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The DCCT\/EDIC cohort is illustrative: early glycemic control produced cardiovascular protection that peaked within a decade and left a lasting legacy. The same strategy applied after prolonged hyperglycemia, however, has not reproduced this benefit. This conceptual Review proposes a framework in which such persistent risk arises from four distinct processes: encoded epigenetic memory, irreversible structural damage, chronic input from dysfunctional organs, and delayed tissue remodeling, each with a different therapeutic logic. Persistence of these encoded marks is established most directly in immune\u2010lineage cells; its extension to cardiomyocytes remains a working hypothesis. Only encoded memory is accessible to chromatin\u2010directed reversal, and only before metabolic stress exhausts the erasure machinery that keeps marks revisable, a time\u2010dependence proposed to explain why early intervention succeeds where late intervention fails. Clinical efficacy therefore may depend on engaging the substrate maintaining pathology rather than normalizing a surrogate biomarker, a substrate\u2010alignment principle consistent with the divergent outcomes of recent cardiometabolic trials. We apply the framework to atherosclerosis, heart failure, and diabetic cardiomyopathy, grade its claims by a three\u2010tier evidence classification, and specify testable predictions that could refute it.<\/jats:p>","DOI":"10.1002\/advs.77260","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T15:51:33Z","timestamp":1787845893000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Memory in Cardiovascular Disease: Encoding, Propagation, and Therapeutic Targeting"],"prefix":"10.1002","volume":"13","author":[{"given":"Cheng","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Central Laboratory The First Hospital of China Medical University  Shenyang Liaoning China"},{"name":"Department of Cardiology The First Hospital of China Medical University  Shenyang Liaoning 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