Cardiac stress (e.g. ischemia, diet, genetics, hypertension) affects the metabolome, proteome, and epigenome, forcing a coordinated, time-sensitive response. Stress-induced changes in metabolic substrate utilization causes a shift in metabolic enzymatic activity and metabolite pools. These metabolites act on proteins through post-translational modifications (PTMs), changing protein activity or localization. Protein PTM induced nuclear localization directly or indirectly influences epigenetic processes (e.g. histone modifications or DNA methylation), causing changes in chromatin accessibility and gene expression. Metabolites can be shuttled to the nucleus to be utilized as substrates for epigenetic modifications, thereby changing local chromatin accessibility, influencing gene expression and ultimately protein abundance.