Ion sequential therapy aligned with pathological changes enhances cardiac function after myocardial infarction.

Abstract

Myocardial infarction (MI) induces critical trace element imbalances that exacerbate adverse ventricular remodeling. Here, we comprehensively map the spatiotemporal dynamics of zinc (Zn) and copper (Cu) ions post-MI and design a sequential Zn-Cu therapeutic regimen tailored to match staged physiological demands. This temporally controlled administration effectively modulates ion levels and significantly improves overall cardiac function, attenuating post-infarction heart failure. Mechanistically, we demonstrate that therapeutic efficacy inherently relies on the precise modulation of the core circadian rhythm gene, period circadian protein homolog 2 (PER2), which controls cellular metabolic homeostasis. To autonomously sustain this molecular regulatory mechanism and further optimize cardiomyocyte repair, we engineer a perfusable epicardial device (PerMed) that maintains stable, localized ion concentrations, thereby minimizing off-target systemic effects. Ultimately, this Zn-Cu sequential therapy offers a highly targeted intervention strategy strictly aligned with the dynamic pathological microenvironment alterations emerging immediately following myocardial infarction.