Effect Of Different Doses Of Simvastatin On Chronic Heart Failure Rabbit Connective Tissue Growth Factor、Steoprotegerin

Objectives By investigate the effects of varying doses of simvastatin on rabbit models of chronic heart failure, to provide the theoretic foundation of the safety and efficacy for simvastatin on chronic heart failure, by monitoring osteoprotegerin and connective tissue growth factor to explore the possible protective mechanism of simvastatin for the rabbits with chronic heart failure.Methods Sixty male rabbits, weighed2.0～2.5kg, provided by the Experimental Animals’ Center of Xinxiang Medical University, were randomly divided into five groups (12rabbits in each group):control group (CON), CHF group, small-dose simvastatin group (SD-SIM), medium-dose simvastatin group (MD-SIM), and the high-dose simvastatin (HD-SIM). Except for the control group, the other4groups received adriamycin (1.5mg/kg) injection, once a week for12weeks through the auricular vein of rabbits, which were observed2weeks after injection.The control group were injected the same doses of normal saline with the other groups, and the same way of administration and the duration of drug use. The SD-SIM, MD-SIM and HD-SIM groups were injected varying dosages of simvastatin together with adriamycin for the first time,0.3mg/kg/d for The SD-SIM,1.5mg/kg/d for MD-SIM, and3mg/kg/d for HD-SIM, diluted separately with5ml saline by intragastric administration for12weeks. The CHF and the CON groups received the same volume of saline by intragastric administration for12weeks. Two weeks after adriamycin injection, Color Doppler ultrasonography were taken for the rabbits, Before the rabbits were sacrificed by the carotid artery to take blood5mL to centrifuged after centrifugation serum was stored at-20℃refrigerator, with enzyme marker immune assay (Elisa,) monitoring of osteoprotegerin, while specimens from the heart, ventricular wall set paraformaldehyde, HE staining of myocardial cell changes in the structure immunohistochemical staining to detect connective tissue growth factor expression.Reusults Compared with the control group, the specimens showed that the left ventricle became attenuated and ventricular chambers got expanded, the SD-SIM groupnd the HD-SIM group, while some CHF rabbits partly showed hydropericardium, Bloody ascites, hydrothorax, but there was no significant.changes in MD-SIM group. The heart function examinations also demonstrated that the left ventricular blood ejection fraction (LVEF) sharply in this group compared with CON group (P<0.01); compared with the MD-SIM group, the heart functions of the SD-SIM and the HD-SIM groups dropped markedly (P<0.05). Hemodynamic exams indicated that the Pressure maximal rate of rise (+dp/dtmax) and Left ventricular systolic pressure (LVSP) in the SD-SIM, the HD-SIM groups and CHF. group both dropped significantly compared with the CON group (P <0.01), and there was a remarkabledrop in the cardiac functions of the SD-SIM and the HD-SIM groups compared with MD-SIM group (P<0.05). Compared with the control group, the SD-SIM, the MD-SIM,. the HD-SIM and the CHF groups the Pressure maximal rate of fall (-dp/dtmax) rised significantly (P<0.01), the SD-SIM, the MD-SIMgroup and the HD-SIM groups.compared to the CHF group rised significantly (P<0.05). HE staining displayed that in the CON group the number of the myocardial cells had decreased, lamellar necrosis。In the simvastatin therapy groups, the overall situation wasbetter than the CHF group, but the myocardial cells also had varied dimensions; in the myocardial cells of the SD-SIM and the HD-SIM groups, the microstructural proliferations were found; the myocardial cells of MD-SIM group were better arranged compared with CON group, and no myocardial necrosis was found, but myocardial cell spaces were expanded and few fibril tissue proliferations were found.Compared with the CON group, the SD-SIM, the MD-SIM, HD-SIM, Connective tissue growth factor (CTGF)、Osteoprotegerin (OPG)expression decreased significantly (P<0.05), compared to the expression of which HD-SIM group and SD-SIM, MD-SIM, less (P<0.05) of CHF group and other groups compared to the expression of most (P<0.05). Conclusion Simvastatin can improve chronic heart failure rabbit left ventricular remodeling and improve cardiac function significantly.which mechanism may have the relevant with the cutting the expression of CTGF and reducing the OPG activity. So CTGF and OPG may be the index of predicting the degree of myocardial ingyry.