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Mechanistic implications of altered protein expression in rheumatic heart disease

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Abstract

Rheumatic heart disease (RHD) is a major cause of cardiovascular morbidity and mortality in low- and middle-income countries, where living conditions promote spread of group A β-haemolytic streptococcus. Autoimmune reactions due to molecular mimicry of bacterial epitopes by host proteins cause acute rheumatic fever (ARF) and subsequent disease progression to RHD. Despite knowledge of the factors that predispose to ARF and RHD, determinants of the progression to valvular damage and the molecular events involved remain incompletely characterised. This review focuses on altered protein expression in heart valves, myocardial tissue and plasma of patients with RHD and pathogenic consequences on RHD. Proteins mainly involved in structural organization of the valve matrix, blood homeostasis and immune response were altered due to RHD pathogenesis. Study of secreted forms of these proteins may aid the development of non-invasive biomarkers for early diagnosis and monitoring outcomes in RHD. Valve replacement surgery, the single evidence-based strategy to improve outcomes in severe RHD, is costly, largely unavailable in low- and middle-income countries (LMIC) and requires specialised facilities. When diagnosed early, penicillin prophylaxis may be used to delay progression to severe valvular damage. Echocardiography and cardiovascular magnetic resonance and the standard imaging tools recommended to confirm early diagnosis remain largely unavailable and inaccessible in most LMIC and both require expensive equipment and highly skilled persons for manipulation as well as interpretation of results. Changes in protein expression in heart valves and myocardium are associated with progressive valvular deformation in RHD. Understanding these protein changes should shed more light on the mechanisms of pathogenicity, while secreted forms of these proteins may provide leads towards a biomarker for non-invasive early detection of RHD.

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Acknowledgments

We are grateful to Dr. Ivana Parker for useful discussion.

Funding

ENL is funded by the National Research Foundation (NRF) of South Africa (DST-NRF) free standing innovation postdoctoral fellowship and an early career development fellowship from the Carnegie Corporation of New York to the University of Cape Town. SS thanks the NRF Blue Skies for support. JMB thanks the NRF for a South African Research Chair. NNAB gratefully acknowledges support from the NRF, SA-MRC and the Ernst and Lily Hausmann Trust.

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Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Faculty of Health Sciences and Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa

    Evelyn N. Lumngwena & Ntobeko A. B. Ntusi

  2. Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Evelyn N. Lumngwena & Jonathan M. Blackburn

  3. Hatter instititute for Cardiovascualar research in Africa, Departmenent of Medicine, 4th floor Chris Barnard Building, University of Cape Town, Cape Town, South Africa

    Evelyn N. Lumngwena & Ntobeko A. B. Ntusi

  4. Centre for the Study of Emerging and Re-emerging Infections (CREMER), Institute for Medical Research and Medicinal Plant Studies (IMPM), Ministry of Scientific Research and Innovation, Yaounde, Cameroon

    Evelyn N. Lumngwena

  5. Department of Civil Engineering, Faculty of Engineering and the Built Environment, University of Cape Town, Cape Town, South Africa

    Sebastian Skatulla

  6. Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa

    Jonathan M. Blackburn

  7. Cape Universities Body Imaging Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Ntobeko A. B. Ntusi

Authors
  1. Evelyn N. Lumngwena
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  2. Sebastian Skatulla
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  3. Jonathan M. Blackburn
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  4. Ntobeko A. B. Ntusi
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Contributions

ENL and NNAB contributed to conceptualisation, ENL and NNAB wrote the first draft, NNAB, JMB and SS supervised the work and all the authors contributed to review and editing and approved the final manuscript.

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Correspondence to Evelyn N. Lumngwena.

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Lumngwena, E.N., Skatulla, S., Blackburn, J.M. et al. Mechanistic implications of altered protein expression in rheumatic heart disease. Heart Fail Rev 27, 357–368 (2022). https://doi.org/10.1007/s10741-020-09993-1

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