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Figure 6. Metabolic therapy strategies in hypertrophic cardiomyopathy. NAD supplementation may boost mitochondrial function by increasing mitochondrial NAD availability and NADH-linked respiration. Elamipretide may ameliorate mitochondrial dysfunction by increasing the formation of respiratory supercomplexes, facilitating efficient electron transferring throughout the electron transport system and lowering reactive oxygen species (ROS) formation. Fatty acid oxidation inhibitors may improve myocardial efficiency by enhancing the metabolic shift away from fatty acids to glucose, which is typical in HCM hearts. However, results have been variable and may depend on patient-specific characteristics. Additionally, beneficial effects may be mediated by pleiotropy and off-target effects. The therapeutic potential of restoring the uptake and oxidation of fatty acids warrants investigation. Myosin inhibitors may confer metabolic benefits via relief of hypercontractility and concomitant lowered ATP consumption. Moreover, safeguarding whole-body metabolic health via exercise and antidiabetic drugs such as glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) is vital to minimize metabolic stress in the HCM heart. The latter drug class potentially provides the additional benefit of increased ketone utilization. Created in BioRender. Nollet E (2025) https://BioRender.com/3uniy0h. HCM: Hypertrophic cardiomyopathy; ADP: adenosine diphosphate; ATP: adenosine triphosphate; NADH: nicotinamide adenine dinucleotide; FAD: flavin adenine dinucleotide; NAD: nicotinamide adenine dinucleotide; SDH: succinate dehydrogenase; CI: complex I; CII: complex II; CIII: complex III; CIV: complex IV.