Why the study?
Cardioprotection in reperfused STEMI has faced persistent translational failure, and a clinically actionable framework for designing future clinical cardioprotection trials is needed.
Future cardioprotection trials in STEMI must align patient selection, phenotype-specific endpoints, and adaptive trial architecture to successfully translate biological efficacy into clinical benefit.
No immediate change to STEMI reperfusion practice; leaves open optimized trial frameworks for cardioprotection.
Purpose of Review To 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 Findings The 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. Summary 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.
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Bulluck et al. (2026) conducted a review in ST-elevation myocardial infarction (STEMI). Cardioprotection strategies was evaluated.
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