A Study On Relationship Between β-adrenergic Receptor And Heart Failure

Background:Heart failure is the most common cause of death in various cardiovasculer diseases. The pathophysiology of heart failure is the neurohormonal activation and ventricular remodeling. The sympathetic nervous system is more importment in neurohormone system and may influence the progress of heart failure with mediated β adrenergic receptor. Thus, it is a key therapy to inhibit the vicious cycle of neurohormone and ventricular remodeling. Recently, a number of clinical trials show that β blockers may not only improve in symptoms of the patients with heart failure, but also prolong survival and reverse remodeling.The investigations show that β1- and β2-adrenoceptors are either downregulated or desensitized in the failing heart. By contrast, the abundance of β3-adrenoceptors appears to increase in human heart failure. This compensatory upregulation of the β3-adrenoceptor could be viewed as a mechanism to prevent further myocyte damage. As heart failure progresses to a later stage, this compensatory mechanism might become maladaptive, with a persistent negative inotropic effect leading to further myocardial depression. However, treatment with β blockers can not benefit for all patients with heart failure. It is not clear that weather β blockers only inhibit selectly to β1- and β2-adrenoceptors or but not inhibit β3-adrenoceptor. The changes and actions of β1-,β2- β3-adrenoceptors before and after therapy of heart failure are not well understood. It is needed further to demonstrate that the relationship among β-adrenoceptor, cytokines and apopotosis in development of heart failure. The recent studies have demonstrated that the changes of density of β-adrenoceptor of human lymphocyte may reflect the state of the myocardium. Moreover, the intact cells of human lymphocyte show an evidence of β3-adrenoceptor subtypes distribution.Objective:To investigate the alteration of expressions of β1-,β2-,β3-adrenoceptor mRNA and their signaling pathway in human lymphocyte and myocardial tissue in patient with heart failure. Meanwhile, to explore the relation among the plasma levels of cytokines, the changes of the levels of β1-,β2-,β3-adrenoceptor mRNA within lymphocyte and myocardium, the apoptosis of lymphocyte and cardiac function. To evaluate the effects of β-blockers on the β-adrenoreceptor signaling pathway, the plasma levels of cytokines and the apoptosis of lymphocyte.Methods:In part Ⅰ, we randomly selected 43 patients with heart failure and 20 cases of healthy persons, and divided into 4 groups according to NYHA. Left ventricular ejection fraction(LVEF) and left ventricular end diastolic diameter(LVEDD) were measured by echocardiography. The pathologic and morphologic studies on myocardial tissue in 24 patients with heart failure of valvular heart disease and 5 control subjects were observed by electron microscopy(EM). mRNA Expression of β1-,β2-,β3-adrenergic receptor in lymphocyte and myocardial tissue were analyzed using the reverse transcriptase-polymerase chain reaction. In part Ⅱ, concentrations of cyclic adenosine monomphsopate(cAMP) and cyclic guanosine monophosphate(cGMP) in plasma and myocardiol were determined by radioimmunoassay(RIA). Plasma and myocardiol tissue levels of nitric oxide synthase(NOS), inducible nitric oxide synthase(iNOS) and nitric oxide(NO) were measured by biochemical analysis. Plasma levels of tumor necrosis factor-α(TNF-α), inerleukin-1β(IL-1β) and inerleukin-6(IL-6) were measured by enzyme-linked immunoassay(ELISA) in 43 patients with various degrees of heart failure and in 20 healthy controls. Apoptosis in lymphocyte was quantified by TUNEL method and the characteristic features of apoptosis were identified by EM. In part Ⅲ, 83 patients with heart failure (NYHA class Ⅱ-Ⅳ) were allocated randomly and evently into metoprolol-treated group and conventional therapy group. All patients received angiotensin converting enzyme inhibitors(ACEI), digitalis, diuretic, nitrate. 43 patients of metoprolol-treated group were started on metopro...