Rheumatic Heart Disease and Myxomatous Degeneration: Differences and Similarities of Valve Damage Resulting from Autoimmune Reactions and Matrix Disorganization

Abstract

Autoimmune inflammatory reactions leading to rheumatic fever (RF) and rheumatic heart disease (RHD) result from untreated Streptococcus pyogenes throat infections in individuals who exhibit genetic susceptibility. Immune effector mechanisms have been described that lead to heart tissue damage culminating in mitral and aortic valve dysfunctions. In myxomatous valve degeneration (MXD), the mitral valve is also damaged due to non-inflammatory mechanisms. Both diseases are characterized by structural valve disarray and a previous proteomic analysis of them has disclosed a distinct profile of matrix/structural proteins differentially expressed. Given their relevance in organizing valve tissue, we quantitatively evaluated the expression of vimentin, collagen VI, lumican, and vitronectin as well as performed immunohistochemical analysis of their distribution in valve tissue lesions of patients in both diseases. We identified abundant expression of two isoforms of vimentin (45 kDa, 42 kDa) with reduced expression of the full-size protein (54 kDa) in RHD valves. We also found increased vitronectin expression, reduced collagen VI expression and similar lumican expression between RHD and MXD valves. Immunohistochemical analysis indicated disrupted patterns of these proteins in myxomatous degeneration valves and disorganized distribution in rheumatic heart disease valves that correlated with clinical manifestations such as valve regurgitation or stenosis. Confocal microscopy analysis revealed a diverse pattern of distribution of collagen VI and lumican into RHD and MXD valves. Altogether, these results demonstrated distinct patterns of altered valve expression and tissue distribution/organization of structural/matrix proteins that play important pathophysiological roles in both valve diseases.

The pathophysiology of RHD and outstanding gaps

“…(72) Exploratory discovery proteomic studies reported alterations in valve tissue proteins involved extracellular matrix (ECM) structural organisation and IR roles in RHD (Table I). (73)(74)(75) Vimentin is a structural protein that binds and stabilises collagen mRNA. (76) Previous studies found that vimentin is a cross reactive target for GAS antibodies, peripheral and heart valve infiltrating T lymphocytes (75) and a neo-angiogenesis initiation factor.…”

“…These functions may affect their binding to integrins and soluble ligands and probably affect signalling mechanisms involved in heart valve pathology. (74,77) Collagen IV, prolargin, biglycan and COMP are major components of the ECM of the spongiosa of heart valves. (73,74) They function in ECM integrity; receptor activity and cell adhesion, cellular migration and proliferation.…”

“…(74,77) Collagen IV, prolargin, biglycan and COMP are major components of the ECM of the spongiosa of heart valves. (73,74) They function in ECM integrity; receptor activity and cell adhesion, cellular migration and proliferation. (77) It is not known if their down regulation is associated with the reduced tissue integrity, repair and growth observed in RHD.…”

“…Apart from regulation of the innate immune response, vitronectin and clusterin have been reported to help in pericellular proteolysis, complement activation, leukocyte recruitment and homeostasis of the fibrinolytic systems in other autoimmune diseases. (73,74,92,93) Vitronectin also has an RDG motive, enabling it to bind to integrins and transmit mechanical stress signals to the cell. (94) It is not known though whether down regulation of vitronectin is associated with loss of valve integrity in RHD.…”

“…Vitronectin has additionally been found to act as co-factor for plasminogen activator inhibitor-1 in regulating ECM degrada- tion. (73,74) Furthermore, vitronectin also binds to complement proteins and the complement system is known for its important role in the development of inflammatory processes associated with diseases such as RHD. (92) Indeed, altered expression of complement factors was confirmed in the serum of RHD patients.…”