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  • Review Article
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Regression of cardiac hypertrophy in health and disease: mechanisms and therapeutic potential

Nature Reviews Cardiology volume 20, pages 347–363 (2023)Cite this article

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Abstract

Left ventricular hypertrophy is a leading risk factor for cardiovascular morbidity and mortality. Although reverse ventricular remodelling was long thought to be irreversible, evidence from the past three decades indicates that this process is possible with many existing heart disease therapies. The regression of pathological hypertrophy is associated with improved cardiac function, quality of life and long-term health outcomes. However, less than 50% of patients respond favourably to most therapies, and the reversibility of remodelling is influenced by many factors, including age, sex, BMI and disease aetiology. Cardiac hypertrophy also occurs in physiological settings, including pregnancy and exercise, although in these cases, hypertrophy is associated with normal or improved ventricular function and is completely reversible postpartum or with cessation of training. Studies over the past decade have identified the molecular features of hypertrophy regression in health and disease settings, which include modulation of protein synthesis, microRNAs, metabolism and protein degradation pathways. In this Review, we summarize the evidence for hypertrophy regression in patients with current first-line pharmacological and surgical interventions. We further discuss the molecular features of reverse remodelling identified in cell and animal models, highlighting remaining knowledge gaps and the essential questions for future investigation towards the goal of designing specific therapies to promote regression of pathological hypertrophy.

Key points

  • Pathological cardiac hypertrophy is a leading risk factor for cardiovascular morbidity and mortality and is associated with increased fibrosis and apoptosis that lead to ventricular stiffness, risk of arrhythmia and impaired cardiac function.

  • Partial reversal of cardiac hypertrophy occurs with many existing heart failure therapies, including renin–angiotensin–aldosterone system, β-adrenergic receptor, calcium-channel and SGLT2 antagonists, but is achieved in only a subset of patients.

  • The potential for reverse remodelling in heart disease is influenced by many factors, including biological sex, genetics, duration of hypertension, BMI, age and disease aetiology.

  • Exercise-induced and pregnancy-induced physiological cardiac hypertrophy is driven by cellular mechanisms distinct from those in pathological hypertrophy, and is completely reversible, whereas moderate exercise in heart failure antagonizes pathological cellular pathways and promotes hypertrophy regression.

  • At the molecular level, hypertrophy regression is associated with metabolic shifts, reduced protein synthesis, extracellular matrix remodelling and altered activity of proteolytic pathways.

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Fig. 1: Cellular signalling pathways of physiological and pathological hypertrophy.
Fig. 2: Molecular features of hypertrophy regression with mechanical unloading.
Fig. 3: Molecular features of cardiac atrophy.

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Acknowledgements

The authors acknowledge support from the National Institutes of Health (T32 HL007822 to T.G.M., T32 GM142607 to M.A.J., and R01HL117138 and R01GM029090 to L.A.L.).

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  1. These authors contributed equally: Thomas G. Martin, Miranda A. Juarros.

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  1. Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA

    Thomas G. Martin, Miranda A. Juarros & Leslie A. Leinwand

  2. BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, USA

    Thomas G. Martin, Miranda A. Juarros & Leslie A. Leinwand

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Martin, T.G., Juarros, M.A. & Leinwand, L.A. Regression of cardiac hypertrophy in health and disease: mechanisms and therapeutic potential. Nat Rev Cardiol 20, 347–363 (2023). https://doi.org/10.1038/s41569-022-00806-6

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