Metabolic Coordination of Physiological and Pathological Cardiac Remodeling

Abstract

Metabolic pathways integrate to support tissue homeostasis and to prompt changes in cell phenotype. In particular, the heart consumes relatively large amounts of substrate not only to regenerate ATP for contraction but also to sustain biosynthetic reactions for replacement of cellular building blocks. Metabolic pathways also control intracellular redox state, and metabolic intermediates and end products provide signals that prompt changes in enzymatic activity and gene expression. Mounting evidence suggests that the changes in cardiac metabolism that occur during development, exercise, and pregnancy as well as with pathological stress (eg, myocardial infarction, pressure overload) are causative in cardiac remodeling. Metabolism-mediated changes in gene expression, metabolite signaling, and the channeling of glucose-derived carbon toward anabolic pathways seem critical for physiological growth of the heart, and metabolic inefficiency and loss of coordinated anabolic activity are emerging as proximal causes of pathological remodeling. This review integrates knowledge of different forms of cardiac remodeling to develop general models of how relationships between catabolic and anabolic glucose metabolism may fortify cardiac health or promote (mal)adaptive myocardial remodeling. Adoption of conceptual frameworks based in relational biology may enable further understanding of how metabolism regulates cardiac structure and function.

Short-chain fatty acid, acylation and cardiovascular diseases

“…The heart is an 'omnivore' , using FAs, glucose, lactate, ketone bodies, and amino acids as metabolic substrates [5,6]. The substrates utilized by the embryonic heart are significantly different from those used by the adult heart.…”

“…As thus, cardiac substrate metabolism is closely related to cardiac function. The myocardial tissues utilize diverse carbon substrates, including fatty acids (FAs), glucose, lactate, ketone bodies, and amino acids [5][6][7]. In mammals, FAs are the primary substrates utilized by the adult hearts, while the fetal hearts rely on glucose (glycolysis) for ATP generation [8][9][10].…”

Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling

“…Despite extensive interests and profound clinical relevance 14 , signaling pathways and pathological triggers of this transition are ill-defined. Numerous studies suggest that metabolic derangement is one of the most important and earliest processes underlying pathological cardiac remodeling in response to hypertension [15][16][17][18][19] . The normal heart preferentially uses fatty acids to produce ATP whereas in the hypertrophied heart, glucose consumption is elevated 20,21 .…”

The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

“…In the ZSF1 rat CMS model, obesity and impaired metabolism have also greatly increased CVD pathology by altering two major metabolic pathways in heart tissue (Fig 5B and 5C)—fatty acid metabolism and BCAA metabolism. In general, cardiac metabolic homeostasis of fatty acid, glucose, ketone bodies, and BCAAs is well established through intertwined regulatory networks [45, 46]. Thus, gene expression of essential enzymes involved in both fatty acid metabolism and BCAA catabolism—ACADM, EHHADH, HADHA, and HADHB—is greatly increased in obese ZSF1 LV heart tissue.…”