Class Act: Pathogenesis of Rheumatic Heart Disease

August 14, 2008

streptococcus_pyogenes.jpgClass act is a feature of Clinical Correlations written by NYU 3rd and 4th year medical students. Prior to publication, each commentary is thoroughly reviewed for content by a faculty member.

Commentary by Matt Stein MS-4; Reviewed by Harold Horowitz MD, Professor, NYU Division of Infectious Diseases and Immunology

In general, acute rheumatic fever (ARF) is a delayed sequela of a group A streptococcus (GAS) pharyngeal infection. Following an initial throat infection, which is often either untreated or incompletely treated, there exists a latent period of two to three weeks before the first signs of acute rheumatic fever become apparent. Weeks after the initial symptoms, patients may present with any of the characteristic manifestations of acute rheumatic fever, including arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum. (1,2)

Knowledge of the specific microbiology of ARF is crucial to understanding the pathophysiology of this disease. GAS is a gram-positive, extracellular bacterial pathogen that typically colonizes the throat or skin. GAS is an organism that has developed many complex virulence mechanisms; it has become the most common cause of bacterial pharyngitis, scarlet fever, and impetigo. There are distinct GAS strains, or serotypes, that have a particularly strong tendency to cause either throat or skin infections. Moreover, streptococci have been further characterized based on the presence of particular M protein structures. There are more than eighty different M protein types of GAS currently described. The M protein has numerous functions in the bacterium, among which is protection from host immune response. More specifically, it has been shown to inhibit antibody binding and complement-derived opsonin deposition,  thereby protecting GAS against phagocytosis by polymorphic neutrophils. (3)

The importance of the GAS M protein in the pathogenesis of rheumatic heart disease extends beyond its value in avoiding host immune response. It has been demonstrated that molecular mimicry, associated with the structure of the M protein, induces cross-reactivity with the host immune system that results in the destruction of cardiac myosin. It has been shown that cross-reactive auto-antibodies against GAS M protein antigens and heart tissue are present in the sera of rheumatic fever patients. The production of mouse and human monoclonal antibodies against GAS confirmed these cross-reactions and identified myosin, tropomyosin, and vimentin as heart auto-antigens cross-reactive with GAS M protein. (4)

Although advances have been made regarding the pathogenesis of rheumatic heart disease (RHD), the specific method by which cross-reacting antibodies lead to myocarditis, endocarditis, and pericarditis is incompletely understood. One model linking humoral and cellular immune responses hypothesizes that the cross-reactive antibodies may bind to the valvular endothelium, leading to inflammation, cellular infiltration, and valvular scarring. Once activated, increased expression of various adhesive molecules by the valvular endothelium facilitates the binding of T cells and a subsequent cycle of scarring neo-vascularization and re-infiltration by lymphocytes. In addition, the particular role of anti-myosin antibodies was studied in a classic experiment in which anti-myosin antibodies from rheumatic fever patient sera were applied to neonatal rat cardiac myocytes. These antibodies caused increased calcium uptake and retention, leading to eventual myocyte dysfunction and death. (5)

It appears that cardiac myosin is very involved in the pathogenesis of RHD. It seems counter-intuitive, therefore, that the most prominent long-term sequela of rheumatic heart disease would be valvular dysfunction, as opposed to myocardial abnormalities. However, myosin is an intracellular protein found in small amounts in valvular tissue. Recent studies have demonstrated that the majority of peptides recognized by the infiltrating T cell clones were exclusively from valvular tissue. (6)

Following the initial valvular insult, the recognition process described above initiates a cascade by which myocyte destruction leads to T-cell recognition of additional myosin epitopes, which allow for more severe valvular damage. Additionally, valvular destruction may expose more valvular epitopes that lead to more specific and localized valvular disease. This hypothesis is also supported by the cross-reactivity that has been demonstrated between myosin and valvular protein, myosin, and M protein, and the three cross-reactive proteins at once. (6)

With this knowledge in mind, a fairly detailed hypothesis has been developed to explain the way in which a GAS infection leads to RHD. Initially, when GAS pharyngitis goes untreated there is  a latent phase which often deceives patients into believing they are cured. The GAS then infects the heart, utilizing a surface M protein with structural similarities to numerous cardiac proteins, including myosin, to trigger an aberrant immune response. This host response leads to autoimmune destruction of myocardium and valvular structures. This begins a cascade in which infiltration and destruction of cardiac valves leads to exposure of additional epitopes, which also cross-react, thereby amplifying the pathogenicity of GAS and furthering valvular disease.



1.  Kaplan EL. Rheumatic fever. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JR, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill;2005:1977-79.

2.  www. uptodate. com (multiple articles), November 2007.

3.  Cunningham MW, McCormack JM, Talaber LR, et al. Human monoclonal antibodies reactive with antigens of the group A Streptococcus and human heart. J Immunol 1988;141:2760-66.

4.  Dale JB, Beachey EH. Epitopes of streptococcal M proteins shared with cardiac myosin. J Exp Med 1985;162:583-91.

5.  Fae, KC, da Silva, DD, Oshiro, SE, et al. Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. J Immunol 2006;176:5662-70.

6.  Cunningham, MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 2000;13:470-511.

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