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A transformative preclinical model of rheumatic heart disease

Nature Reviews Cardiology volume 22, page 700 (2025)Cite this article

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Rheumatic heart disease (RHD) remains the leading cause of acquired heart disease in individuals aged >25 years. Despite being preventable, this condition affects >40 million people worldwide, particularly in low-income countries. RHD is characterized by permanent heart valve damage after a single or repeated bouts of acute rheumatic fever (ARF), a multiorgan autoimmune condition triggered by streptococcal bacterial infection that affects the heart, joints, skin and brain. At present, there is little consensus as to how the disease is initiated after streptococcal infection and how the condition progresses to cause permanent heart damage. In susceptible individuals, the generation of anti-streptococcal antibodies that cross-react with host proteins and the activation of fibroinflammatory cascades initiated by the infection through transforming growth factor-β1 signalling are thought to cause cardiac valve damage. Importantly, the preclinical Lewis rat autoimmune valvulitis (RAV) model replicates key features of ARF and RHD that are present in humans and has emerged as a crucial tool for understanding the underlying pathogenic processes.

In our laboratory, we have shown that passive transfer of hyperimmune serum and T lymphocytes from rats injected with streptococcal M proteins induces cardiac changes in naive rats, which demonstrates the role of both antibodies and T lymphocytes in inducing cardiac damage. Through this research, we have demonstrated the need for robust inflammatory responses, driven by interferon-γ and IL-17A signalling, to promote the development of cardiac pathology. Furthermore, we have also identified the presence of an imbalance between pathogenic and regulatory T cell populations in the RAV model. These mechanistic insights collectively contribute to advancing the field of ARF and RHD research.

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Acknowledgements

The authors’ work is funded by a National Health and Medical Research Council ideas grant (APP 2010336).

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  1. University of New England, Armidale, New South Wales, Australia

    Rukshan Ahamed Mohamed Rafeek & Natkunam Ketheesan

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  1. Rukshan Ahamed Mohamed Rafeek
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  2. Natkunam Ketheesan
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Correspondence to Rukshan Ahamed Mohamed Rafeek.

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Mohamed Rafeek, R.A., Ketheesan, N. A transformative preclinical model of rheumatic heart disease. Nat Rev Cardiol 22, 700 (2025). https://doi.org/10.1038/s41569-025-01203-5

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