Abstract Body (Do not enter title and authors here): Background: Disturbances in heart metabolism contribute to the development of heart failure. However, the metabolic signature associated with different etiologies of end-stage heart failure remains unknown.
Methods: Using ultra-high-performance liquid chromatography-tandem mass spectroscopy, we performed untargeted quantitative metabolomic analysis of left ventricle samples in 41 male patients, including 11 healthy nonfailing heart explants (HC) and 30 end-stage failing hearts from patients diagnosed with ischemic (ICM, n=14) and non-ischemic (NICM, n=16) cardiomyopathy. We analyzed data using partial least squares discriminant analysis and heat maps, and conducted RT-PCR analyses to correlate changes with the expression of metabolic genes.
Results: Among 124 major metabolites identified, significant disruptions in pyrimidines, purines, histidine, and riboflavin metabolism were observed in disease groups, particularly in ICM. Heat map analysis revealed that cellobiose, histamine, histidine, and 1-methyladenosine quantities are particularly lower in the disease groups. Interestingly, ICM and NICM have markedly elevated oxidative stress-related metabolites, such as allantoin, homocysteine, and uric acid. However, glutathione and glutathione disulfide levels specifically decrease in ICM, not NICM. Meanwhile, there are markedly increased glycolytic and oxidative pentose phosphate pathway (PPP) metabolites in ICM, more prominently in NICM. NADH, creatine, and creatinine levels were lower in both disease groups. However, FAD+ and NADP+ were more specifically reduced in ICM. Abnormalities in amino acid metabolism were obviously associated with both conditions, with more significant deviations in ICM. Furthermore, ICM showed more marked dysregulations of purine and histidine metabolic genes; whereas NICM displayed more alterations in the expressions of glycolytic and PPP genes.
Conclusion: Our study identified elevated oxidative stress, dysregulated glucose and amino acid metabolism, and impaired pyrimidine and purine metabolism associated with human end-stage heart failure, with more pronounced changes in ICM. These findings offer new insights into the metabolic distinctions between ICM and NICM, enhancing our understanding of biological pathways underlying the pathogenesis of heart failure.