Metabolic Memory in Cardiovascular Disease: Encoding, Propagation, and Therapeutic Targeting.

Authors

Cheng Cheng, Minghui Tang, Zhaobo Zhang, Ruoyi Qu, Jianfei Pei, Tian Liu, Siyao Qu, Shilong You, Shenshen Cui, Wenke Wang, Rui Zhao, Yingxian Sun, Naijin Zhang

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Volume 13. Issue 54. Pages e77260. Epub Aug 27, 2026.

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 testable predictions that could refute it.

PMID:
42658609
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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