PERSPECTIVES OPINION result from insufficient s­ensitivity of c­linical auscultatory examination. Revisiting the pathogenesis of rheumatic Rheumatic carditis typically occurs as a pancarditis that involves the peri­cardium, fever and carditis myocardium, and endocardium.6 Whereas the occurrence of fibrinous pericarditis and Rajendra Tandon, Meenakshi Sharma, Y. Chandrashekhar, Malak Kotb, verrucous endocarditis or valvulitis is well Magdi H. Yacoub and Jagat Narula characterized, the term ‘myo­carditis’ has been used rather loosely, predominantly on Abstract | Rheumatic fever is one of the most-neglected ailments, and its the basis of the presence of interstitial gran­ pathogenesis remains poorly understood. The major thrust of research has been ulomas. The landmark manuscripts describ­ directed towards cross-reactivity between streptococcal M protein and myocardial ing the histopatho­logy of rheumatic carditis, α‑helical coiled-coil proteins. M protein has also been the focus of vaccine published in the 20th century, defined rheu­ development. The characteristic pathological findings suggest that the primary site of matic myo­carditis by the characteristic rheumatic-fever-related damage is subendothelial and perivascular connective tissue presence of focal interstitial inflammation, 8,9 matrix and overlying endothelium. Over the past 5 years, a streptococcal M protein referred to as Aschoff bodies. N‑terminus domain has been shown to bind to the CB3 region in collagen type IV. This In that latter part of the 20th century, binding seems to initiate an antibody response to the collagen and result in ground streptococcal M proteins were widely substance inflammation. These antibodies do not cross-react with M proteins, and reported to have a pivotal role in the patho­ genesis of rheumatic fever,10 and certain we believe that no failure of immune system and, possibly, no molecular mimicry M serotypes of group A streptococcus— occur in rheumatic fever. This alternative hypothesis shares similarity with collagen such as M types 1, 5, 6, 14, 18, and 24, involvement in both Goodpasture syndrome and Alport syndrome. which are referred to as ‘rheumatogenic’ Tandon, R. et al. Nat. Rev. Cardiol. 10, 171–177; published online 15 January 2013; strains—are particularly associated with doi:10.1038/nrcardio.2012.197 rheumatic fever.5 An α‑helical coiled-coil structure of the M protein is similar to Introduction intramyo­cellular proteins (such as myosin Rheumatic heart disease is known to affect matrix as a common patho­logy to explain and tropomyosin) and molecular mimicry 15 million individuals worldwide;1,2 how­ the systemic nature of r­heumatic fever. between streptococcal and myocellular ever, systematic echocardiographic screen­ contractile proteins was proposed to be ing in endemic areas indicates that this Past theories on pathogenesis r­esponsible for an a­utoimmune response.10 figure is a gross underestimation.3,4 No Rheumatic fever occurs as a sequel to upper The antibodies that target the valves effective methods for primary prevention or respiratory tract group A β‑haemolytic in humans with rheumatic fever are now specific medical therapy are currently avail­ streptococcal infections. The clinical mani­ thought to perhaps not target the M protein, able, because the pathogenesis of rheuma­ festations of rheumatic fever are observed but instead to target the group A carbo­hydrate tic fever remains poorly understood. The 2–6 weeks after streptococcal pharyngitis, from the causative streptococcus strain.11 As pathogenesis of this condition is believed when the throat cultures for bacterial infec­ early as 1968, anti-group A carbo­hydrate anti­ to involve cross reactivity between various tion have become negative and the elevated bodies were shown to be persistently elevated moieties in the causative strepto­coccus antibodies to strepto­coccal enzymes (such in patients with valvulitis,12 and a report pub­ strain and numerous cardiac antigenic as streptolysin O and DNase B) provide the lished 6 years later demonstrated that surgical epitopes; the most-discussed molecular tell-tale evidence of antecedent strepto­coccal removal of inflamed valves resulted in a sig­ mimicry has involved the strepto­coccal infection.5 The long-term consequence of nificant decrease in the level of anti-group A antigen M protein and some sarcomeric rheumatic fever is related to the induction of carbo­hydrate antibodies present in serum.13 proteins. However, this hypo­thesis might permanent cardiac damage.6 A 1987 report These antibodies are also thought to recog­ not adequately explain many features of the on the resurgence of rheuma­tic fever in the nize sequences in α‑helical proteins, such as disease, such as the common basis for intermountain area of the USA revealed myosin and tropomyosin, that behave identi­ the multisystem involvement in rheumatic that carditis, diagnosed on the basis of the cally to the N‑acetyl‑β‑d‑glucosamine domi­ fever, the sparing of the myocardium, and echocardiographic finding of overt or sub­ nant epitope of the group A carbohydrate.14 the specific effects on cardiac valvular clinical mitral valve regurgi­tation, occurred Notably, a high anti-group A carbohydrate tissue. We propose an alternative hypothesis in >90% of patients with rheumatic fever.7 response in patients with rheumatic fever ascribing the subendothelial extracellular Rheumatic carditis might, therefore, be and carditis correlates with poor prognosis an invariable component of rheumatic and valve replacement, and the responses Competing interests fever, and the presumed low frequency of against cardiac myosin S2 fragment peptides The authors declare no competing interests. rheuma­tic carditis in rheumatic fever might correlate with disease activity.15,16 NATURE REVIEWS | CARDIOLOGY VOLUME 10 | MARCH 2013 | 171 © 2013 Macmillan Publishers Limited. All rights reserved PERSPECTIVES Because coiled-coil contractile proteins various manifestations of the disease. The heal without residual damage. Numerous are intracellular (sequestered from extra­ pathological changes also indicate that, arterial beds demonstrate a variable cellular environs by the sarcolemma), mere unlike in the more-common lymphocytic degree of arteri­tis, including the aorta, production of cross-reactive anti­bodies to form of myocarditis, heart muscle cells are coronary vessels, pulmo­nary artery, small these proteins does not establish a causal spared in rheumatic carditis (Figure 1). and large muscular arteries, and even vasa relationship with the disease patho­genesis. vasorum.6,24 These vessels are associated Accordingly, some researchers have pro­ Involvement of extracellular matrix with oedema, and histio­cytic and inflam­ posed that a target that resides on the Pathologically, rheumatic fever is charac­ matory cell infiltration of the intimal and surface of the cell and causes the disease terized by inflammatory changes in sub­ medial layers, which can be associated to begin or ensue exists in addition to endothelial and perivascular collagen with fibrinoid degeneration and, at times, an intracellular biomarker antigen.14,17 An tissue.6,21 In rheumatic carditis, the granu­ thrombosis. Histological findings of the example of this phenomenon occurs in loma formation comprising perivascular renal involvement, mostly obtained by Sydenham chorea, a neurological manifes­ Aschoff nodules has been described as the biopsy, indicate the presence of glomeru­ tation of acute rheumatic fever. The bio­ most-characteristic finding.6,22 The depth litis. Widespread obliterating endarteritis marker antigen for Sydenham chorea in the of perivascular inflammation is limited, of the medium and small renal arteries is brain is tubulin, but the antigen target is a and evidence for inflammation beyond the common, but does not result in any clinical cell-surface antigen that, after binding the perivascular area is infrequent; the myo­ or laboratory abnormalities. Abdominal cross-reactive antibody, leads to calcium/ cardium or interstitium beyond this area pain in rheumatic fever can occur as a calmodulin-­dependent kinase II activation appear largely normal. Microscopically, the result of necrotizing arteritis of visceral and subsequent dopamine release.17 For pericardium is affected in almost all patients arteries. Although pulmonary lesions are rheumatic cardi­tis, some investigators have with active rheumatic fever; however, no not infrequent, the specificity of these suggested that the antibodies might recog­ residual damage in myocardium or peri­ lesions is not certain because most autop­ nize the intracellular biomarker antigen cardium is observed after the acute episode sied patients also had pulmonary oedema cardiac myosin, but that the antigen targeted of rheumatic fever is resolved.6 Unlike from left ventri­cular failure prior to their on the valve surface endothelium in situ is myocardium and pericardium, the valvu­ death. In the alveolar walls, capillary laminin, or some other e­xtracellular or lar tissue often sustains permanent damage endothelial cells proliferate, and analysis basement-membrane protein.18,19 after active carditis.6 Histopathological of the interstitial tissue shows oedema The current paradigm of the patho­ analysis reveals that the mitral valve and inflammatory cells. Vascular lesions genesis dictates that the first damage to is always affected,23 and the aortic valve is of the capillaries and small arteries consist the endocardial surface is antibody medi­ frequently inflamed.6