sST2, producción y papel en las enfermedades cardíacas

Zusammenfassung

INTRODUCTION Serum concentrations of ST2, a member of the interleukin-1 (IL-1) receptor family, represent a significant prognostic marker in heart disease. sST2 is elevated in the peripheral blood of patients with acute myocardial infarction (AMI) and heart failure (HF). High concentrations of sST2 correlate with the degree of necrosis and ventricular systolic dysfunction, and are associated with a higher risk of death and HF during follow-up. The source of sST2 production in response to AMI and in HF is not known, but the identification of the sources of sST2 is relevant to design strategies capable of modulating its signaling and developing therapies aimed to reduce its production. OBJECTIVES The objectives of this study are as follows: 1) to study whether the source of sST2 production in response to AMI is cardiac or extracardiac. 2) To study whether the source of sST2 production in patients with advanced chronic HF is cardiac or extracardiac. 3) To study whether the lungs are a significant source of sST2 in the context of HF. METHODOLOGY Three clinical studies have been carried out: 1) Determination of sST2 concentrations in patients with AMI and ST elevation who underwent primary angioplasty. After the revascularization procedure, blood samples were obtained from the coronary sinus, aortic root, radial artery and brachial vein. 2) Determination of sST2 concentrations in patients with advanced HF. During right and left catheterism procedures, samples were obtained from the aortic root, coronary venous sinus, main pulmonary artery, pulmonary capillary and femoral artery and vein. 3) Determination of sST2 concentrations, in bronchial aspirate and blood, in patients with ventilatory support admitted to the intensive care unit because of acute cardiogenic pulmonary edema, bronchopneumonia and brain disorders. In the same study, an experimental sub study was carried out using a rat model of myocardial infarction by ligation of the anterior descending coronary artery. Molecular biology techniques for sST2 quantification and biochemical stress models in cells to stimulate sST2 synthesis were performed. RESULTS In patients with AMI, sST2 concentrations were elevated but similar at all extraction sites and without a transcardiac gradient between the aortic root and coronary sinus. We obtained similar results in patients with advanced heart failure: no significant gradient was obtained between the different sampling sites. In the experimental model of HF after AMI, the liver and kidney did not show sST2 expression, but the lungs expressed an early and intense increase in sST2, both in terms of RNA levels and protein expression. ST2L/IL-33 expression showed a different pattern in response to AMI between lungs, where expression was decreased after AMI, and myocardium, where expression was increased after AMI. On histopathological examination, sST2 was strongly detected in the alveolar epithelium, and primary human type II pneumocytes secreted sST2 in response to mechanical stress. The relevance of the lungs in the production of sST2 in cardiac diseases was further confirmed in bronchial aspirates obtained from patients with cardiogenic pulmonary edema, where sST2 levels were higher than in patients with bronchopneumonia or neurological disorders. CONCLUSIONS The absence of a transcardiac gradient in patients with AMI and advanced HF supports the hypothesis of a noncardiac source of sST2 production. The lungs are a relevant source of sST2 in heart failure. These results may have implications in the comprehension of disease progression and the development of therapies targeting the ST2 system in patients with heart failure.