Ventricle-specific myocardial protein and metabolite characterisation in healthy humans, with differential regulation in end-stage cardiomyopathies

Abstract

AbstractBackgroundThe 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. The left ventricle is most clinically relevant in research as its dysfunction is the most dominant cause of heart failure whereby right ventricular involvement can exacerbate the condition. However, the molecular composition of the left ventricular adult human myocardium relative to the right ventricle in health and in heart failure has yet to be thoroughly explored.MethodsWe performed unbiased quantitative mass spectrometry analyses on the myocardium of pre-mortem cryopreserved non-diseased human hearts to compare the proteome (n = 27) and metabolome (n = 25) between the normal left and right ventricles. We then characterised the proteome and metabolome of the left and right ventricles within end-stage dilated cardiomyopathy (n = 14 and 13) and ischaemic cardiomyopathy (n = 19-17), respectively. All analyses featured a mix of paired and unpaired samples. Intra-condition comparative analyses were performed to identify differences of molecular abundance between the ventricles, and intra-ventricular analyses were performed between sexes of non-diseased hearts. Novel and innovative techniques were used to merge datasets, increasing the sample size and statistical power. KEGG and Gene Ontology databases were used to perform enrichment analyses and inform metabolic trends.ResultsConstituents of gluconeogenesis, glycolysis, lipogenesis, lipolysis, fatty acid catabolism, the citrate cycle and oxidative phosphorylation were down-regulated in the non-diseased 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 to glutamate ratio, and down-regulation of contractile proteins, indicating a left ventricular pathological bias.ConclusionsThe inter-ventricular molecular analyses within this study aides to fill a critical gap in our understanding of the metabolic differences between the human left and right ventricular myocardium and may be used to inform future therapeutic targets for heart failure processes in one or both the ventricles.