Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/115398
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Type: Journal article
Title: Decreased ATP production and myocardial contractile reserve in metabolic heart disease
Author: Luptak, I.
Sverdlov, A.
Panagia, M.
Qin, F.
Pimentel, D.
Croteau, D.
Siwik, D.
Ingwall, J.
Bachschmid, M.
Balschi, J.
Colucci, W.
Citation: Journal of Molecular and Cellular Cardiology, 2018; 116:106-114
Publisher: Elsevier
Issue Date: 2018
ISSN: 0022-2828
1095-8584
Statement of
Responsibility: 
Ivan Luptak, Aaron L. Sverdlov, Marcello Panagia, Fuzhong Qin, David R. Pimentel, Dominique Croteau, Deborah A. Siwik, Joanne S. Ingwall, Markus M. Bachschmid, James A. Balschi, Wilson S. Colucci
Abstract: Metabolic syndrome is a cluster of obesity-related metabolic abnormalities that lead to metabolic heart disease (MHD) with left ventricular pump dysfunction. Although MHD is thought to be associated with myocardial energetic deficiency, two key questions have not been answered. First, it is not known whether there is a sufficient energy deficit to contribute to pump dysfunction. Second, the basis for the energy deficit is not clear. To address these questions, mice were fed a high fat, high sucrose (HFHS) 'Western' diet to recapitulate the MHD phenotype. In isolated beating hearts, we used 31P NMR spectroscopy with magnetization transfer to determine a) the concentrations of high energy phosphates ([ATP], [ADP], [PCr]), b) the free energy of ATP hydrolysis (∆G~ATP), c) the rate of ATP production and d) flux through the creatine kinase (CK) reaction. At the lowest workload, the diastolic pressure-volume relationship was shifted upward in HFHS hearts, indicative of diastolic dysfunction, whereas systolic function was preserved. At this workload, the rate of ATP synthesis was decreased in HFHS hearts, and was associated with decreases in both [PCr] and ∆G~ATP. Higher work demands unmasked the inability of HFHS hearts to increase systolic function and led to a further decrease in ∆G~ATP to a level that is not sufficient to maintain normal function of sarcoplasmic Ca2+-ATPase (SERCA). While [ATP] was preserved at all work demands in HFHS hearts, the progressive increase in [ADP] led to a decrease in ∆G~ATP with increased work demands. Surprisingly, CK flux, CK activity and total creatine were normal in HFHS hearts. These findings differ from dilated cardiomyopathy, in which the energetic deficiency is associated with decreases in CK flux, CK activity and total creatine. Thus, in HFHS-fed mice with MHD there is a distinct metabolic phenotype of the heart characterized by a decrease in ATP production that leads to a functionally-important energetic deficiency and an elevation of [ADP], with preservation of CK flux.
Keywords: Metabolism; Contractile function; Obesity; Metabolic syndrome; Heart failure
Description: Available online 01 February 2018
Rights: © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
RMID: 0030096412
DOI: 10.1016/j.yjmcc.2018.01.017
Grant ID: http://purl.org/au-research/grants/nhmrc/1037603
Appears in Collections:Medicine publications

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