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 during the natural course of MI, revealing the dynamic changes of these two ions in both time and space. Based on these observed time-dependent ion changing patterns, we innovatively 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, we set the following studied variables: a sham surgery group, an MI group, a Zn ion-only group, a Cu ion-only group, and a group receiving Cu ions followed by Zn ions. The results indicated that the Zn-Cu ion sequential therapy helps regulate the levels of Zn and Cu ions in the serum and significantly improves cardiac function. 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.