Effects Of Simvastatin On Ventricular Remodeling In Rat After Acute Myocardial Infarction

Background and aimsVentricular remodeling after acute myocardial infarction (AMI) is a progressive structural and geometric changes, which at last results in heart failure. Ventricular remodeling includes the myocardial hypertrophy and extracellular matrix (ECM) remodeling. Matrix metalloproteinase (MMPs) and their inhibitors play an important role in the process of ECM remodeling, and the activity of MMPs is modulated by tumor necrosis factor-a (TNF-a) and other inflammatory cytokines. It is all accepted that coronary heart disease (CHD) is also an inflammatory disease. In the last few years, more and more evidence have confirmed that inflammatory cytokines play a critical role in modulating the structure and function of the heart. Elevated circulating levels of TNF-a have been observed in patients with CHD, and the plasma level of TNF-a was closely correlated to the cardiac function and the severity of disease. In the present studies, TNF-a and other inflammatory cytokines are high expression in rats after AMI, and can induce myocardial myocyte hypertrophy and contractile depression. TNF-a may play an important role in the process of ventricular remodeling in rats after AMI.Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are be used for the treatment of plasma lipid abnormalities, and have been widely used in the firstly and secondary prevention of coronary heart disease, Randomized trials have established that statin treatment was associated with lower rates of cardiovascularevents and total mortality. Recent studies emphasized its non-lipid-lowering effect, especially the anti-inflammation effect. Clinical study reported that statins could markedly decrease the TNF-a level in the patients of CHD. Recent studies demonstrated that anti-TNF-a therapy could improve ventricular remodeling and cardiac function in rats with AMI. We hypothesized that statins maybe have beneficial effects on LV remodeling partly related to modulation of myocardial inflammation. Thus, we examined the effects of simvastatin on the expression of TNF-a and early ventricular remodeling in rats with AMI. MethodsRats and infarctionHealthy female Wistar rats, purchased from animal laboratory of Tongji Medical College, Wuhan, China, were randomly divided into Sham group( Sham, n=10),MI control group(MI-C, n=20) and simvastatin group(MI-S, n=20). AMI animal models were induced by left anterior descending branch ligation. Rats in MI-S group were treated with simvastatin (gastric gavage, 20mg/kg/d) for 4 weeks, in MI-C group and Sham group were treated with drinking water.Echocardiography and hemodynamics analysisAfter anesthesia, two-dimensional echocardiography was performed with a phased-array echocardiographic machine; subcostal views including left ventricular end-diastolic diameter (LVEDd), ejection fraction (EF) and fractional shortening (FS) were obtained. Then, rats were prepared for homodynamic analysis. Left ventricular catheter was inserted into left ventricle through the right common carotid artery. The data were gathered from artery and left ventricle, including heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), LV systolic pressure (LVSP), LV end diastolic pressure (LVEDP) and LV pressure maximal rate of rise and fall (+/-dp/dt max).TNF-a, MMP-2, MMP-9 gene expression were determined by RT-PCR.Myocardial MMPs activities were examined by gelatin zymography.Myocardial TNF-a protein production was analyzed by western blotting.Type I collagen production was determined by immunohistochernistry.Statistical analysisAll data were given as mean±SD. The comparisons between >2 groups were made using multivariate ANOVA of independent groups to determine the overall difference, and SNK test was used to determine statistical significance between groups. Probability values <0.05 were considered statistically significant. Linear regression analysis was used to test for the correlations between the TNF-a protein production and LVEDd. ResultsGlobal parametersAfter 4 weeks, there were 10, 12 and 12 rats in Sham, MI-C and MI-S group respectively. There are no significant differences in body weight and lipidemia among three groups. But heart weight and heart/body weight are significantly higher in MI-C group (P<0.01), those in MI-S group markedly reduced (P<0.05) compare with MI-C group.Echocardiographic studiesCompared with sham group, there was significant increased LVEDd (P<0.01), decreased EF and FS (P<0.01) in MI-C and MI-S group. Compared with MI-C group, LVEDd significantly decreased in MI-S group (P<0.01), while EF and FS markedly increased (P<0.01).Hemodynamics analysisIn MI-C and MI-S group, LVEDP significantly increased (P<0.01), while SBP, DBP, LVSP and +/-dp/dt max markedly decreased (P<0.01), and HR did not change compared with sham group (P>0.05). Compared with MI-C group, LVEDP significantly decreased in MI-S group (P<0.01), +/-dp/dt max significantly increased (P<0.01), while SBP, DBP and LVSP had no significant differicence (P>0.05).MMPs gene expression and activity changesCompared with sham group, MMP-2 and MMP-9 gene expression and activity in MI-C and MI-S group markedly increased (P<0.01), MI-S group displayed significant reductions in MMPs gene expression and activity compared with MI-C groupMyocardial TNF-a gene expression and protein productionIn MI-C and MI-S group, TNF-a mRNA expression and protein production markedly increased (P<0.01). Compared with MI-C group, MI-S group displayed significant reductions in both TNF-a mRNA and protein expression (P<0.01).Type I collagen production by immunohistochemistryQuantitative image analysis indicated increased production of type I collagen in non-infarcted area of MI-C and MI-S rats compared with sham rats (P<0.01). Simvastatin treatment could significantly attenuate collagen deposition compared with MI-C rats (P<0.01).Correlations between TNF-a protein production and LVEDdLinear regression analysis indicated that TNF-a protein level correlated positively with LVEDd (MI-C group: r=0.83, i><0.01; MI-S group: r=0.84, P<0.01). ConclusionsEarly simvastatin treatment can attenuate the expression of MMP-2,-9 and type I collagen production in the non-infarcted myocardium, improve left ventricular remodeling and cardiac function in the rats after AMI. The underlying mechanism partially involve in the reduction of the expression of TNF-a, independent of plasma lipids regulating effect.