| Background and ObjectiveCurrently chronic heart failure(CHF) has become one of the major diseases which impair human's health. According to the present research myocardial remodeling is considered as the basic outbreak mechanism of heart failure. Changes of both cardiac cells and extracellular matrix(ECM) form the structural basis of myocardial remodeling. The former consists of the loss of cardiac cells and cardiac hypertrophy, while the latter is mainly composed of deposition of collagen and matrix fibrosis (namely as myocardial fibrosis, abbreviated as MF). MF is a common pathological change of many different etiological diseases when they develop to certain degree. MF is characterized by remarkably increased ECM content or collagen volume fraction (CVF). MF can result in heart failure, cardiac arrhythmias, cardiac expansion and cardiac sudden death; and it is the direct cause for many clinical events. Most recently, it has been found that some factors are closely related with the formation of MF. TGF-β1 is the essential cytokine related to MF. CTGF is a kind of cytokine which is found in recent years. It can result in organ fibrosis. By acting as the information tranduced protein of TGF-β1 CTGF can mediate the function of TGF-β1. Now CTGF is considered as one of the important factors which result in MF. Ang II, Aldosterone, TGF-β1 and ET-1 all can result in MF by increasing CTGF expression. At present CTGF is considered as a new target of anti-MF treatment. It is generally acknowledged that angiotensin receptor blocker (ARB) can ameliorate myocardial remodeling, but the specific working mechanism of ARB has not been elucidated fully. This experiment is trying: to investigate the expressions and the role of connective tissue growth factor (CTGF) and transforming growth factorβ1 (TGF-β1) in the development of myocardial fibrosis in rats with CHF; to observe the mechanism of candesartan to attenuate myocardial remodeling and myocardial fibrosis in rats with CHF; to know the role of MF in the development of CHF.Materials and MethodsAfter 1 week common fed, male Wistar rats were taken to make animal CHF model by suprarenal aortic constriction operation,then they were fed normal food for 8 weeks, Except for no aortic constriction Sham-operated rats(Sham group) were operated in the same way as the other two groups. 10 rats were randomly taken from those rats which had symptoms of heart failure to detect hemodynamic parameters,LVEDP was measured to be higher than 15mmHg,then residues were randomly divided into two groups:HF group and Drug group. Rats in Drug group were given a daily dose of 2mg/kg of candesartan for four weeks by gastric gavage and the other two groups were fed with normal saline also for four weeks. Then hemodynamic parameters of 3 groups rats were examined by multi-lead electric physiological instrument,expressions of TGF-β1 ,CTGF in myocardium were evaluated by qualitative and semiquantitative immunohistochemical staining. Masson staining was used to observe the total Collagen type in the rat's left ventricular interstitial tissue. Collagen volume fraction (CVF),Perivascular collagen area (PVCA) were measured by image analysis.Results1. After the CHF animal model was made eight weeks, the condition of rats in sham group was normal while the rats in the other two groups were in severe chronic heart failure. After 4 weeks of drug intervention, the degree of heart failure in Drug group became less severe compared with the HF group.2. After the CHF animal model was made 12 weeks, SBP, DBP, MAP of three-group rats were as follows(mmHg): sham group: 134.38±8.68, 95.38±9.24, 108.375±8.957; HF group: 119.00±10.30, 82.00±8.19, 94.33±8.80; Drug group: 115.50±10.49, 75.38±9.40, 87.42±8.30. Every index in both HF group and Drug group was lower than that in sham group (P<0.01) , while every index in the Drug group was similar as that in HF group. These data indicate that blood pressure will decrease when rats fall in heart failure; but blood pressure will slightely decrease when rats with heart failure are treated with candesartan.3. After the CHF animal model was made 12 weeks, LVEDP(mmHg),±dp/dtmax and -dp/dtmax(mmHg/s) in each group of rats were as follows: sham group: 4.63±3.58, 5553.50±542.55, 3675.50±410.00; HF group: 21.63±5.71, 4172.13±716.55, 2831.38±501.50; Drug group: 10.00±3.07, 5151.88±376.70, 3486.50±349.10. LVEDP of the sham group was lower than that of the HF group, while the index of the HF group was higher than that of the Drug group.±dp/dtmax and -dp/dtmax in the HF group were lower than that in the sham group and the index in the Drug group was higher than that in the former group (P<0.01) ,while the index in the Drug group was similar to that in sham group(P>0.05). These data show that rats in HF group were in heart failure; and the heart function of rats in Drug group was improved when treated with candesartan.4. After the CHF animal model was made 12 weeks, LVMI%, CVF% and PVCA% in each group of rats were as follows: sham group: 1.87±0.05, 3.54±0.66, 0.59±0.16; HF group: 3.01±0.12, 7.29±1.00, 2.03±0.23; Drug group: 2.16±0.11, 4.31±0.78, 0.89±0.13. The indexes of the HF group were obviously higher than those of the sham group(P<0.01), while the indexes of the candasartan group decreased greatly compared with those of the HF group(P<0.01). These data proved that more fiber tissues deposit in myocardium interstitial tissue of rats in the HF group after they formed heart failure, while degree of myocardial fibrosis was attenuated after candesartan treatment.5. Immunohistochemical examination shows that there were expressions of CTGF in both perivascular and interstitial tissue of left ventricular; while TGF-β1 mainly expressed in left ventricular interstitial tissue. CTGF and TGF-β1 factors expressed in each group as follows(mean positive values): sham group: 106.25±12.45, 93.38±9.00; HF group: 131.71±10.78, 161.00±13.63; Drug group: 117.33±11.61, 116.88±12.24. CTGF expression was lower in vessel smooth muscle in myocardium in the sham group, and its expression increased in the HF group, even in its cardiac interstitial tissue, while its expression decreased in the Drug group. The index among each group was obviously different (HF group/sham group, sham group/Drug group, and Drug group/HF group: P<0.01). TGF-β1 expression in the HF group was higher compared with the other two groups (P<0.01). These data show that CTGF and TGF-β1 expressions are related to MF; candesartan treatment can reverse MF because it decreases the expression of CTGF and TGF-β1.Conclusions1. MF may be an important outbreak mechanism of overload chronic heart failure;2. CTGF and TGF-β1 are involved in the outbreak mechanism of MF in rats with overload chronic heart failure;3. That Candesartan can attenuate myocardial remodeling probably has something to do with decreasing the expressions of TGF-β1 and CTGF;4. Selectively decreasing the expression of CTGF may be a new method to treat myocardial fibrosis. |
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