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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., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: This study was conducted in collaboration with multiple institutions across Australia, with contributions from researchers affiliated with the University of Sydney, the University of Melbourne, and St Vincent’s Hospital, Sydney. All contributors fulfilling authorship criteria have been listed as co-authors, while those who provided additional support are acknowledged in the Acknowledgements section.The research was conducted with oversight from the Human Research Ethics Committee at the University of Sydney (USYD 2021/122). Sample procurement, including donor and heart failure tissue, and data collection and handling were performed in accordance with ethical guidelines. This research was designed to address globally relevant issues in heart failure and cardiomyopathy, and we have designed our sample cohort with this in mind where possible including heart disease prevalence. Additionally, we adhered to international best practices in data analysis and transparent reporting of our findings. All mass spectrometry data have been made available through public repositories, and we have ensured that local regulations concerning human tissue research were strictly followed. Informed consent: All tissue was collected following informed consent., (© 2024. Crown.)

Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5-monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil gender-specific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource. Study of human heart failure is limited by access to human tissue. Here, the authors apply multi-omic screening in human ischaemic and dilated myocardial tissue and matched controls to determine molecular changes common and unique to each aetiology and to reveal differences between male and female hearts. [ABSTRACT FROM AUTHOR]

Introduction: Our previous work revealed that uridine and UDP were associated with 4 separate coronary artery disease (CAD) loci in >1000 subjects in the Framingham Heart Study. Using cryopreserved human myocardial tissue, we now extend our investigations of the uridine, and other pathways, in human ischemic heart disease (IHD). Aims: 1. Determine if previously implicated IHD pathway perturbations in human plasma were also dysregulated in human IHD myocardial tissue; 2. Comprehensively examine the functional genomic pathway perturbations in human IHD myocardium. Methods: 193 metabolites and 5,400 proteins were measured by LC-MS in myocardial tissue from cryopreserved hearts of 14 patients with ischaemic heart disease and 10 healthy donor hearts. Mann-Whitney tests were used to compare the protein and metabolite data in IHD versus controls, and permutation-based FDR. Results: Uridine metabolites uridine (P=7E-6) and uridine metabolite 2-deoxycitidine (P=4.6E-5), and protein uridine 5-monophosphate synthase (P=3.7E-2) were significantly elevated, and proteins pseudouridine 5-phosphatase (P=1.3E-2), and UDP-N-acetlyglucosamine-peptide N-acetlyglucosaminyltansferase (P=2E-3) were significantly decreased in IHD myocardium compared to control. Plasma methionine was previously associated with two CAD loci: WDR12 (P=3.5E-2), and COL4A1/COL4A2 (P=1.5E-2). In IHD myocardium, methionine metabolites taurine (P=1.2E-3) and cysteamine (P=2.7E-4) were significantly elevated, whereas methionine (P=5E-4) was significantly reduced. Purines allantoin and guanosine monophosphate (GMP) were previously associated with two CAD loci: allantoin with PPAP2B (P=1.2E-2); GMP with CDKN2B (P=1.95E-2). Purines allantoin (P=1E-6), ADP (P=1.3E-2), xanthosine (P=3.1E-2) and xanthenuric acid (P=2E-4) were significantly elevated in ischaemic myocardium, whereas cAMP was reduced (P=4.8E-2). Conclusions: Integration of genomic, proteomic, and metabolomic data in a large community-based cohort and in human IHD myocardium implicates the uridine, methionine, and purine pathways. These highly novel findings may offer new therapeutic strategies in IHD, which we will investigate mechanistically in model systems. [ABSTRACT FROM AUTHOR]