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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 (SSO\u2082) programme arc \u2013 AMIHOT \u2192 AMIHOT-II \u2192 IC-HOT \u2192 IC-HOT-MICRO \u2013 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\u2009\u2265\u20092.6% 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>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 \u2013 as the SSO\u2082 programme arc suggests \u2013 cardioprotection in STEMI may yet deliver clinically meaningful benefit.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11886-026-02401-4","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T03:09:42Z","timestamp":1786504182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reperfusion Injury and Infarct Size: Why Translation has Been Difficult, and How We Move Forward"],"prefix":"10.1007","volume":"28","author":[{"given":"Heerajnarain","family":"Bulluck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek J.","family":"Hausenloy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"issue":"22","key":"2401_CR1","doi-asserted-by":"publisher","first-page":"2196","DOI":"10.1016\/j.jacc.2024.02.056","volume":"83","author":"FGP Welt","year":"2024","unstructured":"Welt FGP, Batchelor W, Spears JR, Penna C, Pagliaro P, Ibanez B, Drakos SG, Dangas G, Kapur NK. 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