Reperfusion Injury and Infarct Size: Why Translation has Been Difficult, and How We Move Forward.

purpose of reviewTo evaluate the reasons underlying the translational failure of cardioprotection in reperfused ST-elevation myocardial infarction (STEMI) and propose a framework for designing future clinical cardioprotection trials. RECENT

findingsThe 2024 JACC Scientific Statement on reperfusion injury reframed the field as a network of interrelated injury pathways but stopped short of providing a clinically actionable framework. Contemporary cardioprotection trials in enriched patient STEMI cohorts have produced largely neutral results: STEMI-DTU, PiCSO-AMI-I, EURO-ICE, and COOL AMI EU failed to demonstrate cardioprotection on cardiovascular magnetic resonance (CMR) infarct size. Although the PITRI trial showed reduced periprocedural platelet reactivity with cangrelor there was no reduction in infarct size or microvascular obstruction (MVO), exemplifying proximal target engagement without affecting imaging surrogates. In contrast, the supersaturated oxygen (SSO₂) programme arc - AMIHOT → AMIHOT-II → IC-HOT → IC-HOT-MICRO - showed progressive patient enrichment yielding a progressive mechanistic signal, particularly in patients with severe coronary microvascular dysfunction. The Collaborative Registry on CMR in STEMI confirmed MVO ≥ 2.6% of left ventricular mass as an independent predictor of heart failure hospitalisation and all-cause death. The EU-CARDIOPROTECTION IMPACT criteria provide a preclinical standard for clinical translation. Translational failure of cardioprotection reflects misalignment between heterogeneous biology and trial design, not biological irrelevance. A biological ceiling cannot be excluded but is unlikely to be the dominant barrier. The path forward is to align patient selection, phenotype-specific endpoints, and adaptive trial architecture, and to test mechanical interventions together with pharmacological adjuncts rather than in isolation. When these elements are aligned - as the SSO₂ programme arc suggests - cardioprotection in STEMI may yet deliver clinically meaningful benefit.