Effects Of Trimetazidine And Ramipril On Myocardial Fibrosis In Rats With Chronic Heart Failure

Recent studies show that myocardial fibrosis is the commonpathological changes in a variety of heart disease, is one of the mainperformance of the ventricular remodeling. Trimetazidine（TMZ) is apiperazine derivatives.With improved myocardial metabolism,relievemyocardial ischemia,improve the myocardial contractility force andreduce infarction size,and so on.Achieved good efficacy in clinicalapplications.But its efficacy is the same whether ACEI combination ofboth drugs and the efficacy of treatment is called cornerstone CHF needsfurther research. This study was to explore in the same conditions throughthe expression of transforming growth factor beta1and collagen typeI,comparing trimetazidine and ramipril alone and combined ofmyocardial fibrosis of chronic heart failure rats.Objective:The model of myocardial fibrosis in rats with chronic heart failurewas established by abdominal aortic constriction, from cellular andmolecular level to observe the expression of TGF-β1and type I collagenin the myocardium of rats with heart failure, investigate trimetazidine andramipril alone or combined application effect on myocardial fibrosis inrats with chronic heart failure by immunohistochemiscal staining andRT-PCR.Methods:1Randomly drawing10rats from60male Wistar rats assham-operated group (sham group), and the others were made chronicheart failure model by abdominal aortic constriction, and the leftventricular end diastolic pressure (LVEDP)≥15mmHg was taken asstandard. When the chronic heart failure model was successfully established, residues were randomly divided into4groups, the modelgroup, trimetazidine group, ramipril group, Combination group（trimetazidine＋ramipril）,and10rats in each group. The rats of thesham group were operated in the same way as others, except for no aorticconstriction.2To observe the end of all groups,Hemodynamic parametersLVEDP and the maximum change rate of left ventricular pressure riseand fall (±dp/dtmax) were detected by multi-lead electric physiologicalinstrument, and taken the left ventricle to calculation the left ventricularmass index (LVMI).3By HE and Masson staining to observe pathological changes ofleft ventricular myocardial tissue, simultaneous detection of myocardialcollagen volume fraction.4Ultrastructure of left ventricular myocardium of rats in the TEMobservation.5By SP immunohistochemical staining to detect the expression ofTGF-β1and type I Collagen protein in left ventricular myocardium ofrats.6To detect the level of TGF-β1and type I Collagen mRNA in left ventricular myocardium by RT-PCR.Results:1Hemodynamics parameters are as follows: The±dp/dtmaxinSham group, model group, trimetazidine group, ramipril group,Combination group （trimetazidine＋ramipril） were(5330.63±121.82)mmHg/s�'�（4306.79±134.66） mmHg/s,m(4164.84±57.34)mmHg/s�'�(2896.17±72.91)mmHg/s,(4784.03±81.43)mmHg/sand (3364.30±103.78)mmHg/s,(4856.88±75.27)mmHg/s and (3430.47±148.11)mmHg/s,(5042.14±112.02)mmHg/s and (3993.86±70.47)mmHg/s；The LVEDP in Sham group, model group, trimetazidinegroup, ramipril group, Combination group（trimetazidine＋ramipril）were(6.15±0.60)mmHg,(16.97±0.58)mmHg,(9.69±0.17)mmHg、 (9.35±0.27)mmHg,(7.89±0.51)mmHg.Compared with Molel group, the±dp/dtmaxand the LVEDP were increased; increased in Trimetazidinegroup,Ramipril group and Combination group, but there were nosignificant difference between Trimetazidine group and Ramipril group(p﹥0.05).Specially in Combination group (p <0.01).2HE staining: In sham group, myocardial cell structure clear,anddense connections. In model groups, myocardial cells loose structure,fracture, disorganized.Drug intervention group had a significantlyimproved, the combined treatment group the most significant change.Masson staining: in sham group, there was not collagen deposition. Formodel groups, a lot of collagen deposition around the myocardial cellsand blood vessels. The drug intervention groups were seen a smallamount of collagen deposition,and the combination group was the least.3The LVMI and CVF in Sham group, model group, trimetazidinegroup, ramipril group, Combination group（trimetazidine＋ramipril）were(2.10±0.12)‰,(8.54±0.72)%;(4.76±0.25)‰,(31.92±0.99)%,(3.07±0.15)‰,(18.06±0.60)%;(2.93±0.24)‰,(17.35±0.65)%;(2.57±0.21)‰,(12.10±1.31)%. Compared with the model group, trimetazidine group, ramiprilgroup and combined treatment group,CVF and LVMI decreasedsignificantly (P<0.01), the combined treatment group the most significantchange (P <0.01).4Each group of left ventricular myocardial ultrastructure of rats：sham group cardiac muscle cells in normal visible nodules, arranged inneat rows. The structure of mitochondria and filaments were integrated.Stromal cells in a small amount of collagen fibers attached to fine fibersmajority. Model group muscle wire fracture, arranged disorder loose,muscle membrane of mitochondria plexiform gathered, higherdensity.Increased electron density matrix between crest, mitochondriavacuoles, membrane rupture, endoplasmic reticulum expansion, part ofthe muscle cell disruption, interstitial collagen fibers in the mixed net-likealternate between myocardial cells, drug intervention groups were significantly reduced. The combination was the weakest.5TGF-β1and type collagen I expression by Immunohistochemicalin each group of left ventricular myocardial tissue:Sham group showed nopositive reflection, model group showed a strong positive reaction,andcould see a lot of brown particles,drug intervention groups weresignificantly reduced. The combination was the weakest.6The mRNA level of TGF-β1and type collagen I by RT-PCR ineach group of left ventricular myocardial tissue: of rats:Compared thesham group, the mRNA level of TGF-β1and type collagen I in modelgroups increased obviously (P<0.01), compared with the model group,the mRNA level of TGF-β1and COL-I in trimetazidine group, ramiprilgroup and combined treatment group,the differences were obvious (p<0.01).Compared with the trimetazidine group and ramipril group,Aboveindexes improved were no significant difference(p﹥0.05).Especially,inthe combination group (p <0.01).Results:1Trimetazidine can effectively inhibit myocardial fibrosis in ratswith CHF.2Trimetazidine against CHF myocardial fibrosis in rats and ramiprilbasic same, and both have synergy.