Metabolic and Proteomic Defects in Human Hypertrophic Cardiomyopathy

Previs, M.; O'Leary, T.; Wood, N.; Morley, M.; Palmer, B.; LeWinter, M.; Yob, J.; Pagani, F.; Petucci, C.; Kim, M. S.; Margulies, K.; Arany, Z.; Kelly, D.; Day, S.

doi:10.1101/2021.08.18.455967

bioRxiv · 10.1101/2021.08.18.455967

Metabolic and Proteomic Defects in Human Hypertrophic Cardiomyopathy

Previs, M.·O'Leary, T.·Wood, N.·Morley, M.·Palmer, B.·LeWinter, M.·Yob, J.·Pagani, F.·Petucci, C.·Kim, M. S.·Margulies, K.·Arany, Z.·Kelly, D.·Day, S.

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Abstract

RationaleImpaired cardiac energetics in hypertrophic cardiomyopathy (HCM) is thought to result from increased ATP utilization at the sarcomere and is believed to be central to pathophysiology. However, the precise defects in cardiac metabolism and substrate availability in human HCM have not been defined. ObjectiveThe purpose of this study is to define major disease pathways and determine the pool sizes of intermediary metabolites in human HCM. Methods and ResultsWe conducted paired proteomic and metabolomic analyses of septal myectomy samples from patients with HCM and compared results to non-failing control human hearts. Increased abundance of extracellular matrix and intermediate filament / Z-disc proteins, and decreased abundance of proteins involved in fatty acid oxidation and cardiac energetics was evident in HCM compared to controls. Acyl carnitines, byproducts of fatty acid oxidation, were markedly depleted in HCM samples. Conversely, the ketone body 3-hydroxybutyrate, lactate, and the 3 branched chain amino acids, were all significantly increased in HCM hearts, suggesting that they may serve as alternate fuel sources for the production of ATP. ATP, nicotinamide adenine dinucleotide (NADH), NADP and NADPH, and acetyl CoA were also severely depleted in HCM hearts. Based on measurements from human skinned muscle fibers, the magnitude of observed reduction in ATP content in the HCM hearts would be expected to decrease the rate of cross-bridge detachment, implying a direct effect of energy depletion on myofilament function that could contribute to diastolic dysfunction. ConclusionsHCM hearts display profound deficits in cardiac energetics, marked by depletion of fatty acid derivatives and compensatory increases in other metabolites that could serve as alternate fuel sources. These results lend support to the paradigm that energy depletion contributes to the pathophysiology of HCM and also have important therapeutic implications for the future design of metabolic modulators to treat HCM.

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Previs, M., O'Leary, T., Wood, N., Morley, M., Palmer, B., LeWinter, M., Yob, J., Pagani, F., Petucci, C., Kim, M. S., Margulies, K., Arany, Z., Kelly, D., Day, S.. 2021-08-19. Metabolic and Proteomic Defects in Human Hypertrophic Cardiomyopathy. https://doi.org/10.1101/2021.08.18.455967

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