Research Of Neuregulin-1 Therapy In Systolic Insufficiency Heart Failure

As a member of epidermal growth factor family, the signal molecule—neuregulin-1(NRG-1) was generally expressed,the physiology function of which can be embodied when it's binding with a series of PTK receptor,ErbB,along with the cell membrane.The research so far has proved that neuregulin-1 plays very important role in cell differentiation,multiplication,proliferation,survival,apoptosis as well as cell-cell interaction. Apart from the critical role in the process of cardic development,recently it has been found that the NRG-1/ErbB signal transducting system contributes greatly to the maintenance of cardiac structural and functional integrity.Animal experiments have showed that short-term intravenous administration of recombinant NRG-1 improves cardiac function and survival in different models of cardiomyopathy, including toxic, ischemic, dilated, and viral cardiomyopathy. Investigation in human beings of small sample and the second phase clinical preliminary test of Zesheng company from Shanghai also showed that short-term intravenous administration of recombinant NRG-1 could improve cardiac function and physical labor toleration of heart failure patients. Nevertheless,the small sample of the investigation,the ignorance of the influence of remedium basis to study result as well as the discrepancy between patients,and done without using randomized,double-blind,Placebo-Controlled research method undermine the reliability of the results, which need further verification. Futhermore,it is because that the drug is in the clinical observation stage,the security of it should be futher evaluated.The patients enroled in our study are all stable chronic contractable heart failure patients that received standard therapy for heart failure at least more than one month and cardiac function of which fluctuateⅡ-Ⅲclass.Meanwhile,we employ randomized,double-blind,Placebo-Controlled research mothed to estimate the effectivity and security of the drug,and try to approach the contribution as well as mechanism of NRG-1 in the developing process of chronic heart failure,and then definitude the perspective of it's clinical application.16 enroled patients are all stable heart failure patients hospitalized in cardiovascular department of the 2nd affiliated hospital of Jilin University form February to December of 2008,each patient has been difinitely diagnosed as chronic contractable heart failure and received standard therapy for heart failure at least more than one month..Twelve patients are male and the other four are famale,the age of them fluctuate from 22 to 64,and the mean age is 48±13.46. The medical history of each patient enroled was collected as usual,including age,sex, case history,time received standard therapy for heart failure, symptom, physical sign etc., definite the cardiac function condition of each patient according their clinical manifestation in accordance with the NYHA cardiac functional grading, and then divide the patients randomly with random digits table into two group—standard therapy group(group of placebo) and NRG-1 therapy group(test group).It is presented that each group contains 8 patients respectively after the blindness was exposed. Male of the test group is five and female is three,the age of them fluctuats from 31 to 65(42.5±10.85); while the placebo group contains seven male and 1 female,the age of them are 22-65(53.5±14.19).The patients of test group were administrated of recombinant NRG-1 intravenously(1.2ug/kg/day) as well as standard therapy for heart failure(ACEI/ARB,β-blocker diuretics,digoxin) via the gastrointestinal tract,while the placebo group receives placebo and standard therapy for heart failure.The administration time is ten hour every day and initial administration time may fluctuat 1 hour up and down. The study period is 90 days.Unless the demand of patients condition,all patients should not receive diuretics,pressor or hypotensive drug(dopamine,Sodium Nitroprusside or Nitroglycerin),cardiotonic(digitalis,milrinone etc.) and other drugs targeting chronic heart failure intravenously. All patients has no limitation n drug using at follow-up phase. Take six- minute floor walking test,Minnesota life quality evaluation and measure the serum NT-proBNP concentration at the beginning,11days,30days,90days of the study respectively;measure the LVEF% at the beginning and 30days of the study; measure the cardiothoracic ratio of the patients at the beginning and 90days of the study;record blood presure and heart rate before and 2 hours after the drug administration; record the rehospitalization rate of each group at 30days and 90 days of the sdudy and record all bad events within the study. The effictivity indices are six- minute floor walking test,score of Minnesota life quality evaluation,serum NT-proBNP concentration,LVEF%,cardiothoracic ratio as well as the rehospitalization rate, and evaluate the security of the drug in according with the patients'blood presure and heart rate begin and 2 hours after the drug administration as well as the bad events within the study.The 16 patients all completed the study.All observation indices between the two groups at the beginning of the study have no statistical difference,redering the two group have comparability. The distance of the six-minute walking test of test group is longer than that of placebo group at 11days,30days and 90days of the sdudy(P <0.01); the score of Minnesota life quality evaluation and the concentration of serum NT-proBNP of test group is lower than that of placebo group at 11days,30days and 90days of the sdudy(P <0.01);the serum NT-proBNP concentration of the placebo group rise continuously and there is statistical difference between 30days,90days and the beginning of the study(P <0.01).the LVEF% of test group is higher than that of placebo group at 30days of the study(P <0.01);there is no statistical changing of cardiothoracic ratio between 90days and beginning of the study of both group;the rehospitalization rate of test group is lower than that of placebo group at 30days and 90days of the study(P <0.01);the blood presure and heart rate between the beginning and 2 hours after the administration of the test group have no statistical difference;the incidence rate of the bad events of test group is higher than that of the placebo group, most of the bad events are gastrointestinal tract adverse effect, and patients can tolerant most of them..Clinical control study presents that short-term intravenous administration of recombinant NRG-1 could lower the serum NT-proBNP concentration,improve cardiac function,boost the physical labor tolerance,ameliorate the lift quality and cut down the rehospitalization rate of chronic contractible heart failure patients. The recombinant NRG-1 has little influence at the cardiothoracic ratio of chronic contractible heart failure patients in a short time. Gastrointestinal tract adverse effect may be observed when using recombinant NRG-1 while most of the adverse effect are tolerable.The recombinant NRG-1 have no significant influence to the patients'blood pressure and heart rate.