Cytokines Expression And Ventricular Remodeling Following Coronary Microembolization In Rats: Intervention With Carvedilol

ObjectivesTo establish a model of coronary microembolization (CME) in rats by the use of the autogeneic microthrombotic particles. To explore the changes of myocardial pro-inflammatory and fibrogenic cytokines after coronary microembolization in rats. To observe the effect of carvedilol at different dose on myocardial cytokines expression and ventricular remodeling.MethodsWe created a rat model of CME by injecting a suspension of microthrombotic particles generated from the rat clots into left ventricle when clamping the ascending aorta. Forty SD rats were randomly divided into four groups, each consisted of ten rats: sham-operation group(SO), CME model group(ME), low-dose carvedilol intervention group(LCAR,1.0mg?kg-1?d-1) and high-dose carvedilol intervention group(HCAR,10.0mg?kg-1?d-1). A microscopy incorporated with an image analysis software was employed to calculate the number of micro-myocardial infarction(Nmmi) and the fraction of micro-myocardial infarction(Ammi) in sections with HE-staining, to measure the collagen volume fraction(CVF) in sections with Sirius-Red-staining, to detect the density of the expressiong of TNF-α, IL-1β, TGF-β1 and MMP-9 in sections with immunohistchemical staining, to calculate the myocyte apoptosis rate(Rapo) in sections with TUNEL-staining. Two-dimensional Echocardiography was performed to monitor left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular fraction shortering (LVFS) and left ventricular ejection fraction (LVEF); and electrophysiolography was utilized to measure left ventricular systolic pressure(LVSP), left ventricular maximum positive dp/dt (+LVdp/dtmax) and left ventricular end diastolic pressure(LVEDP) during chronic phase of CME.Results1. The expression of cytokines and ventricular remodeling during chronic phase of CME.Compared with group of SO, both Nmmi and Ammi were increased in group of ME (P<0.01, each) 28 days after operation. Compared with group of SO, the expression of TNF-α, IL-1β, TGF-β1 and MMP-9 were increased in group of ME (P<0.01,each) 28 days after operation. Compared with group of SO, both CVF and Rapo were increased in group of ME (P<0.01,each) 28 days after operation. Compared with group of SO, both LVEDD and LVESD were increased in group of ME, but LVFS and LVEF were reduced(P<0.01,each). Compared with group of SO, both LVSP and +LVdp/dtmax were decreased in group of ME (P<0.01,each), but LVEDP was increased (P<0.01).2. The effect of cavedilol at different dose on myocardial cytokines expression and ventricular remodeling.Compared with group of ME, the expression of TNF-α, IL-1β, TGF-β1 and MMP-9 were decreased(P<0.01,each), both CVF and Rapo were decreased(P<0.01,each), LVEDD and LVESD were smaller(P<0.01,each), LVEF and LVFS was higher(P<0.01,each), +LVdp/ dtmax were increased and LVEDP was decreased(P<0.01,each), heart rate were slowed down(P<0.01,each) in the two groups of different doses 28 days after operation. Except for LVSP, the above-mentioned changes were more remarkable in group of HCAR compared to group of LCAR(P<0.05).3. The relationships among cytokines and ventricular remodeling parametersMyocyte interstitial CVF was positively correlated with the expression of IL-1β and TGF-β1(r=0.81 and 0.93, P<0.01), the activity of MMP-9 was obviously positively correlated with the expression of TNF-αand IL-1β(r=0.90 and 0.91, P <0.01), and Rapo was positively correlated with the expression of TNF-α(r=0.88, P<0.01).Conclusions1. Left ventricle is undergoing progressive remodeling after CME due to myocyte apoptosis, micro-vessel loss and interstitial collagen fiber proliferation, which may be associated with the abnormal expressions of myocardial cytokines.2. Impairment of cardiac function after CME is mainly due to the ventricular remodeling.3. Carvedilol is able to decrease myocyte apoptosis and interstitial collagen fiber proliferation through down-regulating the expressions of pro-inflammatory and fibrogenic cytokine following CME, and these beneficial effects ultimately translate to improve ventricular function.