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Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges

Nature Reviews Cardiology (2023)Cite this article

Subjects

Abstract

Cardiac metabolism is vital for heart function. Given that cardiac contraction requires a continuous supply of ATP in large quantities, the role of fuel metabolism in the heart has been mostly considered from the perspective of energy production. However, the consequence of metabolic remodelling in the failing heart is not limited to a compromised energy supply. The rewired metabolic network generates metabolites that can directly regulate signalling cascades, protein function, gene transcription and epigenetic modifications, thereby affecting the overall stress response of the heart. In addition, metabolic changes in both cardiomyocytes and non-cardiomyocytes contribute to the development of cardiac pathologies. In this Review, we first summarize how energy metabolism is altered in cardiac hypertrophy and heart failure of different aetiologies, followed by a discussion of emerging concepts in cardiac metabolic remodelling, that is, the non-energy-generating function of metabolism. We highlight challenges and open questions in these areas and finish with a brief perspective on how mechanistic research can be translated into therapies for heart failure.

Key points

  • Substrate preference in the heart changes in response to environmental stress and occurs in physiological and pathological hypertrophy.

  • Metabolic remodelling coupled with mitochondrial dysfunction leads to energy starvation in the failing heart.

  • Rewiring of substrate metabolism contributes to the cardiac stress response via epigenomic and signalling mechanisms.

  • Metabolic changes in both cardiomyocytes and non-cardiomyocytes contribute to pathological remodelling of the heart.

  • The new paradigm for studying metabolic remodelling in heart failure faces challenges but also offers opportunities to develop novel therapies to treat heart failure.

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Fig. 1: Remodelling of substrate metabolism in physiological and pathological hypertrophy.
Fig. 2: Cardiac metabolic remodelling in pathological and physiological conditions.
Fig. 3: Metabolic control of protein function and gene expression in heart failure.
Fig. 4: Metabolism in non-cardiomyocytes in heart failure.

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Acknowledgements

The authors are supported in part by the US NIH (grants HL142628, HL149695, HL144778, HL110349 and HL144937) to R.T.

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Authors and Affiliations

  1. Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany

    Julia Ritterhoff

  2. Mitochondria and Metabolism Center, Department of Anaesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA

    Julia Ritterhoff & Rong Tian

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  1. Julia Ritterhoff
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The authors contributed equally to all aspects of the article.

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Correspondence to Julia Ritterhoff or Rong Tian.

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Competing interests

R.T. is listed as a co-inventor on a patent application submitted by the University of Washington, USA, regarding the targeting of NAD+ metabolism to treat inflammation in heart failure, and is a member of the Scientific Advisory Board of Cytokinetics, USA. J.R. declares no competing interests.

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Nature Reviews Cardiology thanks John Elrod, who co-reviewed with Andrew Gibb; Gary Lopaschuk; Yibin Wang; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Anaplerosis

Metabolic pathway that replenishes intermediates of the tricarboxylic acid cycle.

Catabolism

Metabolic pathways that break down molecules into smaller units, which can be oxidized to generate energy.

Efferocytosis

The process by which apoptotic cells are removed by phagocytic cells, primarily macrophages.

Insulin resistance

Impairment of proper insulin and glucose absorption by cells, which results in excessive glucose levels in the blood.

Lipotoxicity

Deleterious effects of lipid accumulation in non-adipose tissues that can lead to cellular dysfunction or cell death.

Oxidative phosphorylation

The production of ATP by the mitochondrial respiratory chain.

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Ritterhoff, J., Tian, R. Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges. Nat Rev Cardiol (2023). https://doi.org/10.1038/s41569-023-00887-x

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