Protective Effects Of Val And Sac/Val On Radiation Induced Heart Damage

Background and Objective:Radiation therapy(RT)is currently one of the main ways to treat thoracic tumors.If the anatomical site of the tumor is adjacent to the heart,it will inevitably cause radiation-induced heart damage(RIHD).In addition,there is currently no clear and effective treatment for RIHD in clinical practice.Sacubitril/valsartan(Sac/Val)has a better curative effect than angiotensin receptor blocker(ARB)-Valsartan(Val)in animal models of myocardial infarction and heart failure(HF)patients.We hypothesize that Sac/Val is more cardioprotective than Val in the RT-induced rabbit heart injury model.This additional benefit may be related to its better inhibition of cardiac fibrosis(CF)in the RIHD model.This study intends to explore the protect effects and mechanisms of Val and Sac/Val on RIHD.Methods:Intensity modulated radiation therapy(IMRT)technology was used to construct a RIHD animal model with a single whole-heart irradiation of 20 Gy.Twenty-four New Zealand rabbits were randomly divided into 4 groups,6 in blank control group(Control),6 in IMRT group,6 in IMRT+Val 10 mg/d group,and 6 in IMRT+Sac/Val 20 mg/d group.Control group and IMRT group were fed saline at the same time.Body weight,general condition,tumor necrosis factor-α(TNF-α),myocardium injury markers,N Terminal pro Brain Natriuretic Peptide(NT-proBNP),super oxide dismutuse(SOD)and electrocardiogram(ECG)and ultrasonic echocardiography(UCG)were tested in each group before RT and 4,6 and 8 weeks after RT.At 8 weeks after RT,one animal in each group was sacrificed and the heart tissues was collected for morphological analysis using HE and Masson staining.Western blot was used to detect the expression of Smad 3 protein in the heart tissue.Results:1.Compared with control group,the ventricular rate began to slow down 4 weeks after RT in IMRT group and IMRT+Val group,and there was no significant change in IMRT+Sac/Val group before and after RT.2.Compared with control group,R wave amplitude decreased in IMRT group 4 weeks after RT,and the amplitude decreased significantly at 6 and 8 weeks after RT(all P<0.05).Compared with IMRT group,R wave amplitude of IMRT+Val group and IMRT+Sac/Val was not significantly reduced at 4 weeks after RT,and IMRT+Sac/Val group gradually increased at 6 weeks after RT.IMRT+Sac/Val group was significantly higher than that in IMRT+Val group at 8 weeks after RT(P<0.05).3.Compared with control group,IMRT group had significant T wave depression 6 weeks after RT(P<0.01),IMRT+Sac/Val group was less depressed than IMRT+Val group.T wave depression in IMRT+Val group was more obvious than that in IMRT+Sac/Val group in 8 weeks after RT(P<0.05).4.Compared with control group,different degrees of pericardial effusion occurred in each RT group 8 weeks after RT.Compared with IMRT group,the degree of pericardial effusion in IMRT+Val group and IMRT+Sac/Val group was reduced and the number of rabbits with more pericardial effusion was less.5.The left ventricular ejection fraction(LVEF)of IMRT group was significantly lower than that of control group at 6 weeks after RT(P<0.05).LVEF of IMRT+Val group and IMRT+Sac/Val group began to decrease at the 6th week after RT,and was significantly lower than that of control group at the 8th week after RT(all P<0.01).At 8 weeks after RT,LVEF in IMRT+Sac/Val group was significantly higher than that in IMRT group and IMRT+Val group(all P<0.01).6.There was no significant difference in the left ventricular end diastolic diameter(LVDd)of the four groups within 6 weeks after RT(all P>0.05).Eight weeks after RT,LVDd of IMRT group was significantly larger than that of control group(P<0.05),and LVDd of IMRT+Sac/Val group was significantly smaller than that of IMRT+Val group(P<0.01).7.TNF-α in IMRT group,IMRT+Val group,IMRT+Sac/Val group began to increase at 4 weeks after RT,and TNF-α in IMRT+Sac/Val group decreased compared with IMRT+Val group at 8 weeks after RT(P<0.01).8.cTnI and BNP gradually increased in IMRT group,IMRT+Val group and IMRT+Sac/Val group at 4 and 6 weeks after RT,while there was no significant increase at 8 weeks after RT in that of IMRT+Val group and IMRT+Sac/Val group(all P>0.05).9.SOD of IMRT group,IMRT+Val group and IMRT+Sac/Val group gradually decreased 4 weeks after RT.Compared with IMRT group,IMRT+Val group and IMRT+Sac/Val group increased significantly after 8 weeks(all P<0.05),there was no significant difference in SOD between IMRT+Val group and IMRT+Sac/Val group(P>0.05).10.Compared with control group,expression level of Smad 3 protein in IMRT+Sac/Val group 8 weeks after RT was significantly lower than that in IMRTH+Val and IMRT groups(all P<0.01).11.HE staining showed that IMRT group had increased inflammatory cells and interstitial edema 8 weeks after RT,while IMRT+Sac/Val group had reduced inflammatory cell infiltration,hyperemia,edema and necrosis.12.Masson staining showed that myocardial collagen fibers were significantly proliferated in IMRT group,and significantly decreased in IMRT+Sac/Val group.