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A self-reinforcing cycle hypothesis in heart failure pathogenesis

Abstract

Heart failure is a progressive syndrome with high morbidity and mortality rates. Here, we suggest that chronic exposure of the heart to risk factors for heart failure damages heart mitochondria, thereby impairing energy production to levels that can suppress the heart’s ability to pump blood and repair mitochondria (both energy-consuming processes). As damaged mitochondria accumulate, the heart becomes deprived of energy in a ‘self-reinforcing cycle’, which can persist after the heart is no longer chronically exposed to (or after antagonism of) the risk factors that initiated the cycle. Together with other previously described pathological mechanisms, this proposed cycle can help explain (1) why heart failure progresses, (2) why it can recur after cessation of treatment, and (3) why heart failure is often accompanied by dysfunction of multiple organs. Ideally, therapy of heart failure syndrome would be best attempted before the self-reinforcing cycle is triggered or designed to break the self-reinforcing cycle.

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Fig. 1: Overview of energy metabolism in the failing heart.
Fig. 2: Proposed self-reinforcing cycle of energy deprivation in heart failure pathogenesis.

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C.F.-P. conceived the hypothesis. C.F.-P. and E.H. conceived, wrote and edited the manuscript and drafted the figures. G.D.L. made key edits and additions to the intellectual content and figures. All authors contributed to the critical analysis of the literature.

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Correspondence to Carlos Fernandez-Patron or Eugenio Hardy.

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Fernandez-Patron, C., Lopaschuk, G.D. & Hardy, E. A self-reinforcing cycle hypothesis in heart failure pathogenesis. Nat Cardiovasc Res 3, 627–636 (2024). https://doi.org/10.1038/s44161-024-00480-6

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