Proteomic and metabolomic analyses of the human adult myocardium reveal ventricle-specific regulation in end-stage cardiomyopathies

• Published in: Communications biology 2024-12, Vol.7 (1), p.1666-17, Article 1666
• Main Authors: Hunter, Benjamin, Li, Mengbo, Parker, Benjamin L., Koay, Yen Chin, Harney, Dylan J., Pearson, Evangeline, Cao, Jacob, Chen, Gavin T., Guneratne, Oneka, Smyth, Gordon K., Larance, Mark, O’Sullivan, John F., Lal, Sean
• Format: Article
• Language: English
• Subjects: 13; 631/114; 631/45/320; 631/45/475; 692/4019/592/2726; 692/699/75/230; 82/58; 82/79; 82/80; Adult; Aged; Biomedical and Life Sciences; Cardiomyopathies - metabolism; Cardiomyopathy; Congestive heart failure; Dilated cardiomyopathy; Female; Genetic analysis; Gluconeogenesis; Glucose metabolism; Glycolysis; Heart diseases; Heart failure; Heart Ventricles - metabolism; Humans; Ischemia; Life Sciences; Lipid metabolism; Lipogenesis; Lipolysis; Male; Mass spectroscopy; Metabolic pathways; Metabolism; Metabolome; Metabolomics; Metabolomics - methods; Middle Aged; Muscle contraction; Myocardium; Myocardium - metabolism; Oxidative metabolism; Oxidative phosphorylation; Phosphorylation; Proteome - metabolism; Proteomes; Proteomics; Proteomics - methods; Pyruvic acid
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-07306-y

The left and right ventricles of the human heart are functionally and developmentally distinct such that genetic or acquired insults can cause dysfunction in one or both ventricles resulting in heart failure. To better understand ventricle-specific molecular changes influencing heart failure development, we first performed unbiased quantitative mass spectrometry on pre-mortem non-diseased human myocardium to compare the metabolome and proteome between the normal left and right ventricles. Constituents of gluconeogenesis, glycolysis, lipogenesis, lipolysis, fatty acid catabolism, the citrate cycle and oxidative phosphorylation were down-regulated in the left ventricle, while glycogenesis, pyruvate and ketone metabolism were up-regulated. Inter-ventricular significance of these metabolic pathways was then found to be diminished within end-stage dilated cardiomyopathy and ischaemic cardiomyopathy, while heart failure-associated pathways were increased in the left ventricle relative to the right within ischaemic cardiomyopathy, such as fluid sheer-stress, increased glutamine-glutamate ratio, and down-regulation of contractile proteins, indicating a left ventricular pathological bias. Human myocardial proteomic and metabolomic analyses reveal ventricle-specific metabolic remodelling from normal hearts to heart failure, showing differential regulation in glucose and lipid metabolism, with a left ventricular pathological bias.