Pathology and pathogenesis of rheumatic heart disease

Abstract

Cardiovascular disease is on the rise. In India and other developing countries, rheumatic heart disease (RHD) continues to be a major public health problem and contributes to significant cardiac morbidity and mortality. RHD in the juvenile age group namely juvenile mitral stenosis is a variant which is unique to the Indian subcontinent. Severe valve deformities lead to high morbidity and mortality. Despite various measures no appreciable decline in prevalence of RHD has been documented. At autopsy, mitral valve was most commonly affected either alone or in combination with aortic and tricuspid valves. Both functional and organic involvement of tricuspid valve was documented. It has been convincingly demonstrated that molecular mimicry between Streptococcus pyogenes antigen and human proteins lead to autoimmune reactions both humoral and cell mediated causing RF/RHD. Heart tissues namely the valves, left atrial appendage (LAA) and myocardium reveal variable amounts of infiltration by lymphocytes. Significant endocarditis and valvulitis is observed in these cases. CD4+ T cells are most likely the ultimate effectors of chronic valve lesions in RHD. They can recognize Streptococcal M5 protein peptides and produce various inflammatory cytokines such as TNF-alpha, IFN-gamma, IL-10, IL-4 which could be responsible for progressive fibrotic valvular lesions. Cardiac myosin has been defined as a putative autoantigen recognized by autoantibodies of RF patients. Cross reactivity between cardiac myosin and group A beta hemolytic Streptococcal M protein has been adequately demonstrated. Cardiac myosin has been shown to produce myocarditis in rats and mice. Valvulitis/ endocarditis has been observed in excised LAA, cardiac valves and in hearts at autopsy from cases of RHD. The disease predominantly affects the valvular endocardium culminating in crippling valve deformities. Endocardial infiltrate and their migration into the valve substance has been elegantly demonstrated in rats and mice. Immune responses against cardiac myosin lead to valvular heart disease and infiltration of the heart by Streptococcal M protein reactive T lymphocytes. Mitral valves showed various degrees of calcification. An interesting observation is the nature of calcification in diseased/distorted valves in RHD. Recent studies indicate that calcification is not merely an inactive, "dystrophic" process but involves a regulated inflammatory process associated with expression of osteoblast markers and neoangiogenesis. Increased plasma osteopontin levels correlated with severity of mitral valve calcification. Further evidence of inflammation is supported by high levels of advanced oxidation protein products and high sensitive C-reactive protein in plasma detected in patients with RHD. Presence of inflammatory cells and increased expression of several cytokines in cases of "end stage" RHD reflects a possible subclinical, ongoing insult/injury to some unrecognized antigenic stimulus by beta hemolytic Streptococcal antigens that have sensitized/primed the various target tissues and which further culminate in permanent valve deformities.