Metabolic Abnormalities and Reprogramming in Cats with Naturally Occurring Hypertrophic Cardiomyopathy

BACKGROUND AND AIMS: The heart is a metabolic organ rich in mitochondria. The failing heart reprograms to utilize different energy substrates, which increase its oxygen consumption. These adaptive changes contribute to increased oxidative stress. Hypertrophic cardiomyopathy (HCM) is a common heart condition, affecting approximately 15% of the general cat population. Feline HCM shares phenotypical and genotypical similarities with human HCM, but the disease mechanisms for both species are incompletely understood. Our goal was to characterize global changes in metabolome between healthy control cats and cats with different stages of HCM. METHODS: Serum samples from 83 cats, the majority (70/83) of which were domestic shorthair and included 23 healthy control cats, 31 and 12 preclinical cats with American College of Veterinary Internal Medicine (ACVIM) stages B1 and B2, respectively, and 17 cats with history of clinical heart failure or arterial thromboembolism (ACVIM stage C), were collected for untargeted metabolomic analysis. Multiple linear regression adjusted for age, sex and body weight was applied to compare between control and across HCM groups. RESULTS: Our study identified 1253 metabolites, of which 983 metabolites had known identities. Statistical analysis identified 167 metabolites that were significantly different among groups (adjusted P < 0.1). About half of the differentially identified metabolites were lipids, including glycerophospholipids, sphingolipids and cholesterol. Serum concentrations of free fatty acids, 3-hydroxy fatty acids and acylcarnitines were increased in HCM groups compared with control group. The levels of creatine phosphate and multiple Krebs cycle intermediates, including succinate, aconitate and α-ketoglutarate, also accumulated in the circulation of HCM cats. In addition, serum levels of nicotinamide and tryptophan, precursors for de novo NAD+ biosynthesis, were reduced in HCM groups versus control group. Glutathione metabolism was altered. Serum levels of cystine, the oxidized form of cysteine and cysteine-glutathione disulfide, were elevated in the HCM groups, indicative of heightened oxidative stress. Further, the level of ophthalmate, an endogenous glutathione analog and competitive inhibitor, was increased by more than twofold in HCM groups versus control group. Finally, several uremic toxins, including guanidino compounds and protein bound putrescine, accumulated in the circulation of HCM cats. CONCLUSIONS: Our study provided evidence of deranged energy metabolism, altered glutathione homeostasis and impaired renal uremic toxin excretion. Altered lipid metabolism suggested perturbed structure and function of cardiac sarcolemma membrane and lipid signalling.