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

Myocardial infarction (MI) can induce an imbalance in the trace element ion microenvironment within the human body. This study preliminarily explored the changing patterns of zinc (Zn) and copper (Cu) ions after MI, revealing the dynamic changes of these two ions in both time and space. Based on these observed time-dependent ion changing patterns, we designed a Zn-Cu ion sequential therapy to precisely meet the staged demands of the body for trace elements after MI. To verify the efficacy of the Zn-Cu ion sequential therapy (experimental group), we set the following studied variables: a sham group, a MI group, a Zn ion-only group, and a Cu ion-only group. The results indicated that the administration of sequential Zn-Cu ion therapy effectively modulated serum zinc and copper ion levels, subsequently enhancing various cardiac function parameters. For instance, the left ventricular ejection fraction (LVEF) in the Zn-Cu group exhibited a marked improvement, increasing from 22.96±2.87% post-myocardial infarction (MI) to 37.83±5.32% by day 28. Furthermore, we utilized a perfusable multifunctional epicardial device (PerMed) to construct a stable ion microenvironment "reservoir" within the infarcted area, achieving precise control over ion concentrations and thereby optimizing the repair and regeneration of cardiomyocytes. Further research revealed that the efficacy of the ion sequential therapy depends on the precise regulation of Period circadian protein homolog 2 (Per2), which is closely related to the circadian rhythm. In summary, this study proposes an innovative therapeutic strategy, namely designing an ion sequential therapy that aligns with the pathological changes induced by alterations in the microenvironment after MI.