Eukaryotes must balance the metabolic and cell death actions of mitochondria via control of gene expression and cell fate by chromatin, thereby functionally binding the metabolome and epigenome. This interaction has far-reaching implications for chronic diseases in humans, the most common of which are those of the cardiovascular system. The most devastating consequence of cardiovascular disease, heart failure, is not a single disease, diagnosis, or endpoint. Human and animal studies have revealed that, regardless of etiology and symptoms, heart failure is universally associated with abnormal metabolism and gene expression – to frame this as cause or consequence, however, may be to wrongfoot the question. This essay aims to challenge current thinking on metabolic–epigenetic crosstalk in heart failure, presenting hypotheses for how chronic diseases arise, take hold, and persist. We unpack assumptions about the order of operations for gene expression and metabolism, exploring recent findings in noncardiac systems that link metabolic intermediates directly to chromatin remodeling. Lastly, we discuss potential mechanisms by which chromatin may serve as a substrate for metabolic memory, and how changes in cellular transcriptomes (and hence in cellular behavior) in response to stress correspond to global changes in chromatin accessibility and structure. Heart failure is a ruinous destination for many afflicted with cardiovascular disease and is not a single condition or single set of diagnostic criteria; instead, it manifests through an intricate series of molecular and systemic malfunctions ranging from the suborganelle level to the multiple organ systems of the body.Regardless of the etiology, humans with, and animal models of, heart failure are characterized by abnormal metabolism and gene expression, some aspects of which are compensatory responses to the disease whereas others promulgate injury.Close communication between the metabolome and the epigenome sets basal susceptibility to various heart failure symptoms. This communication entrains detrimental conditions in metabolic–epigenetic memory and thus may be a target for novel treatments.