Energy depletion has been highlighted as an important contributor to the pathology of
hypertrophic cardiomyopathy (HCM), a common inherited
cardiac disease. Pharmacological reversal of energy depletion appears an attractive approach and the use of
perhexiline has been proposed as it is thought to shift myocardial metabolism from
fatty acid to
glucose utilisation, increasing
ATP production and myocardial efficiency. We used the Mybpc3-targeted knock-in mouse model of HCM to investigate changes in the cardiac metabolome following
perhexiline treatment. Echocardiography indicated that
perhexiline induced partial improvement of some, but not all hypertrophic parameters after six weeks. Non-targeted metabolomics, applying ultra-high performance liquid chromatography-mass spectrometry, described a phenotypic modification of the cardiac metabolome with 272 unique metabolites showing a statistically significant change (p < 0.05). Changes in
fatty acids and acyl carnitines indicate altered
fatty acid transport into mitochondria, implying reduction in
fatty acid beta-oxidation. Increased
glucose utilisation is indirectly implied through changes in the glycolytic,
glycerol,
pentose phosphate,
tricarboxylic acid and pantothenate pathways. Depleted
reduced glutathione and increased production of
NADPH suggest reduction in oxidative stress. These data delineate the metabolic changes occurring during improvement of the HCM phenotype and indicate the requirements for further targeted interventions.