Patients With Heart Failure Cardiac Remodeling Mediated By Factors In Clinical Studies

Background Myocardial remodeling is an essential process of the origination and progression of congestive heart failure (CHF), and is a determinant factor of morbidity and mortality. There are various types of stimuli acting directly or indirectly via cellular mediators within myocardium, and hence promoting myocardial remodeling after the initiation of myocardial damage. Circulatory and local renin-angiotensin system (RAS) play a key role in pathologic process of CHF, and Ang II is an effectory peptide in this process . Ang II induces biological effects by AT1-or AT2- receptors. However, there is limited and conflicting information on the status of Ang II receptors in chronically failing human heart. There are many new evidences suggesting that inflammatory cytokines also play important roles in myocardial remodeling in addition to neurohormone. MAPKs is a common pathway that extracellular signals cause reactions in nucli. The MAPK subfamilies, the ERK, the JNK and the p38-MAPK regulate genes expression which influences cardiomyocyte proliferation, hypertrophy, apoptosis or necrosis. There is lack of information on MAPK subfamilies in human failing heart. Purposes In the present study, we selected patients with different degree heart failure, from two major sides (cytokines and Ang II), i.e., from peripheral to local, and from changes of plasma levels to expressions of mRNA in myocardium, and combining with clinical features. The changes of myocardial III structure and activation of intracellular stress-responsive signaling pathways were investigated. The experiments were designed to explore: 1. the relationship among the plasma levels of cytokines and the changes of genes expression within myocardium and their network regulation in patients with heart failure; 2. the correlation between cytokines and renin-angiotensin; 3. the relation among myocardial AT1 -/AT2- receptor expressions in the failing heart, myocardial remodeling and cardiac function; 4. cellular signaling transduction pathways via activations of p38 MAPK, INK, and ERK in the failing heart. Methods In part I, we randomly selected 52 patients with CHF and 30 cases of healthy persons, and divided into 4 groups according to NYHA. Cardiac function parameters were measured by echocardiography. Plasma levels of tumor necrosis factor- alpha (TNF- ci), interleukin-6 (IL-6) , soluble TNF receptor I (sTNF-RI) and transforming growth factor (TGF)- P were measured by enzyme-linked immunoassay in 52 CHF patients with various degrees of heart failure and in 30 healthy controls. Concentrations of PRA and Ang II in plasma were determined by RIA. In part II, pathologic and morphologic studies on myocardial tissue in 3 lpatients with CHF of valvular heart disease and 5 control subjects were observed by optical and electronic microscope. mRNA expression of TNF- a, iNOS and AT1-/AT2-receptors in myocardial tissue were analyzed using the reverse transcriptase-polymerase chain reaction. In part III, Using Western blotting assay, activations of JNK, p38 MAPK and ERK in myocardial tissue were examined. Results 1. Plasma concentrations of TNF- a , IL-6 and sTNF-RI were significantly increased, and plasma levels of TGF- P were significantly decreased in patients with CHF. And these parameters were positively...