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Valve biology and rheumatic heart disease pathogenesis

Nature Cardiovascular Research volume 5, pages 204–217 (2026)Cite this article

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Abstract

Rheumatic heart disease (RHD) is an acquired chronic inflammatory disease of the heart valves. Regarded as an autoimmune sequela of Streptococcus pyogenes infection, RHD is triggered by the development of carditis during acute rheumatic fever and persists as chronic rheumatic valvulitis in a proportion of patients with acute rheumatic fever. Permanent valve tissue damage ensues, often leading to heart failure. Effective interventions for established RHD are lacking and valve surgery is currently the only treatment option. The limited number of therapeutic targets for heart valve diseases reflects the complexities of studying the mechanisms underlying early valve pathobiology. However, technological advances now enable in-depth profiling of peripheral blood and valve tissue samples from people with RHD, opening new avenues to interrogate human-specific disease processes. In this Review, we revisit established immunological principles of RHD pathogenesis in light of emerging studies. We also explore both systemic and tissue-centric research gaps to advance our understanding of disease mechanisms and to identify human-relevant therapeutic strategies for RHD.

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Fig. 1: Timeline of RHD pathogenesis research highlighting key findings over six decades.
Fig. 2: Immunopathology of early and chronic valvulitis.
Fig. 3: Changes in the heart valve leaflet throughout progression from health to RHD.
Fig. 4: Trends in systemic autoimmunity overlaid with progressive valve inflammation and opportunities for clinical intervention.

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Acknowledgements

We acknowledge support from the National Health and Medical Research Council of Australia Ideas grant (2039228, to H.K.V.) and the National Heart Foundation of Australia Vanguard grant (107962, to H.K.V. and A.S). We acknowledge support from the Fox Family Foundation. This work was supported by the Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, which is supported by a Novo Nordisk Foundation grant (NNF21CC0073729, to S.Y., E.R.P. and H.K.V.). E.R.P is supported by a National Health and Medical Research Council Investigator grant. H.K.V. was supported by a Postdoctoral Fellowship (106645) from the National Heart Foundation of Australia and is currently supported by a Future Leader Fellowship (109309) from the National Heart Foundation of Australia.

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  1. Murdoch Children’s Research Institute, The Royal Children’s Hospital, Melbourne, Victoria, Australia

    Serene Yeow, Hannah Frost, Enzo R. Porrello, Andrew Steer & Holly K. Voges

  2. Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

    Serene Yeow, Enzo R. Porrello & Holly K. Voges

  3. Department of Paediatrics, School of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia

    Hannah Frost, Enzo R. Porrello, Andrew Steer & Holly K. Voges

  4. Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia

    Enzo R. Porrello

  5. Royal Children’s Hospital, Melbourne, Victoria, Australia

    Andrew Steer

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S.Y. drafted the manuscript. All authors reviewed and edited the manuscript.

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Yeow, S., Frost, H., Porrello, E.R. et al. Valve biology and rheumatic heart disease pathogenesis. Nat Cardiovasc Res 5, 204–217 (2026). https://doi.org/10.1038/s44161-026-00792-9

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