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Figure 4. Altered substrate utilization in the hypertrophic cardiomyopathy (HCM) heart. Metabolism in the HCM heart is characterized by a shift away from fatty acid uptake and oxidation toward increased glucose uptake. Fatty acid uptake and oxidation become increasingly impaired as cardiac remodeling and disease severity worsen, which is especially prominent in genotype-negative (G-) patients. Based on current literature, lipotoxicity does not appear to be an inherent feature of HCM, despite lowered fatty acid use. Glycolysis and glycogen turnover are elevated in HCM, although it is unknown how this may change throughout the disease. The preferred metabolic fate of glucose is incompletely understood. Multiomics studies suggest no increase in anaerobic lactate production and sustained input into the TCA. Glucose input into biosynthetic pathways such as the pentose phosphate pathway may be altered in a genotype-specific manner. Created in BioRender. Nollet E (2025) https://BioRender.com/53r16kv. TCA: Tricarboxylic acid cycle.