Effects Of CAMP In Lymphocytes Of Patients With Heart Failure On The Function Of Peripheral T Help Lymphocyte

Background and ObjectiveBeing at the vital stage of various heart attacks,heart failure is a serious and complex clinic syndrome and has a quite high mobility and mortality.The unusual activation of neuroendocrine is one of the most important influencing factors in the process of patho-physiology.However,there are few,if any,reported studies of the over-activation of sympathetic and its relationship with the immune system in heart failure at home and abroad.Previous research finds that peripheral blood lymphocyte has theβ-adrenoceptor (β-ARs) function and the signal transduction system of theβ-ARs-cAMP shares strikingly similar features with that of the cordis parenchyma cell.As both aresubject to adjustments of catecholamine hormone,lymphocyte has been used to study the change ofβ-ARs cells in human hearts.The change ofβ-ARs-cAMP system in lymphocyte with the influence of norepinephrine might be one of the major causes of the functional changes of T help(Th) lymphocyte in heart failure patients.Recently,it is reported thatβ-receptor blocking pharmacons could effectively reduce the levels of inflammatory cytokines such as tumor necrosis factors-α(TNF-α)and interleukin-6(IL-6)and improve Th1-h2 balacne;however,the specific working mechanism is still unclear.Belonging to the non-choice third generation ofβ-receptor blockers,Carvedilol is mainly used to reduce the side effects of sympathetic nervous system and has been proved in many clinic studies to effectively reduce the general mortality of chronic heart failure patients.Through a correlational analysis of cAMP,Th1 and Th2 and their relationship with heart function,the present thesis aims to study the significance of the malfunctions of peripheral T-lympholeukocyte in chronic heart failure patients,to explore the influence ofβARs the signal transduction system on the functions of T-cell differentiations,and through observing the change of the above relationships before and after Carvedilol treatments,to reveal the effects ofβ-receptor blocking pharmacons on immunomodulation.MethodsSixty—nine patients with chronic,30 males and 29 females, aged 54.8±9.9,with the left ventricular ejection fraction(LVEF)＜45 %by echocardiography and New York Heart Association(NYHA)cardiac function classificationⅡ—Ⅲ,were treated with carvedilol added on ACEI,diuretics and digitalis regimen for 4 months with a target dosage of 25 mg/d.Thirty healthy persons were studied as control.Peripheral blood mononuclear cells(PBMCs) were colletted from all persons including before and after carvedilol treatment and compared with those of 30 healthy persons,interferon-γ(IFN-γ) and tumor necrosis factor-a(TNF-a) were used as markers for the differentiation of Th1 subsets and interleukin-4(IL-10) for the Th2 subsets.After being stimulated with PHA,the levels of TNF-a,interleukin-10(IL-10) and Cyclic Adenosine monophosphate(cAMP) in culture supematants were measured by enzyme-linked immunosorbent assay(ELISA),IFN-γand IL-10 in CD4~+T lymphocytes were quantified by 3-color flow cytometry after bring stimulated with phorbol myristate acetate(PMA)and ionomyccin and plasma brain natriuretic peptide(BNP) level were tested using radio-immunity.By use of HPSonos 5500 color Doppler ultrasonic instrument,the left ventricular end-diastolic diameter(LVEDd),left ventricular ejection fraction(LVEF) and cardiac index(CI) were measured.The p value＜0.05 was considered statistically significant.Statistical Analysis were performed using SPSS version 13.0.Results(1) The levels of lymphocyte cAMP in the heart failure patients were significantly lower than those of the normal controls and IFN-γ/IL-10 were significantly higher than those of the normal controls (both P＜0.01).(2) Multiple regression analysis confirmed that the lymphocyte cAMP level was negatively correlated with IFN-γ/IL-4 and TNF-a/IL-10 ratio and BNP level(Y=-0.172 X+2.18,R~2=0.3872,P＜0.01;Y=-0.746X+3.58,R~2=0.3659,P＜0.01;Y=-108.8136X+1163.3817,R~2=0.3448, P＜0.01),and positively correlated with LVEF(Y=0.0691X+0.0544, R~2=0.4133,P＜0.01).The ratio of IFN-γ/IL-10 and TNF-a/IL-10 was positively correlated with BNP level and LVEDd(P＜0.01),and negatively correlated with LVEF and CI(P＜0.05 or P＜0.01).(3) After treatment of carvedilol,IFN-γ/IL-4 ratio in the heart failure patients were dramatically decreased(P＜0.01) and lymphocyte cAMP were increased(P＜0.05 or P＜0.01).(4) The level of cAMP,IFN-γand IL-10 heart failure patients with different pathogenic factors have no significant difference(P＞0.05).Conclusion The malfunction of CD+4 Th cells might be one of the working mechanisms of patho-autoimmune response in CHF patients.These cells are involved in myocardial damage and cardiac ventricle remodeling. As cAMP of lymphocyte is an important molecular natter in adjusting the functions of T-cells of sympathetic,tests of its levels could be used to learn about CHF patients' T-cells,predict their conditions,and guide the effective treatments withβ-receptor blockers.Through the increasing introduction ofβ-ARs to generate more cAMP,Carvedilol could be used to improve Th1-Th2 balance and adjust immunomodulation,offering another piece of evidence to support the use ofβ-receptor blockers in treating heart failures.