Effects Of Long-term Combination Therapy With Carvediol, Captopril And Spironolactone On Cryoinjury Size And Cardiac Function In A Rat Model Of Acute Myocardial Cryoinjury

Objective: currently, coronary artery disease is the leading cause of congestive heart failure(CHF). With coronary artery disease progress, acute myocardial infarction often occurs. Larger area of myocardiac infarction often results in ventricular remodeling and leads to left ventricular systolic and diastolic dysfunction. As the disease progresses, the patients will present with heart failure specific symptoms and suffer congestive heart failure. In the process of heart failure, the activation of neurohormonal system plays an important role. Thus, inhibition of neurohormonal system is very important in suppression ventricle remodeling and prevention of heart failure. Many large scale clinical trials have confirmed that the inhibition of neurohormonal system could delay ventriclular remodeling and prevent heart dysfuntion. In our clinical practice, we found the combination use of the above three drugs could significant improve the patients symptoms and even reverse ventricular remodeling in some patients. Thus, we designed this study to observe the effects of combination therapy with carvedilol, spironolactone and captopril on the hemodynamics in rats with myocardial infarction, and discuss the undrlying mechanisms.Methods: 100 male wistar rats weighting about 200g were used in our study. The heart was exposed through a 1.0- to 1.5-cm left lateral thoracotomy. Cryoinjury of the LVFW was performed with the use of an round copper probe 6-mm in diameter cooled to -190℃by immersion in liquid nitrogen for five minutes. It was applied to the LVFW in extension for 5 seconds and then closed thoracic cavity immediately. When the rats'breathing restored, we repeatedly cryoinjuried the LVFW in situ to ensure a transmural cryoinjury according to the protocol.The rats survived after 24 hours were randomized into four groups :①sham group (n=12);③AMI group (n=16)⑤captopril+carvedilol group (n=16)⑥captopril+carvedilol+ sprinolcatone group (n=12). Treatments were given to all groups 24 hours after operation. The detailed dosage was as follows. Carvedilol (5mg/kg), captopril (25 mg/kg), and sprinolaction (20 mg/kg). All the drug was dissolved in water and given through gastric tube (2ml/rat), whereas the controlgroup was given equal volume water.We invasively evaluated the hemodynamic parameter, cardiac function, heart rate and blood pressure by catheter (American Power Lab ). We used Masson specific stain to observe collogen and transmission electron microscope to determine the struction changes (HITACHI-7500 Lectronmicroscope).Results: After 14 weeks treatment, 10 dead during the study and 50 survived at the end of study (12 in AMI, 13 in AMI + combination, 13 in AMI+capt.+car and 12in sham group) 1 Effects on injury area,aorta pressure and heart rate after 14 week treatment in AMI rats(Table.1,Fig. 4):Injury area: Compared with AMI group, The injury area in AMI+combination group and AMI+ captopril +carvedilo group was smalle(rP<0.05). However, Compared with AMI+ captopril +carvedilo group, the injury area of AMI+combination is even smaller(P<0.05).2 Effects on systolic function after 14 weeks treatment in AMI rats(Table.2,Table3):Compared with sham group, there was no sginificant difference in systolic pressure ( P>0.05 ) between AMI+combination group and sham group. However, systolic pressure in the other two groups was significantly lower when compared with AMI+combination group(P<0.05). 3.Effects on diastolic function after 14 weeks treatment in AMI rats (Table.4):3.1 Compared with AMI group, the LVEDP in AMI + CAPT + CARV group and AMI + combination group was lower (P<0.05)3.2 The -dp/dt in AMI + combination group was higher than those in other two groups (p<0.05), indicating the diastolic function was improved.3.3 Compared with sham group, the IVRT of AMI group islonger, there was no statistical difference between AMI+combination group and sham group(P>0.05, the IVRT in AMI +combination was significantly shorter than those in other two groups(P<0.05), suggesting the diastolic function was improved.4 the relation of myocardial infarction size and LVSEP (n=38,r=-0.45,p<0.01, LVSP=152.34-1.33AERA). (fig.2)5 the relation of myocardial infarction size and -dp/dt (n=38,r=-0.49, p<0.01, dp/dtmin=6930.1-79.02 AREA). (fig.1)6 The plot of myocardial infarction size and T.(n=38,r=0.41, p<0.05,T=6.46+0.19AREA)(fig.3)Conclusions: Combination use of captopril,carvedilol and sprinolcatone could improve blood circulation function in AMI rats, rise LVSP, lower LVEDP, improve blood hemodynamics, improve diastolic function and systolic function, reduce myocardial necrosis size and inhibit ventricle remodeling. Combination use the three drugs had more efficacy in the treatment of AMI.