Gene expression of endothelin receptors in replaced rheumatic mitral stenotic valves / Expressão gênica de receptores de endotelina em valvas mitrais reumáticas estenóticas substituídas

OBJECTIVES: Rheumatic fever is a highly prevalent disease in Brazil, and it poses a major public health problem. It is the leading cause of acquired heart disease in childhood and adolescence. The aim of this study was to evaluate the gene expression of ET-3 and its receptors, in replaced rheumatic mitral valves. METHODS: We studied the gene expression of endothelin-3 (ET-3) and its receptors, endothelin receptor A and endothelin receptor B (ETr-A and ETr-B), in the rheumatic mitral valves of 17 patients who underwent valve replacement surgery. The samples also underwent a histological analysis. RESULTS: Our data showed that almost all patients, regardless of individual characteristics such as gender or age, expressed the endothelin receptor genes, but did not express the genes for ET-3. In quantitative analysis, the ETr-A/GAPDH mean ratio was 33.04 ± 18.09%; while the ETr-B/GAPDH mean ratio was 114.58 ± 42.30%. Regarding histopathological individual features, the frequency of fibrosis is 100%, 88.23% of mononuclear infiltrate, 52.94% of neovascularization, 58.82% of calcification and absence of ossification. CONCLUSION: The presence of receptors ETr-A and ETr-B in rheumatic mitral valves suggests its interaction with the system of circulating endothelins, particularly ETr-B (known for acting in the removal of excess endothelin) detected in a greater proportion, which could explain the lack of expression of endothelin in rheumatic mitral valve, process to be elucidated.

OBJETIVOS: A febre reumática é uma doença altamente prevalente no Brasil, e representa um importante problema de saúde pública. É a principal causa de cardiopatia adquirida na infância e adolescência. O objetivo deste estudo foi avaliar a expressão gênica de ET-3 e seus receptores, em valvas mitrais reumáticas substituídas. Métodos: Estudamos a expressão gênica de endotelina-3 (ET-3) e de seus receptores, receptor da endotelina A e receptor da endotelina B (ETr-A e ETr-B), nas valvas mitrais reumáticas de 17 pacientes que se submeteram à cirurgia de troca valvar. As amostras também foram submetidas à análise histológica. RESULTADOS: Nossos dados mostraram que praticamente todos os pacientes, independentemente de características individuais, como sexo ou idade, expressaram os genes de receptores de endotelina, porém não expressaram os genes para ET-3. Na análise quantitativa, a média da proporção ETr-A/GAPDH foi de 33,04 ± 18,09%; enquanto que a média da proporção ETr-B/GAPDH foi de 114,58 ± 42,30%. Em relação às características histopatológicas individuais, a frequência de fibrose foi de 100%, infiltrado mononuclear de 88,23%, neovascularização de 52,94%, calcificação de 58,82% e houve ausência de ossificação. CONCLUSÃO: A presença de receptores ETr-A e ETr-B em valvas mitrais reumáticas sugere sua interação com o sistema de endotelinas circulantes, particularmente ETr-B (reconhecido por atuar na remoção do excesso de endotelina), detectado em maior proporção, o que poderia explicar a ausência da expressão de endotelina em valva mitral reumática, processo a ser elucidado.

Overexpression of Transforming Growth Factor-beta1 in the Valvular Fibrosis of Chronic Rheumatic Heart Disease

For the purpose of determining the pathogenic role of transforming growth factor-beta1 (TGF-beta1) in the mechanism of chronic rheumatic heart disease, we evaluated the expression of TGF-beta1, proliferation of myofibroblasts, and changes in extracellular matrix components including collagen and proteoglycan in 30 rheumatic mitral valves and in 15 control valves. High TGF-beta1 expression was identified in 21 cases (70%) of rheumatic mitral valves, whereas only 3 cases (20%) of the control group showed high TGF-beta1 expression (p<0.001). Additionally, increased proliferation of myofibroblasts was observed in the rheumatic valves. High TGF-beta1 expression positively correlated with the proliferation of myofibroblasts (p=0.004), valvular fibrosis (p< 0.001), inflammatory cell infiltration (p=0.004), neovascularization (p=0.007), and calcification (p<0.001) in the valvular leaflets. The ratio of proteoglycan to collagen deposition inversely correlated with TGF-beta1 expression in mitral valves (p=0.040). In conclusion, an ongoing inflammatory process, the expression of TGF-beta1, and proliferation of myofibroblasts within the valves have a potential role in the valvular fibrosis, calcification, and changes in the extracellular matrix that lead to the scarring sequelae of rheumatic heart disease.

Serum alpha-1-antitrypsin in ischemia and rheumatic heart diseases.

Tissue damage, inflammation and necrosis are hallmarks of myocardial infarction. In the present study significant elevations of serum alpha-1-antitrypsin were noted in coronary artery disease and angina cases. Interestingly chronic rheumatic heart disease which is also characterized by tissue injury. Inflammation revealed normal levels of serum alpha-1-antitrypsin. The level in chronic rheumatic heart disease was 3.37 +/- 0.57 mumol/mt/ml (control level was 3.37 +/- 0.54 mumol/mt/ml). The corollary of these observations is that in heart diseases acute phase response in terms of enhanced levels of alpha-1-antitrypsin differ depending on the causative factors. Except chronic rheumatic heart disease, in all other stressful states studied there is (to a certain degree) an altered systemic homeostasis and haemostasis. On the other hand chronic rheumatic heart disease encompass certain amount of acute phase status in terms of tissue damage and inflammation does exist unaccompanied by altered systemic homeostasis and haemostasis. However, bacteriological etiologies predominate the triggered immune responses. It is hypothesised that serum alpha-1-antitrypsin enhancement will not occur even though acute phase state exists if specific immune responses are also a part of the disease manifestation.

Zinc in rheumatic heart valves.

This study included 48 patients with chronic rheumatic heart disease, 60 control subjects for plasma zinc comparison and 20 control specimens of heart valves from postmortem cases of accident deaths. Plasma and cardiac tissue levels of zinc in patients with rheumatic heart disease were significantly lowered compared to controls. Since zinc is important in the synthesis of nucleic acids and proteins it may influence tissue growth, reparative process and structure and function of biomembrane. Low zinc levels may also influence cell mediated immunity and may increase susceptibility of patients to infection and increased rheumatic activity which needs further study.

Immunohistochemical characterization of Aschoff nodules and endomyocardial inflammatory infiltrates in resected left atrial appendages.

Presence of Aschoff nodules and other chronic inflammatory cells in the left atrial appendage even in the absence of rheumatic activity has been reported in a high percentage of patients with chronic rheumatic valvular heart disease. This study was conducted on 37 left atrial appendages resected at the time of closed mitral valvotomy. Aschoff nodules were present in 61.2 percent of resected appendages, positivity being 71.4 percent in the age group of 20 years of less and 53.3 percent in patients more than 20 years of age. The histological findings did not change significantly in the presence of activity. The frequency of Aschoff nodules and chronic inflammatory cells and their subtypes also did not show any correlation with age, sex, duration of symptoms or severity of mitral stenosis.