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

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.