Distinguishing persistent memory from reprogramming in cardiovascular epigenetics

Abstract Background Previous metabolic exposure can influence cardiovascular risk long after treatment begins. Chromatin changes offer one explanation, but their presence during disease does not establish memory. This Review examines which findings support persistent metaboloepigenetic states and which demonstrate reprogramming under continued stress. Main body We apply eight operational criteria to 43 study-specific evidence units and report persistence, mechanistic causality, cardiovascular relevance and human evidence separately. The assessment distinguishes exposure withdrawal from incomplete recovery, persistent dysfunction from functional recall, and prevention of induction from reversal of an established state. Human diabetes cohorts identify histone acetylation and DNA methylation signatures associated with previous glycaemia and subsequent complications; these findings concern mainly microvascular outcomes and do not establish chromatin-mediated cardiovascular risk. Controlled glucose-recovery studies in human CD34+ progenitors, endothelial cells and a monocytic cell line provide complementary evidence of persistence. General trained-immunity models clarify metabolic and chromatin mechanisms, whereas oxidised lipoprotein, diabetes and post-infarction models provide more direct cardiovascular links. Inflammatory persistence in vascular smooth muscle deserves separate consideration from lactylation-associated calcification, for which postwithdrawal memory remains unestablished. Mechanical unloading and pressure-relief studies reveal persistent myocardial features, although metabolic causation and chromatin storage are incompletely resolved. A research agenda is proposed for longitudinal, cell-resolved biomarker validation and interventions delivered after state establishment. Conclusion Selected immune and vascular experiments support metaboloepigenetic memory, and human studies identify plausible molecular carriers. The assessed evidence does not complete the causal chain from a persistent, cell-defined chromatin state to later human cardiovascular events. Study-specific timing and intervention data should determine the claim; neither disease association nor an aggregate evidence score can substitute for them.