| PrefacePost -myocardial infarction (MI) remodeling can importantly affect cardiac function and the prognosis for survival. Both cardiac renin - angiotensin - aldo-sterone system (RAAS) and cytokine tumor necrosis factor - alpha (TNF - α) are activated after MI. Recent data demonstrated a significant interaction between the cardiac RAAS and TNF - a in the remodeling heart after MI, which might play an important role in the development and progression of ventricular remodeling. Contribution of cardiac TNF - a to ventricular remodelling is catching more and more attention , thereby, acting as a potential target for the treatment.The cardiac benefits of AT1 receptor antagonist may be mediated in part through blockading the overexpression of cardiac Ang II , in turn decreasing adverse effects of cardiac Ald and TNF - α.In the present study ,we determined cardiac Ang II , Aid contents and the expression of TNF - α in MI rats, and investigated the effect of a selective, non - peptide AT1 receptor antagonist— varlsartan on ventricular remodeling as well as its effect on cardiac RAAS and the expression of cytokine TNF - α.Materials and methods50 healthy female Wistar rats were randomly divided into 3 groups. In experimental group and control group , each respectively had 20 rats. A left thora-cotomy was performed in the fourth intercostals space, and the pericadium wasopened with the ligation of the left coronary artery . All experimental rats received valsartan solution 15mg/kg/d in one milliliter tap water by intragastric administration. In sham - operated group, 10 rats were treated in the same way as previously described except for coronary ligation. 28 days after surgery, all rats were killed. The hearts were excised and then the LV , including the septum was cut into two parts from apex to base. The apex of each heart was immersed in 4% paraformaldehyde in phosphate - puffered saline for more than 24 hours. Subsequently , the heart was embeded in paraffin. Transverse serial sections 5 μm thick were cut. HE staining observed the changes of left ventricular structure, Rats with less than 20% of infarct size were excluded from analysis. VG staining was used for the determination of noninfarcted myocardial collagen volum factor and TNF - α was examined with immunohistochemical method. The remaining noninfarcted myocardium was cut and stored at -70℃ for cardiac Ang II and Ald contents by using radioimmunoassay . All the results were scanned and semi - quantitatively analyzed by computer. SPSS 11.5 software was adopted to examine all values.Results1. Within 24 hours of operation ,21 rats died,with 9 in control group, 10 in experimental group and 2 in sham - operated group. Thus, operative mortality was 42%. Three of twenty - nine rats were dead during the post - MI 7 - days treatment,with 2 in control group, 1 in experimental group. The reasons of death were uncertain. The total mortality was 48%.2. Morphometric analysis with HE staining:Left coronary artery occlusion produced myocardial infarction. Rats with less than 20% of infarct size were excluded from analysis. In the end ,21 rats were analysed, with 6 in control group,7 in experimental group and 8 in sham -operated group. The infarct sizes were similar for experimental and control group ( P > 0. 05 ). The left ventricular transverse diameter of the control group was markedly increased compared with sham - operated rats ( p < 0. 001). The change on the rats treated by valsartan was less than that of control group (P <0.05).3. Morphometric analysis with VG staining:Collagen proliferation obviously increased much more in control group than that in sham - operated group( p < 0.001). but after the treatment with valsartan it decreased more than that in control group ( p < 0.05 ).4. Staining of TNF - a in noninfarcted myocardium with immunohischemical method :The location of TNF - a was mainly cardiac interstitium. The expression of this cytokine was not confined to the infarct or peri - infarct zones but also could be detected in cardiac myocytes within the noninfarcted myocardium . The tissue from the sham - operated groups exhibited weak expression of TNF - α The expression of TNF - α increased both in experimental and control group. In control group , the expression of TNF - a is the most significant. Moreover, optical density values in control group were the highest among all of the three groups (TNF - α, vs experimental group, p < 0. 05; vs sham - operated group, p < 0.001).5. Determination of noninfarcted myocardial Ang II, Ald content by using radioimmunoassay :Ang II,Ald contents in noninfarcted myocardium obviously increased much more in control group than that in sham - operated group ( p < 0.05-0.001), but after the treatment with valsartan it decreased more than that in control group (p < 0.05-0.001).DiscussionPost - myocardial infarction ( MI) remodeling is a complex process involving biochemical, structural and geometric changes. Meanwhile, it affects the in-farcted and noninfarcted zone of left ventricle. Recent data demonstrated a significant interaction between the cardiac RAAS and TNF - α in the remodeling heart after MI,which might play an important role in the development and progression of ventricular remodeling. Cardiac Ang II plays an important role in ventricular remodeling. The most Ang II effects related to remodeling involve activation of the type 1 receptor ( ATI). Ang E and aldosterone can stimulate exces-sive accumulation of collagen within the cardiac interstitium. In previous studies , TNF - a upregulation has been showed after infarction in areas of the myocardium where LV dilation and wall thinning are occurring. TNF - α - induced changes in LV structural remodeling were accompanied by a loss of myocardial fibrillar collagen in the myocardium, consistent with a TNF - α - induced increase in MMP expression. TNF - α has been shown to contribute to ongoing cell loss in the heart through stimulation of apoptosis. ATI receptor upregulation induced by aldosterone and TNF - α enhances Ang II - mediated cardiac fibro-blast resposes that favor fibrosis.The cardiac benefits of ATI receptor antagonist may result not only from diminished ATI receptors, but also from increased stimulation of growth - inhibitory Ang II type 2 receptors. The effect of ATI receptor antagonist on the cardiac RAAS and expression of TNF - α of the infarcted heart is uncertain.Therefore, the aim of the present study was to investigate the effect of val-sartan on ventricular remodeling, and to evaluate whether the effects of varlsar-tan on cardiac RAAS and the expression of cytokine TNF -α are related to postinfarct remodeling. We estabilished rat acute myocardial infarction model by left coronary artery ligation and observed the effect of valsartan on cardiac RAAS and TNF - α. The major finding of this study are as follows: (1) Chronic AT1 receptor antagonist valsartan prevents ventricular dilation and fibrosis in nonin-farcted LV myocardium. (2) MI is also associated with the rise in cardiac Ang II , Ald levels, and upregulation of cardiac TNF - α, during which ventricular remodeling are ongoing.Thus these findings suggestsed an association between the rise in cardiac Ang II , Ald , TNF - a and ventricular remodeling. The beneficial effect of valsartan on ventricular remodeling after MI is related to AT1 - subtype receptor blockade, tissue Ang 1 and Aid levels reduction, and downregulation of cardiac TNF-α.Conclusion1. Ventricular remodeling happened 28 days after AMI in rats.
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