Myocardial metabolic remodeling in human end-stage ischemic and non-ischemic cardiomyopathy

Heart failure (HF) is linked to disturbances in heart metabolism. Metabolomics shows promise in identifying cardiac-specific metabolic changes across different types of heart disease. However, direct comparison of metabolomic changes in myocardial tissues from humans with end-stage ischemic (ICM) and nonischemic (NICM) heart failure is scarce.

Left ventricles were collected from patients with end-stage ICM (n = 14) and NICM (n = 15), along with nonfailing donors (n = 11). Untargeted metabolomics assessed organic acids, amino acids, purines, and pyrimidines. Data were analyzed using partial least squares-discriminant analysis (PLS-DA), heat maps, Kruskal-Wallis with Dunn test, and ANOVA. RT-PCR and Western blotting were used to examine the expression of metabolic genes.

Myocardial metabolites could distinguish diseased from nonfailing hearts; however, ICM and NICM samples often overlapped, despite ICM patients having higher rates of diabetes and hyperlipidemia. Glycolytic and TCA metabolites showed no differences within the groups. Notably, myocardial UDP-N-Acetyl-glucosamine and O-GlcNAcylation levels were consistently lower, despite increased expression of hexosamine pathway genes in both disease groups. Several amino acids decreased, yet branched-chain amino acids remained stable in ICM and NICM hearts. Both groups showed hyperhomocysteinemia and increased urea cycle intermediates. Glutathione (GSH) and glutathione disulfide (GSSG) levels were depleted regardless of glutathione synthesis gene expression. Adenylated purines and pyrimidines were reduced, with increased purine degradation and a notable upregulation of NC5E, an extracellular nucleotidase, in both disease groups. While ATP and NAD+ levels stayed relatively stable, NADH, FAD+, and NADP+ levels decreased in diseased hearts. Catalase was upregulated in both disease groups despite elevated markers of oxidative stress.

Human end-stage heart failure is characterized by altered glucose and amino acid metabolism, heightened oxidative stress, increased purine breakdown, and reduced pyrimidine levels, with no differences observed between ischemic and nonischemic cardiomyopathy. These findings enhance our understanding of metabolic alterations in failing human hearts.