The Complement-Glycocalyx Axis in Myocardial Ischemia-Reperfusion Injury: A Proposed Endothelial Checkpoint Linking Inflammation to Microvascular Obstruction

Microvascular obstruction (MVO) remains a major determinant of adverse remodeling and prognosis after successful reperfusion for ST-elevation myocardial infarction (STEMI), highlighting the gap between restoration of epicardial patency and effective tissue-level reperfusion. This Review examines whether complement activation and endothelial glycocalyx injury can be integrated into a mechanistic framework linking inflammatory signaling to coronary microvascular injury. A focused narrative synthesis prioritized experimental and human studies relevant to myocardial ischemia-reperfusion, C3a/C3aR and C5a/C5aR1 signaling, glycocalyx biology, and MVO. Human observations associate complement activation with endothelial and glycocalyx abnormalities, while controlled endothelial-cell experiments support C3a-C3aR-Rac1- and C5a-C5aR1-RhoA-dependent cortical remodeling, impaired glycocalyx integrity, reduced nitric oxide bioavailability, and proadhesive activation. Separately, myocardial I/R experiments show that glycocalyx preservation can reduce pericapillary edema and MVO. These complementary findings support individual mechanistic links but do not establish the complete complement-glycocalyx-MVO sequence within a single clinically realistic, blood-perfused reperfusion model. We therefore propose the complement-glycocalyx endothelial checkpoint as an operational and falsifiable framework rather than an established biological entity. Direct validation should combine complement target engagement, coronary glycocalyx structure, endothelial function, and CMR-defined microvascular injury within the same reperfusion model before clinical translation is considered.