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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.)