Metabolic-epigenetic vulnerability in cardiometabolic HFpEF: One-carbon metabolism, DNMT maintenance, and methylation instability.

Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is characterized by the frequent co-occurrence of obesity, central adiposity, insulin resistance, type 2 diabetes mellitus, and low-grade inflammation. How these exposures sustain myocardial remodeling remains uncertain. One-carbon metabolism provides a plausible biochemical interface between nutrient stress and epigenetic regulation: S-adenosylmethionine (SAM) donates methyl groups, whereas S-adenosylhomocysteine (SAH) inhibits methyltransferases. Altered nicotinamide N-methyltransferase (NNMT) flux, homocysteine-related SAH retention, and metabolic regulation of DNA methyltransferase (DNMT) and ten-eleven translocation (TET) enzymes could therefore reshape DNA methylation and hydroxymethylation. Direct human evidence remains sparse: available HFpEF methylation data are blood-derived rather than myocardial, and cardiac or adjacent models support individual components of the framework but not a continuous disease-specific pathway. We therefore view DNA methylation as a context-dependent regulatory layer that may amplify or stabilize inflammatory, fibrotic, and metabolic programs rather than as a uniform initiating cause. Accordingly, translational studies should prioritize compartment-specific target engagement, reversibility, and biomarker-guided patient selection rather than assume a role for methylation-directed therapy.