Myocardial ischemia–reperfusion injury after acute myocardial infarction: spatiotemporal mechanisms and endotype-matched multi-target modulation by compounds from traditional Chinese medicine

Myocardial ischemia-reperfusion (I/R) injury remains a major determinant of outcome after acute myocardial infarction (AMI) despite timely primary percutaneous coronary intervention (PPCI). Although epicardial patency is routinely restored, incomplete tissue reperfusion, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and maladaptive inflammation often limit myocardial salvage and promote adverse remodeling. In this narrative review, I/R injury is synthesized as a spatiotemporal, multicompartment network in which dominant mechanisms and actionable nodes shift from seconds to weeks and across cardiomyocytes, the coronary microvasculature, and systemic immune-metabolic programs. This framework helps explain why many single-target, single-window cardioprotective strategies have shown robust preclinical benefit yet failed to improve outcomes in contemporary ST-segment elevation myocardial infarction (STEMI) trials, where heterogeneity in ischemic time, comorbidities, microvascular injury patterns, and background pharmacotherapy reshapes injury topology and dilutes target-dominant subgroups. We propose an endpoint-anchored approach that distinguishes cardiomyocyte-vulnerability, microvascular-bottleneck, and resolution-deficient endotypes and matches interventions to phase-specific objectives using compartment-aligned endpoint stacks and target-engagement biomarkers. Within this rationale, defined bioactive compounds derived from traditional Chinese medicine (TCM) and selected standardized preparations are evaluated as potential network modulators with plausible actions on mitochondrial vulnerability, immunothrombosis, endothelial integrity, and inflammatory resolution. Translational priorities include stringent standardization, pharmacokinetic/pharmacodynamic (PK/PD)-informed dosing, PCI-compatible safety and drug-drug interaction assessment, and biomarker-guided trial designs enriched for mechanistically matched endotypes.