Rheumatic Heart Valve Disease Pathophysiology and Underlying Mechanisms

Abstract

Rheumatic heart valve disease (RHVD) is a post-infectious sequel of acute rheumatic fever resulting from an abnormal immune response to a streptococcal pharyngitis that triggers valvular damage. RHVD is the leading cause of cardiovascular death in children and young adults, mainly in women from low and middle-income countries. It is known that long-term inflammation and high degree of fibrosis leads to valve dysfunction due to anatomic disruption of the valve apparatus. However, since public and private investments in RHVD studies are practically inexistent the number of publications is scarce. This disease shows different natural history and clinical presentations as compared to other degenerative heart valve diseases. Although more than five decades passed after the pioneering studies on the pathogenesis of RHVD, it is still unclear how self-tolerance mechanisms fail in this disease, and how humoral and cellular inflammatory responses are interconnected. Despite that pathological mechanisms have been already proposed for RHVD, none of them are able to explain the preferential involvement of the mitral valve. This review focuses on pathophysiology and underlying mechanisms of RHVD.

Keywords: autoimmunity; inflammation; mitral valve; pathogenesis; rheumatic heart disease.

Figure 1

Gross pathology and histological aspects of rheumatic mitral valve at the end stage of RHVD. (A,B) Atrial and ventricular sides of mitral valves excised from female, 49 year-old patient, showing thick leaflets with retraction. (C) Mitral valve excised from male, 61 year-old, showing calcification. (D) Representative Hematoxylin and Eosin staining of anterior mitral valve leaflet showing presence of nodular calcification. Scale bar = 500 μm.

Figure 2

Histological comparison between normal mitral valves and rheumatic mitral valves. (A) Masson trichrome staining showing focal fibrosis and thickening of rheumatic mitral valves. Representative images are shown. (B) Representative immunohistochemistry staining for CD45⁺ cells evidencing a high frequency of leukocytes. Scale bars = 300 mm. (C) Picrosirius red staining showing uneven collagen deposition. Representative images are shown. Scale bars = 200 μm.

Figure 3

Schematic representation of the mechanisms of the pathogenesis of rheumatic heart valve disease. Following group A Streptococcus (GAS) invasion of the pharyngeal epithelium, GAS recognize and process bacterial antigens and present them to B lymphocytes. Activated B cells produce antibodies that are able to recognize epitopes in several sites in the host and also activate T lymphocytes. In the heart, cross reactive T cell clones and antibodies act against heart valve constituents leading to an intense inflammatory process culminating in valve dysfunction.

Figure 4

Histological comparison between neoangiogenesis in rheumatic mitral valve and calcific aortic valve. (A,B) Representative immunohistochemistry image for CD31⁺ staining evidencing presence of immature vessels in RHVD mitral valve and calcific aortic valve interstitium. Scale bars = 300 mm. (C) Representative immunofluorescence image showing cell co-expressing LYVE-1 and podoplanin demonstrating presence of lymphatic vessels in rheumatic mitral valves. Scale bars = 100 μm.