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  • Review Article
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Cardiovascular involvement in glycogen storage diseases

Nature Reviews Cardiology volume 23, pages 39–59 (2026)Cite this article

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Abstract

Glycogen storage diseases are rare conditions affecting both sexes that are caused by inherited deficiencies of enzymes involved either in glycogen synthesis or breakdown, or in glycolysis. The liver and skeletal muscle are usually the most affected tissues. However, because glycogen has an important role in cardiac development and function, several glycogen storage diseases are associated, at least indirectly, with cardiac disorders, some of which have severe consequences from the first months of life. Early identification of these conditions is, therefore, an important issue, and implementation of strategies to prevent fatal outcomes due to cardiovascular disease is vital. In this Review, we discuss the pathophysiological mechanisms and the preclinical, clinical and epidemiological evidence for cardiovascular involvement in various glycogen storage diseases. We also describe interventions that can help preserve heart function, including changes in nutrition and exercise, as well as the few available molecular therapies to address the underlying metabolic anomalies.

Key points

  • Glycogen is needed for normal cardiac development and metabolism, but the precise expression and role of the many enzymes involved in glycogen metabolism remain to be elucidated.

  • Glycogen storage diseases (GSDs) are rare genetic conditions affecting both sexes and are caused by deficiencies of enzymes involved either in glycogen synthesis or breakdown, or in glycolysis.

  • Many GSDs are directly or indirectly associated with an increased risk of cardiovascular disease, with a broad spectrum of clinical presentations and outcomes.

  • Some GSDs manifest early in life with stereotypical features, whereas others present later and can be confused with other disorders; cardiologists should be vigilant for ‘red flags’ suggesting undiagnosed GSDs.

  • Supportive cardiovascular care, ranging from routine medication to heart transplantation, is required in patients with GSDI; enzyme replacement therapy (which is available only for GSDII) can improve cardiac outcomes.

  • Novel therapies are needed to improve cardiac outcomes in GSDs; gene therapies addressing underlying genetic abnormalities have shown promise in early-phase clinical trials.

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Fig. 1: Glycogen storage diseases and related conditions.
Fig. 2: The structure and functions of glycogen in the heart.

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Acknowledgements

Research by T.P., C.F.-L. and M.A.M. is funded by the Spanish Ministry of Economy and Competitiveness and Fondos Feder (grants PI22/00201, PI21/00381 and FORT23/00023, respectively). R.M.C. is supported in part by the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (BRC) (NIHR203331). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Research by C.F.-L. and A.L. is funded by Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International grant programme (IIG_FULL_2021_007).

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Author notes

  1. These authors contributed equally: Tomàs Pinós, Richard M. Cubbon.

Authors and Affiliations

  1. Mitochondrial and Neuromuscular Disorders Unit, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain

    Tomàs Pinós

  2. Biomedical Research Networking Centre on Rare Diseases (CIBERER), Madrid, Spain

    Tomàs Pinós, Miguel A. Martín & Joaquín Arenas

  3. Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK

    Richard M. Cubbon

  4. Department of Sport and Computer Science, Section of Physical Education and Sports, Faculty of Sport, Universidad Pablo de Olavide, Sevilla, Spain

    Alfredo Santalla

  5. Research Institute of Hospital 12 de Octubre (“imas12”), Madrid, Spain

    Carmen Fiuza-Luces

  6. i+HeALTH Strategic Research Group, European University Miguel de Cervantes, Valladolid, Spain

    Alejandro Santos-Lozano

  7. Mitochondrial and Neuromuscular Diseases Laboratory, Research Institute of Hospital “12 de Octubre” (“imas12”), Madrid, Spain

    Miguel A. Martín & Joaquín Arenas

  8. Department of Sports Science and Clinical Biomechanics, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

    Joachim Nielsen & Niels Ørtenblad

  9. Biomedical Research Networking Centre on Frailty and Healthy Ageing (CIBERFES), Madrid, Spain

    Alejandro Lucia

  10. Department of Sport Sciences. Faculty of Medicine, Health and Sports. Universidad Europea de Madrid, Madrid, Spain

    Alejandro Lucia

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Contributions

T.P., R.M.C., C.F.-L., A.S.-L., J.N., N.Ø. and A.L. researched data for the article. T.P., R.M.C., A.S., C.F.-L., A.S.-L., J.N., N.Ø. and A.L. contributed to discussions of content. T.P., J.N., N.Ø. and A.L. wrote the manuscript. T.P., R.M.C., A.S., C.F.-L., M.A.M., J.A., J.N., N.Ø. and A.L. reviewed/edited the manuscript before submission.

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Correspondence to Tomàs Pinós, Carmen Fiuza-Luces or Alejandro Lucia.

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R.M.C. has received speaker’s fees from Janssen Oncology. The other authors declare no competing interests.

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Nature Reviews Cardiology thanks Priya Kishnani, who co-reviewed with Rebecca Koch and Monika Williams; Giuseppe Limongelli, who co-reviewed with Emanuele Monda; and Ros Quinlivan for their contribution to the peer review of this work.

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Glossary

Amylopectin-like polyglucosan bodies

Aberrant glucose polymers that differ in structure and appearance from glycogen and are less soluble. They accumulate in tissues and are a common feature of some GSDs (GSDIV and GSDXV), neurodegenerative diseases and physiological ageing.

Fasciculoventricular pathways

Uncommon pre‐excitation variants characterized by accessory connections between the bundle of His and the ventricles.

Limit dextrins

When a branched polysaccharide (such as glycogen) is hydrolysed enzymatically, glucose units are removed one at a time until a branch point (that is, a limit dextrin) is reached. Further hydrolysis requires a different enzyme, glycogen phosphorylase.

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Pinós, T., Cubbon, R.M., Santalla, A. et al. Cardiovascular involvement in glycogen storage diseases. Nat Rev Cardiol 23, 39–59 (2026). https://doi.org/10.1038/s41569-025-01171-w

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