Ischaemic cardiomyopathy is the most common cause of heart failure and often coexists with diabetes mellitus which worsens patient symptom burden and outcomes. Yet, their combined effects are seldom investigated and are poorly understood. To uncover the influencing molecular signature defining ischaemic cardiomyopathy with diabetes, we performed multi-omic analyses of ischaemic and non-ischaemic cardiomyopathy with and without diabetes against healthy age-matched donors. Tissue was sourced from pre-mortem human left ventricular myocardium. Fatty acid transport and oxidation proteins were most down-regulated in ischaemic cardiomyopathy with diabetes relative to donors. However, the down-regulation of acylcarnitines, perilipin, and ketone body, amino acid and glucose metabolising proteins indicated lipid metabolism may not be entirely impaired. Oxidative phosphorylation, oxidative stress, myofibrosis, and cardiomyocyte cytoarchitecture also appeared exacerbated principally in ischaemic cardiomyopathy with diabetes. These findings indicate diabetes confounds the pathological phenotype in heart failure, and the need for a paradigm shift regarding lipid metabolism.

The authors have declared no competing interest.

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This work was funded by the R.T. Hall Trust (RQ112) and philanthropic donations to the University of Sydney. This work was also supported by the National Health and Medical Research Council (NHMRC) of Australia and the National Heart Foundation (NHF) of Australia. The contents of the published material are solely the responsibility of the individual authors and do not reflect the view of NHMRC or the NHF. J.O.S. is supported by an NSW OHMR EMCR grant (G212785), NHF Vanguard Grant (105595), NHF Future Leader Fellowship (104853), and an NHMRC/MRFF CVD award (2024161). M.P. was supported by a Postdoctoral Research Fellowship from the School of Mathematics and Statistics, University of Melbourne. Metabolomics Workbench raw data availability is supported by NIH grant U2C-DK119886 and OT2-OD030544 grants.

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The methods of procurement, storage and use of donated human myocardium were approved by the Human Research Ethics Committee at The University of Sydney (USYD 2021/122).

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