Experimentally observed phenomena on cardiac energetics in heart failure emerge from simulations of cardiac metabolism

Fan Wu, Jianyi Zhang, Daniel A. Beard

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

The failing heart is hypothesized to suffer from energy supply inadequate for supporting normal cardiac function. We analyzed data from a canine left ventricular hypertrophy model to determine how the energy state evolves because of changes in key metabolic pools. Our findings - confirmed by in vivo 31P-magnetic resonance spectroscopy - indicate that the transition between the clinically observed early compensatory phase and heart failure and the critical point at which the transition occurs are emergent properties of cardiac energy metabolism. Specifically, analysis reveals a phenomenon in which low and moderate reductions in metabolite pools have no major negative impact on oxidative capacity, whereas reductions beyond a critical tipping point lead to a severely compromised energy state. The transition point corresponds to reductions in the total adenine nucleotide pool (TAN) of -30%, corresponding to the reduction observed in humans in heart failure [Ingwall JS, Weiss RG (2004) Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 95(2):135-145]. At given values of TAN and the total exchangeable phosphate pool during hypertrophic remodeling, the creatine pool attains a value that is associated with optimal ATP hydrolysis potential. Thus, both increases and decreases to the creatine pool are predicted to result in diminished energetic state unless accompanied by appropriate simultaneous changes in the other pools.

Original languageEnglish (US)
Pages (from-to)7143-7148
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number17
DOIs
StatePublished - Apr 28 2009

Keywords

  • Computational biology
  • Energy metabolism
  • Hypertrophy
  • Mitochondria

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