Stock Ticker

Valve biology and rheumatic heart disease pathogenesis

  • Carapetis, J. R., Steer, A. C., Mulholland, E. K. & Weber, M. The global burden of group A streptococcal diseases. Lancet Infect. Dis. 5, 685–694 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Carapetis, J. R. et al. Acute rheumatic fever and rheumatic heart disease. Nat. Rev. Dis. Primers 2, 15084 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ferrari, A. J. et al. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 403, 2133–2161 (2024).

    Article 

    Google Scholar
     

  • Coffey, S. et al. Global epidemiology of valvular heart disease. Nat. Rev. Cardiol. 18, 853–864 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Ojha, U. et al. Temporal trend analysis of rheumatic heart disease burden in high-income countries between 1990 and 2019. Eur. Heart J. Qual. Care Clin. Outcomes 10, 108–120 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zühlke, L. et al. Clinical outcomes in 3343 children and adults with rheumatic heart disease from 14 low- and middle-income countries. Circulation 134, 1456–1466 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Katzenellenbogen, J. M. et al. The End Rheumatic Heart Disease in Australia Study of Epidemiology (ERASE) Project: data sources, case ascertainment and cohort profile. Clin. Epidemiol. 11, 997–1010 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stacey, I. et al. Rheumatic heart disease mortality in Indigenous and non-Indigenous Australians between 2010 and 2017. Heart 109, 1025–1033 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Gewitz, M. H. et al. Revision of the jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography. Circulation 131, 1806–1818 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Gupta, M., Lent, R. W., Kaplan, E. L. & Zabriskie, J. B. Serum cardiac troponin I in acute rheumatic fever. Am. J. Cardiol. 89, 779–782 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hirani, K. et al. Acute rheumatic fever. Lancet 405, 2164–2178 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Beaton, A. et al. Secondary antibiotic prophylaxis for latent rheumatic heart disease. New Engl. J. Med. 386, 230–240 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Remenyi, B. et al. Improved long-term survival for rheumatic mitral valve repair compared to replacement in the young. World J. Pediatr. Congenit. Heart Surg. 4, 155–164 (2013).

    Article 
    PubMed 

    Google Scholar
     

  • Karthikeyan, G. et al. Research priorities for the secondary prevention and management of acute rheumatic fever and rheumatic heart disease: a National Heart, Lung, and Blood Institute workshop report. BMJ Glob. Health 8, e012468 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zühlke, L. et al. Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study). Eur. Heart J. 36, 1115–1122 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Steer, A. C. & Carapetis, J. R. Acute rheumatic fever and rheumatic heart disease in indigenous populations. Pediatr. Clin. North. Am. 56, 1401–1419 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Vervoort, D., Antunes, M. J. & Pezzella, A. T. Rheumatic heart disease: the role of global cardiac surgery. J. Card. Surg. 36, 2857–2864 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Cunningham, M. W. Molecular mimicry, autoimmunity, and infection: the cross-reactive antigens of group A Streptococci and their sequelae. Microbiol. Spectr. 7, 1128 (2019).

    Article 

    Google Scholar
     

  • Guilherme, L., Kalil, J. & Cunningham, M. Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease. Autoimmunity 39, 31–39 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kalil, J. & Guilherme, L. Rheumatic fever: a model of autoimmune disease due to molecular mimicry between human and pathogen proteins. Crit. Rev. Immunol. 40, 419–422 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Kaplan, M. H. & Suchy, M. L. Immunologic relation of streptococcal and tissue antigens: II. cross-reaction of antisera to mammalian heart tissue with a cell wall constituent of certain strains of group A Streptococci. J. Exp. Med. 119, 643–650 (1964).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kaplan, M. H. & Svec, K. H. Immunologic relation of streptococcal and tissue antigens. J. Exp. Med. 119, 651–666 (1964).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dale, J. B. & Beachey, E. H. Epitopes of streptococcal M proteins shared with cardiac myosin. J. Exp. Med. 162, 583–591 (1985).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cunningham, M. W. et al. Human and murine antibodies cross-reactive with streptococcal M protein and myosin recognize the sequence GLN-LYS-SER-LYS-GLN in M protein. J. Immunol. 143, 2677–2683 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gulizia, J. M., Cunningham, M. W. & McManus, B. M. Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves. Evidence for multiple cross-reactive epitopes. Am. J. Pathol. 138, 285–301 (1991).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Van De Rijn, I., Sabriskie, J. & McCarty, M. Group A streptococcal antigens cross-reactive with myocardium. Purification of heart-reactive antibody and isolation and characterization of the streptococcal antigen. J. Exp. Med. 146, 579–599 (1977).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shikhman, A. R., Greenspan, N. S. & Cunningham, M. W. A subset of mouse monoclonal antibodies cross-reactive with cytoskeletal proteins and group A streptococcal M proteins recognizes N-acetyl-β-D-glucosamine. J. Immunol. 151, 3902–3913 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Galvin, J. E., Hemric, M. E., Ward, K. & Cunningham, M. W. Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin. J. Clin. Invest. 106, 217–224 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guilherme, L. et al. Human heart–infiltrating t-cell clones from rheumatic heart disease patients recognize both streptococcal and cardiac proteins. Circulation 92, 415–420 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Martins, T. B. et al. Comprehensive analysis of antibody responses to streptococcal and tissue antigens in patients with acute rheumatic fever. Int. Immunol. 20, 445–452 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Faé, K. C. et al. PDIA3, HSPA5 and vimentin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients. J. Autoimmunity 31, 136–141 (2008).

    Article 

    Google Scholar
     

  • Karthikeyan, G., Fung, E. & Foo, R. S. Y. Alternative hypothesis to explain disease progression in rheumatic heart disease. Circulation 142, 2091–2094 (2020). This commentary proposed that the preferential involvement of the mitral valve in RHD might be explained by the interplay between increased hemodynamic stress and TGFβ-mediated fibrotic remodeling.

    Article 
    PubMed 

    Google Scholar
     

  • Bright, P. D., Mayosi, B. M. & Martin, W. J. An immunological perspective on rheumatic heart disease pathogenesis: more questions than answers. Heart 102, 1527–1532 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • McGregor, R. et al. Mapping autoantibodies in children with acute rheumatic fever. Front. Immunol. 12, 702877 (2021).

  • McGregor, R. et al. PhIP-seq uncovers marked heterogeneity in acute rheumatic fever autoantibodies. JCI Insight 11, e196619 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chung, A. W. et al. Systems immunology reveals a linked IgG3–C4 response in patients with acute rheumatic fever. Immunol. Cell Biol. 98, 12–21 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lorenz, N. et al. An acute rheumatic fever immune signature comprising inflammatory markers, IgG3, and Streptococcus pyogenes-specific antibodies. iScience 27, 110558 (2024).

  • Vanderlugt, C. L. & Miller, S. D. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2, 85–95 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Middleton, F. M., McGregor, R., Webb, R. H., Wilson, N. J. & Moreland, N. J. Cytokine imbalance in acute rheumatic fever and rheumatic heart disease: mechanisms and therapeutic implications. Autoimmun. Rev. 21, 103209 (2022). High-content serology profiling of ARF autoantibodies demonstrated vast repertoire heterogeneity across patients and enabled identification of new cardiac targets of ARF autoantibodies through orthogonal validation.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kim, M. L. et al. Dysregulated IL-1β-GM-CSF axis in acute rheumatic fever that is limited by hydroxychloroquine. Circulation 138, 2648–2661 (2018). TH1 cell-skewed inflammation in ARF (through IL-1β) promotes expansion of a potentially disease-driving T cell subset (GMCSF+, CXCR3+) that promotes transition from systemic inflammation to tissue-specific autoimmunity.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Muhamed, B., Parks, T. & Sliwa, K. Genetics of rheumatic fever and rheumatic heart disease. Nat. Rev. Cardiol. 17, 145–154 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Muhamed, B., Shaboodien, G. & Engel, M. E. Genetic variants in rheumatic fever and rheumatic heart disease. Am. J. Med. Genet. C Semin. Med. Genet. 184, 159–177 (2020). Meta-analysis evaluating 66 candidate gene studies of RHD, shortlisted single-nucleotide polymorphisms in TGFB1 and IL1B associated with RHD susceptibility and highlighted the need for large-scale genome-wide association studies for RHD.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gray, L. -A. et al. Genome-wide analysis of genetic risk factors for rheumatic heart disease in aboriginal australians provides support for pathogenic molecular mimicry. J. Infect. Dis. 216, 1460–1470 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Parks, T. et al. Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania. Nat. Commun. 8, 14946 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Machipisa, T. et al. Association of novel locus with rheumatic heart disease in Black African individuals. JAMA Cardiol. 6, 1000–1011 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Auckland, K. et al. The human leukocyte antigen locus and rheumatic heart disease susceptibility in South Asians and Europeans. Sci. Rep. 10, 9004 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kirvan, C. A. et al. IgG2 rules: N-acetyl-β-D-glucosamine-specific IgG2 and Th17/Th1 cooperation may promote the pathogenesis of acute rheumatic heart disease and be a biomarker of the autoimmune sequelae of Streptococcus pyogenes. Front. Cardiovasc. Med. 9, 919700 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Krisher, K. & Cunningham, M. W. Myosin: a link between streptococci and heart. Science 227, 413–415 (1985).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kaplan, M. H., Bolande, R., Rakita, L. & Blair, J. Presence of bound immunoglobulins and complement in the myocardium in acute rheumatic fever. New Engl. J. Med. 271, 637–645 (1964).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lotfi, N. et al. Roles of GM-CSF in the pathogenesis of autoimmune diseases: an update. Front. Immunol. 10, 1265 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Middleton, F. et al. Perturbation of the T cell compartment underlies rheumatic fever pathogenesis. Preprint at SSRN https://doi.org/10.2139/ssrn.5145933 (2025).

  • Faé, K. C. et al. CXCL9/Mig mediates T cells recruitment to valvular tissue lesions of chronic rheumatic heart disease patients. Inflammation 36, 800–811 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Godfrey, D. I., Koay, H. -F., McCluskey, J. & Gherardin, N. A. The biology and functional importance of MAIT cells. Nat. Immunol. 20, 1110–1128 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Anderson, J. et al. Immune signature of acute pharyngitis in a Streptococcus pyogenes human challenge trial. Nat. Commun. 13, 769 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ozkaya, M. et al. The number and activity of CD3+TCR Vα7.2+CD161+ cells are increased in children with acute rheumatic fever. Int. J. Cardiol. 333, 174–183 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Toor, D. & Sharma, N. T cell subsets: an integral component in pathogenesis of rheumatic heart disease. Immunol. Res. 66, 18–30 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Surve, N. Z. et al. A longitudinal study of antibody responses to selected host antigens in rheumatic fever and rheumatic heart disease. J. Med. Microbiol. 70, 5 (2021).

  • Mukherjee, S. et al. Proteomic analysis of human plasma in chronic rheumatic mitral stenosis reveals proteins involved in the complement and coagulation cascade. Clin. Proteomics 11, 35 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guttapadu, R. et al. Profiling system-wide variations and similarities between rheumatic heart disease and acute rheumatic fever–a pilot analysis. PLoS Negl.Trop. Dis. 17, e0011263 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gao, G. et al. Identification of altered plasma proteins by proteomic study in valvular heart diseases and the potential clinical significance. PLoS ONE 8, e72111 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Salie, M. T. et al. Data-independent acquisition mass spectrometry in severe rheumatic heart disease (RHD) identifies a proteomic signature showing ongoing inflammation and effectively classifying RHD cases. Clin. Proteomics 19, 7 (2022). Large proteomics study using data-independent acquisition and machine learning approaches that presents an unbiased characterization of the RHD inflammatory state, supplying candidate biomarkers of RHD that might provide insights into pathogenesis.

  • Diamantino Soares, A. C. et al. Circulating cytokines predict severity of rheumatic heart disease. Int. J. Cardiol. 289, 107–109 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Tormin, J. P. A. S. et al. Cytokine gene functional polymorphisms and phenotypic expression as predictors of evolution from latent to clinical rheumatic heart disease. Cytokine 138, 155370 (2021). This study used a multiplex quantification assay to provide a comprehensive characterization of cytokine profiles in people with RHD, then correlated specific cytokine markers and gene single-nucleotide polymorphisms to disease prognosis in these individuals.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Silva, V. R. et al. Decreased cytokine plasma levels and changes in T-cell activation are associated with hemodynamic improvement and clinical outcomes after percutaneous mitral commissurotomy in patients with rheumatic mitral stenosis. Front. Cardiovasc. Med. 7, 604826 (2021).

  • Bilik, M. Z. et al. Serum Levels of IL-17 and IL-23 in patients with rheumatic mitral stenosis. Medicine 95, e3562 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Neves, E. G. A. et al. Systemic cytokines, chemokines and growth factors reveal specific and shared immunological characteristics in infectious cardiomyopathies. Cytokine 148, 155711 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ueno, H. Human circulating T follicular helper cell subsets in health and disease. J. Clin. Immunol. 36, 34–39 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, Z. et al. Circulating follicular T helper cells and humoral reactivity in rheumatic heart disease. Life Sci. 245, 117390 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wen, Y., Zeng, Z., Gui, C., Li, L. & Li, W. Changes in the expression of Th17 cell-associated cytokines in the development of rheumatic heart disease. Cardiovas. Pathol. 24, 382–387 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Xiao, F. et al. Sex-dependent aortic valve pathology in patients with rheumatic heart disease. PLoS ONE 12, e0180230 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, C., Xiao, Z. & Yang, D. Association between the expression of T helper type 17 cell-related cytokines and valve damage in rheumatic heart disease. Mol. Biotechnol. 67, 4257–4270 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Yeh, C. -Y. et al. Activated human valvular interstitial cells sustain interleukin-17 production to recruit neutrophils in infective endocarditis. Infect. Immun. 83, 2202–2212 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, Z. et al. IL-17A induces valvular endothelial inflammation and aggravates calcific aortic valve disease. Biochem. Biophys. Res. Commun. 672, 145–153 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Morris, K., Mohan, C., Wahi, P. L., Anand, I. S. & Ganguly, N. K. Increase in activated T cells and reduction in suppressor/cytotoxic T cells in acute rheumatic fever and active rheumatic heart disease: a longitudinal study. J. Infect. Dis. 167, 979–983 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Roberts, S. et al. Pathogenic mechanisms in rheumatic carditis: focus on valvular endothelium. J. Infect. Dis. 183, 507–511 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bas, H. D. et al. A shift in the balance of regulatory T and T helper 17 cells in rheumatic heart disease. J. Invest. Med. 62, 78–83 (2014).

    Article 
    CAS 

    Google Scholar
     

  • Mukhopadhyay, S. et al. Circulating level of regulatory T cells in rheumatic heart disease: an observational study. Indian Heart J. 68, 342–348 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rafeek, R. A. M., Ketheesan, N., Good, M. F., Pandey, M. & Lepletier, A. Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease. mBio 16, e0382324 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, Z. et al. CD4+ T cells and TGFβ1/MAPK signal pathway involved in the valvular hyperblastosis and fibrosis in patients with rheumatic heart disease. Exp. Mol. Pathol. 114, 104402 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, M. O. & Flavell, R. A. TGF-β: a master of all T cell trades. Cell 134, 392–404 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, A. C. & Gotlieb, A. I. Transforming growth factor-β regulates in vitro heart valve repair by activated valve interstitial cells. Am. J. Pathol. 173, 1275–1285 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, L. et al. Overexpression of transforming growth factor-β1 in the valvular fibrosis of chronic rheumatic heart disease. J. Korean Med. Sci. 23, 41–48 (2008).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Passos, L. S. A. et al. Prothymosin alpha: a novel contributor to estradiol receptor alpha-mediated CD8+ T-cell pathogenic responses and recognition of type 1 collagen in rheumatic heart valve disease. Circulation 145, 531–548 (2022). This study compared proteomic profiles of mitral valve tissue from healthy individuals and people with RHD, uncovering new mechanisms of CD8⁺ T cell cytotoxicity linked to estrogen receptor signaling, and demonstrated that incorporating the valve tissue microenvironment enhances the resolution of disease mechanisms.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rojas, M. et al. Molecular mimicry and autoimmunity. J. Autoimmunity 95, 100–123 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Carapetis, J. et al. A plasma protein biomarker signature that differentiates acute rheumatic fever from related clinical presentations. Preprint at Res. Sq. https://doi.org/10.21203/rs.3.rs-4345781/v1 (2025).

  • Resende, A. L., da, S., Neves, E. G. A., Cavalcante, B. M. & Dutra, W. O. Systemic soluble and cellular immune response in acute rheumatic fever and rheumatic heart disease: a systematic review of human studies. Pathogens 14, 1185 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eyi̇ol, A. et al. Relationship of serum HLA-B alleles and TNF-α with rheumatic heart disease. Turk. J. Med. Sci. 48, 724–729 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Amoils, B. et al. Aberrant expression of HLA-DR antigen on valvular fibroblasts from patients with active rheumatic carditis. Clin. Exp. Immunol. 66, 88–94 (1986).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Arts, R. J. W., Joosten, L. A. B. & Netea, M. G. The potential role of trained immunity in autoimmune and autoinflammatory disorders. Front. Immunol. 9, 298 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bennett, J. et al. Understanding group A streptococcal pharyngitis and skin infections as causes of rheumatic fever: protocol for a prospective disease incidence study. BMC Infect. Dis. 19, 633 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lorenz, N. et al. Serological profiling of group A Streptococcus infections in acute rheumatic fever. Clin. Infect. Dis. 73, 2322–2325 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Raynes, J. M. et al. Serological evidence of immune priming by group A Streptococci in patients with acute rheumatic fever. Front. Microbiol. 7, 1119 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meira, Z. M. A., Goulart, E. M. A., Colosimo, E. A. & Mota, C. C. C. Long term follow up of rheumatic fever and predictors of severe rheumatic valvar disease in Brazilian children and adolescents. Heart 91, 1019–1022 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reményi, B. et al. World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease—an evidence-based guideline. Nat. Rev. Cardiol. 9, 297–309 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rwebembera, J. et al. 2023 World Heart Federation guidelines for the echocardiographic diagnosis of rheumatic heart disease. Nat. Rev. Cardiol. 21, 250–263 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Williamson, J. M. et al. The impact of acute rheumatic fever diagnosis on rheumatic heart disease severity. Glob. Heart 20, 72 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aschoff, L. The rheumatic nodules in the heart. Ann. Rheum. Dis. 1, 161–166 (1939).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hinton, R. B. et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ. Res. 98, 1431–1438 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shapero, K., Wylie-Sears, J., Levine, R. A., Mayer, J. E. & Bischoff, J. Reciprocal interactions between mitral valve endothelial and interstitial cells reduce endothelial-to-mesenchymal transition and myofibroblastic activation. J. Mol. Cell. Cardiol. 80, 175–185 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gee, T. W., Richards, J. M., Mahmut, A. & Butcher, J. T. Valve endothelial-interstitial interactions drive emergent complex calcific lesion formation in vitro. Biomaterials 269, 120669 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pinto, A. R. et al. Revisiting cardiac cellular composition. Circ. Res. 118, 400–409 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, H., Leinwand, L. A. & Anseth, K. S. Cardiac valve cells and their microenvironment—insights from in vitro studies. Nat. Rev. Cardiol. 11, 715–727 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shu, S. et al. Cellular landscapes of nondiseased human cardiac valves from end-stage heart failure–explanted heart. Arter. Thromb. Vasc. Biol. 42, 1429–1446 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Wang, X. et al. Single-cell analysis reveals the loss of FABP4-positive proliferating valvular endothelial cells relates to functional mitral regurgitation. BMC Med. 22, 595 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bartoli-Leonard, F., Zimmer, J. & Aikawa, E. Innate and adaptive immunity: the understudied driving force of heart valve disease. Cardiovasc. Res. 117, 2506–2524 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guilherme, L. et al. Rheumatic heart disease: proinflammatory cytokines play a role in the progression and maintenance of valvular lesions. Am. J. Pathol. 165, 1583–1591 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Scalzi, V. et al. Anti-endothelial cell antibodies in rheumatic heart disease. Clin. Exp. Immunol. 161, 570–575 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rastogi, M. et al. Anti-endothelial cell antibody rich sera from rheumatic heart disease patients induces proinflammatory phenotype and methylation alteration in endothelial cells. Genes Dis. 5, 275–289 (2018). This study demonstrated an interaction between autoantibodies and endothelial cells that triggers upregulation of inflammatory genes, contributing to the maintenance of a localized inflammatory state.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kanitkar, M. & Denton, C. P. The role of endothelial cells in autoimmune rheumatic disease. Curr. Opin. Physiol. 37, 100732 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Delunardo, F. et al. Streptococcal-vimentin cross-reactive antibodies induce microvascular cardiac endothelial proinflammatory phenotype in rheumatic heart disease. Clin. Exp. Immunol. 173, 419–429 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meier, L. A. et al. CD301b/MGL2+ mononuclear phagocytes orchestrate autoimmune cardiac valve inflammation and fibrosis. Circulation 137, 2478–2493 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Faragher, J. L. et al. Autoimmune valvular carditis requires endothelial cell TNFR1 expression. Arter. Thromb. Vasc. Biol. 43, 943–957 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Xian, S. et al. Activation of activin/Smad2 and 3 signaling pathway and the potential involvement of endothelial‑mesenchymal transition in the valvular damage due to rheumatic heart disease. Mol. Med. Rep. 23, 10 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wylie-Sears, J., Aikawa, E., Levine, R. A., Yang, J. -H. & Bischoff, J. Mitral valve endothelial cells with osteogenic differentiation potential. Arter. Thromb. Vasc. Biol. 31, 598–607 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Bai, L. et al. Anti-IL-17 inhibits PINK1/parkin autophagy and M1 macrophage polarization in rheumatic heart disease. Inflammation 48, 870–884 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gomes, N. F. A. et al. Histopathological characterization of mitral valvular lesions from patients with rheumatic heart disease. Arq. Bras. Cardiol. 116, 404–412 (2021).

  • Rajamannan, N. M. et al. Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation. Circulation 111, 3296–3301 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yoshioka, M. et al. Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis. Nat. Med. 12, 1151–1159 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mariscalco, G. et al. Imbalance between pro-angiogenic and anti-angiogenic factors in rheumatic and mixomatous mitral valves. Int. J. Cardiol. 152, 337–344 (2011).

    Article 
    PubMed 

    Google Scholar
     

  • Osinski, V. et al. Profibrotic VEGFR3-dependent lymphatic vessel growth in autoimmune valvular carditis. Arterioscler. Thromb. Vasc. Biol. 44, 807–821 (2024). Initial evidence emerging from animal models of autoimmune valvulitis suggests a role for VEGFR3-mediated lymphangiogenesis, with this phenomenon being identified in the mitral valves of people with RHD.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, A. C., Joag, V. R. & Gotlieb, A. I. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am. J. Pathol. 171, 1407–1418 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shun, C. -T. et al. Activation of human valve interstitial cells by a viridians Streptococci modulin induces chemotaxis of mononuclear cells. J. Infect. Dis. 199, 1488–1496 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Elhewala, A. A., Sanad, M., Soliman, A. M., Sami, M. M. & Ahmed, A. A. Matrix metalloproteinase-9 in pediatric rheumatic heart disease with and without heart failure. Biomed. Rep. 14, 4 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rutkovskiy, A. et al. Valve interstitial cells: the key to understanding the pathophysiology of heart valve calcification. J. Am. Heart Assoc. 6, e006339 (2017).

  • De Oliveira Martins, C. et al. Distinct mitral valve proteomic profiles in rheumatic heart disease and myxomatous degeneration. Clin. Med. Insights Cardiol. 8, 79–86 (2014). The fibrotic pathology observed in RHD valves is uniquely associated with an imbalance and disorganization of extracellular matrix components, driven in part by TNF and MMP-25 signaling networks.

    Article 

    Google Scholar
     

  • Martins, C. D. O. et al. Rheumatic heart disease and myxomatous degeneration: differences and similarities of valve damage resulting from autoimmune reactions and matrix disorganization. PLoS ONE 12, e0170191 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Päll, T. et al. Soluble CD44 interacts with intermediate filament protein vimentin on endothelial cell surface. PLoS ONE 6, e29305 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhong, J. et al. Vitronectin-binding PAI-1 protects against the development of cardiac fibrosis through interaction with fibroblasts. Lab Invest. 94, 633–644 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tincani, A., Rebaioli, C. B., Taglietti, M. & Shoenfeld, Y. Heart involvement in systemic lupus erythematosus, anti-phospholipid syndrome and neonatal lupus. Rheumatology 45, iv8–iv13 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Voskuyl, A. E. The heart and cardiovascular manifestations in rheumatoid arthritis. Rheumatology 45, iv4–iv7 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Pan, S. -Y. et al. Cardiac damage in autoimmune diseases: target organ involvement that cannot be ignored. Front. Immunol. 13, 1056400 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pandian, N. G. et al. Recommendations for the use of echocardiography in the evaluation of rheumatic heart disease: a report from the American Society of Echocardiography. J. Am. Soc. Echocardiogr. 36, 3–28 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Walker, G. A., Masters, K. S., Shah, D. N., Anseth, K. S. & Leinwand, L. A. Valvular myofibroblast activation by transforming growth factor-β. Circ. Res. 95, 253–260 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Choi, J. -H. et al. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J. Exp. Med. 206, 497–505 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cardeira-da-Silva, J. et al. Antigen presentation plays positive roles in the regenerative response to cardiac injury in zebrafish. Nat. Commun. 15, 3637 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Driscoll, K., Cruz, A. D. & Butcher, J. T. Inflammatory and biomechanical drivers of endothelial-interstitial interactions in calcific aortic valve disease. Circ. Res. 128, 1344–1370 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lupieri, A. et al. Rheumatic heart valve disease: navigating the challenges of an overlooked autoimmune disorder. Front. Cardiovasc. Med. 12, 1537104 (2025).

  • Sikder, S. et al. Group A streptococcal M-protein specific antibodies and T-cells drive the pathology observed in the rat autoimmune valvulitis model. Autoimmunity 52, 78–87 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Chen, Y. et al. Global burden and trend of rheumatic heart disease among women of childbearing age, 1990–2021, with projection to 2040. BMC Cardiovasc. Disord. 25, 580 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Afshan, G. et al. Circulating prothymosin alpha and immunoglobulin G3 in acute rheumatic fever and rheumatic heart disease: a case-control study. Am. Heart J. Plus 59, 100630 (2025).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sarkar, S. et al. Association of rheumatic fever & rheumatic heart disease with plausible early & late-stage disease markers. Indian J. Med. Res. 145, 758–766 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, Z. et al. Chronic mitral valve fibrosis in rheumatic heart disease: from immune trigger to inflammatory and mechanical progression. J. Am. Heart Assoc. 14, e045169 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wilson, N. J. et al. The treatment of acute rheumatic fever: novel use of hydroxychloroquine. Pediatr. Infect. Dis. J. 39, e120–e122 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Asrial, A. A. et al. Effect of dapagliflozin on patients with rheumatic heart disease mitral stenosis. J. Clin. Med. 12, 5898 (2023).

  • Ambari, A. M. et al. Angiotensin converting enzyme inhibitors (ACEIs) decrease the progression of cardiac fibrosis in rheumatic heart disease through the inhibition of IL-33/sST2. Front. Cardiovasc. Med. 7, 115 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chockalingam, A. et al. Safety and efficacy of enalapril in multivalvular heart disease with significant mitral stenosis—SCOPE-MS. Angiology 56, 151–158 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Ferguson, J. Valvular disease of the heart, accompanied by rheumatic subcutaneous nodules. BMJ 1, 1150–1150 (1885).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fraser, W. J., Haffejee, Z., Jankelow, D., Wadee, A. & Cooper, K. Rheumatic Aschoff nodules revisited. II: Cytokine expression corroborates recently proposed sequential stages. Histopathology 31, 460–464 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kemeny, E., Grieve, T., Marcus, R., Sareli, P. & Zabriskie, J. B. Identification of mononuclear cells and T cell subsets in rheumatic valvulitis. Clin. Immunol. Immunopathol. 52, 225–237 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lannigan, R. & Zaki, S. Location of gamma globulin in the endocardium in rheumatic heart disease by the ferritin-labelled antibody technique. Nature 217, 173–174 (1968).

    Article 

    Google Scholar
     

  • Source link

    Get RawNews Daily

    Stay informed with our RawNews daily newsletter email

    Valve biology and rheumatic heart disease pathogenesis

    Real Madrid v Manchester City: Line-ups, stats and preview

    Capitol agenda: Trump’s Doral demands ripple through GOP

    What on earth’s happening to the Greggs share price?