Metabolic Memory in Cardiovascular Disease: Encoding, Propagation, and Therapeutic Targeting
Abstract
Cardiovascular risk in metabolic disease persists long after the initiating metabolic abnormalities are corrected, a phenomenon termed metabolic memory. 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-lineage cells; its extension to cardiomyocytes remains a working hypothesis. Only encoded memory is accessible to chromatin-directed reversal, and only before metabolic stress exhausts the erasure machinery that keeps marks revisable, a time-dependence 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-alignment 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-tier evidence classification, and specify…
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