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Modification of myocardial substrate use as a therapy for heart failure

Nature Clinical Practice Cardiovascular Medicine volume 3, pages 490–498 (2006)Cite this article

Abstract

Despite advances in treatment, chronic heart failure is still associated with significant morbidity and a poor prognosis. The scope for further advances based on additional neurohumoral blockade is small. Effective adjunctive therapies acting via a different cellular mechanism would, therefore, be attractive. Energetic impairment seems to contribute to the pathogenesis of heart failure. The findings from several studies have shown that the so-called metabolic agents could have potential as adjunctive therapies in heart failure. These agents cause a shift in the substrate used by the heart away from free fatty acids, the oxidation of which normally provides around 70% of the energy needed, towards glucose. The oxygen cost of energy generation is lessened when glucose is used as the substrate. In this review we aim to draw attention to the metabolic alteration in heart failure and we present evidence supporting the use of metabolic therapy in heart failure.

Key Points

  • Emerging evidence shows that, irrespective of the etiology, an energetic impairment contributes to the pathogenesis of heart failure

  • Patterns of substrate use in heart failure are complex and depend on species, cause, duration, underlying coronary artery disease, endothelial dysfunction, and the presence of genetic and other comorbidities

  • Myocardial use of fatty acids costs more oxygen per unit of ATP generated than glucose

  • Animal models and small-scale human studies suggest benefits with the use of agents that shift myocardial substrate use from free fatty acids towards glucose, but larger human studies are needed

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Figure 1: The glucose–fatty acid cycle in cardiomyocyte mitochondria.
Figure 2: Effects of metabolic agents on myocardial metabolism in cardiomyocyte mitochondria.
Figure 3: The effect of perhexiline treatment in patients with ischemic or nonischemic heart failure.

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Author information

Authors and Affiliations

  1. British Heart Foundation Research Fellow Department for Cardiovascular Medicine, University of Birmingham, Birmingham, UK

    Khalid Abozguia & Michael Frenneaux

  2. the Head of the Department for Cardiovascular Medicine, University of Birmingham, Birmingham, UK

    Khalid Abozguia & Michael Frenneaux

  3. professor of physiological biochemistry in the University Laboratory of Physiology, University of Oxford, Oxford, UK

    Kieran Clarke

  4. Specialist Registrar in the Department of Cardiology, Queens Medical Centre, Nottingham University Hospital, Nottingham, UK

    Leong Lee

Authors
  1. Khalid Abozguia
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  2. Kieran Clarke
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  3. Leong Lee
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  4. Michael Frenneaux
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Corresponding author

Correspondence to Khalid Abozguia.

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Competing interests

Michael Frenneaux has applied for a patent for the use of perhexiline therapy in chronic heart failure patients. The other authors declared they have no competing interests.

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Abozguia, K., Clarke, K., Lee, L. et al. Modification of myocardial substrate use as a therapy for heart failure. Nat Rev Cardiol 3, 490–498 (2006). https://doi.org/10.1038/ncpcardio0583

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