. doi:10.1038/s41586-025-08898-z