Metabolic Reserve of the Heart: The Forgotten Link Between Contraction and Coronary Flow

Kassiotis, Christos; Rajabi, Mitra; Taegtmeyer, Heinrich

doi:10.1016/j.pcad.2007.11.005

Cited by 40 publications

(38 citation statements)

References 134 publications

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“…Although these 2 pathologies are vastly different in their clinical presentation, the hypertrophic and diabetic hearts share signs of a return to the fetal gene program and impaired metabolic reserve. 4 We discuss potential defects in several parallel pathways that could limit the ability of the failing heart to meet energetic demand. Specifically, we examine the role of intracellular and mitochondrial calcium in regulating mitochondrial metabolism, changes in mitochondrial transporter expression signaling between the mitochondria and the cytosol via intermediate exchange and redox regulation, the mitochondria as signaling organelles, and finally the role of the triacylglyceride pool in regulating mitochondrial function through fuel provision and lipid signaling.…”

mentioning

confidence: 99%

Matrix Revisited

Carley

Taegtmeyer

Lewandowski

2014

Circulation Research

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Metabolic signaling mechanisms are increasingly recognized to mediate the cellular response to alterations in workload demand, as a consequence of physiological and pathophysiological challenges. Thus, an understanding of the metabolic mechanisms coordinating activity in the cytosol with the energy-providing pathways in the mitochondrial matrix becomes critical for deepening our insights into the pathogenic changes that occur in the stressed cardiomyocyte. Processes that exchange both metabolic intermediates and cations between the cytosol and mitochondria enable transduction of dynamic changes in contractile state to the mitochondrial compartment of the cell. Disruption of such metabolic transduction pathways has severe consequences for the energetic support of contractile function in the heart and is implicated in the pathogenesis of heart failure. Deficiencies in metabolic reserve and impaired metabolic transduction in the cardiomyocyte can result from inherent deficiencies in metabolic phenotype or maladaptive changes in metabolic enzyme expression and regulation in the response to pathogenic stress. This review examines both current and emerging concepts of the functional linkage between the cytosol and the mitochondrial matrix with a specific focus on metabolic reserve and energetic efficiency. These principles of exchange and transport mechanisms across the mitochondrial membrane are reviewed for the failing heart from the perspectives of chronic pressure overload and diabetes mellitus.

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mentioning

confidence: 99%

Matrix Revisited

Carley

Taegtmeyer

Lewandowski

2014

Circulation Research

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“…Considering that cardiac metabolism is closely related to function (24,33,35,40), we aimed at evaluating linkages between strain-dependent variations in metabolic flux and functional parameters. Previous studies have reported positive association 1) between glycolysis and functional parameters relevant to myocardial work (1,13,45) and 2) LCFA oxidation and myocardial perfusion (8,20,28,41).…”

Section: H81mentioning

confidence: 99%

Mouse strain differences in metabolic fluxes and function of ex vivo working hearts

Vaillant

Lauzier

Poirier

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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In mice, genetic background is known to influence various parameters, including cardiac function. Its impact on cardiac energy substrate metabolism-a factor known to be closely related to function and contributes to disease development-is, however, unclear. This was examined in this study. In commonly used control mouse substrains SJL/JCrNTac, 129S6/SvEvTac, C57Bl/6J, and C57Bl/6NCrl, we assessed the functional and metabolic phenotypes of 3-mo-old working mouse hearts perfused ex vivo with physiological concentrations of 13C-labeled carbohydrates (CHO) and a fatty acid (FA). Marked variations in various functional and metabolic flux parameters were observed among all mouse substrains, although the pattern observed differed for these parameters. For example, among all strains, C57Bl/6NCrl hearts had a greater cardiac output (+1.7-fold vs. SJL/JCrNTac and C57Bl/6J; P < 0.05), whereas at the metabolic level, 129S6/SvEvTac hearts stood out by displaying (vs. all 3 strains) a striking shift from exogenous FA (∼−3.5-fold) to CHO oxidation as well as increased glycolysis (+1.7-fold) and FA incorporation into triglycerides (+2-fold). Correlation analyses revealed, however, specific linkages between 1) glycolysis, FA oxidation, and pyruvate metabolism and 2) cardiac work, oxygen consumption with heart rate, respectively. This implies that any genetically determined factors affecting a given metabolic flux parameter may impact on the associated functional parameters. Our results emphasize the importance of selecting the appropriate control strain for cardiac metabolic studies using transgenic mice, a factor that has often been neglected. Understanding the molecular mechanisms underlying the diversity of strain-specific cardiac metabolic and functional profiles, particularly the 129S6/SvEvTac, may ultimately disclose new specific metabolic targets for interventions in heart disease.

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“…etomoxir, ranolazine) are being studied as therapies for heart failure 51 . A more detailed discussion of this area is beyond the scope of this article but may be found in recent comprehensive reviews 52, 50, 51, 48 .…”

Section: Myocardial Perfusion and Energeticsmentioning

confidence: 99%