| Part 1Establishment of ischemic heart disease animal model and full quantitative dynamic evaluation by CMR.Background:A large animal model of chronic coronary artery disease(CAD)is crucial for the understanding the underlying pathophysiological processes of chronic CAD and consequences for cardiac structure and function.The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a swine model and to evaluate the changes of myocardial structure,myocardial motility,and myocardial viability during coronary stenosis.Materials and Methods:A total of 30 swine(including 24 experimental animals and 6 control)were enrolled.The chronic ischemia model was constructed by using Ameroid constrictor in experimental group.The 24 experimental animals were further divided into 4 groups(6 animals in each group)and were sacrificed at 1,2,3 and 4 weeks after operation for pathological examination,respectively.Cardiac magnetic resonance(CMR)was performed preoperatively and weekly postoperatively until sacrificed.CMR cine images,rest/adenosine triphosphate(ATP)stress myocardial contrast perfusion and LGE were performed and analyzed.The rest wall thickening(WT)score was calculated from rest cine images.The MPRI(myocardial perfusion reserve index)and MPR(myocardial perfusion reserve)were calculated based on rest and stress perfusion images.Pathology staining including triphenyltetrazolium chloride,HE and picrosirus red staining were performed after swine were sacrificed and collagen volume fraction(CVF)was calculated.The time to formation of ischemic,hibernating,and infarcted myocardium was recorded.Results:In experimental group,from 1w to 4w after surgery,the rest WT score decreased gradually from 35.2±2.0%,32.0±2.9%to 30.5±3.0%and finally 29.06±1.78%,p<0.001.Left ventricular ej ection fraction was also impaired during modeling(58.9±12.6,56.3±10.1,55.3±9.0,53.8±9.9,respectively).And the MPR and MPRI also decreased stepwise with extent of surgery time(MPRI dropped from 2.1±0.4,2.0±0.2 to 1.8±0.3 and finally 1.7±0.1,p=0.004;MPR dropped from 2.3±0.4,2.1±0.2 to 1.9±0.4 and finally 1.8±0.1,p<0.001).Stronger associations between MPR,MPRI and CVF were paralleled lower wall thickening scores in fibrosis-affected areas.The ischemic myocardium was first appeared in the first week after surgery(ten segments),hibernated myocardium was first appeared in the second week after surgery(seventeen segments).LGE was first appeared in eight swine in the third weeks after surgery(16 segments).At 4w after surgery,average 9.6g scar tissue was found among 6 swine.At the same time,histological analysis established the presence of fibrosis and ongoing apoptosis in the infarcted area.Conclusion:Combing myocardial motion and stress perfusion have the capability to accurately identify the progress of chronic myocardial ischemia.Part 2Evaluation of ischemic myocardium,hibernating myocardium and infarcted myocardium by stress T1 mapping without contrast enhancementBackground:Early and accurate detection of ischemic myocardium and hibernating myocardium is essential for the treatment of coronary artery disease(CAD).We aim to evaluate the value of CMR stressT1 mapping in detecting ischemic myocardium,hibernating myocardium and infarcted myocardium in a mini-swine model,by using pathology as gold standard.Materials and Methods:Twelve adult male Chinese mini-swine with the induction of coronary artery stenosis by ameroid constrictor and six control swine were enrolled.CMR T1 mapping and perfusion images with both rest and adenosine triphosphate(ATP)stress,and late gadolinium enhancement image were performed at baseline and 4 weeks postsurgery.Pathological staining including TTC staining,HE staining,Masson staining,Picrosirius staining and CD31 staining,and electron microscopy,was used as the gold standard,and the accuracy of T1 mapping was analyzed by ROC analysis.Results:In experimental group,the T1 reactivity of infarcted myocardium(ΔT1=8.5±2.4 ms,δ T1=0.6±0.3%),hibernating myocardium(ΔT1=10±2 ms,δT1=0.8 ±0.5%)and ischemic myocardium(ΔT1=10±2ms,δ T1=0.9±0.2%)of the significantly lower than the remote myocardial(Δ T1=53±7 ms,δT1=4.7±0.6%)and normal myocardium(ΔT1=56±11ms,δT1=4.9±1.1%).ROC analysis showed that ΔT1 had high diagnostic value in detecting ischemic myocardium,and the area under curve(AUC)was 0.84(P<0.001).The value of rest T1 in the diagnosis of myocardial infarction was higher(AUC=0.95,P<0.001).When rest T1 and ΔT1 were combined,the diagnostic efficacy of ischemic and infarcted myocardium was improved(AUC of 0.89 and 0.97,respectively,P<0.001).Using pathology as the gold standard,ROC analysis showed that the AUC of ΔT1(AUC=0.828)and δT1(AUC=0.827)was slightly higher than that of LGE(AUC=0.797)in detecting hibernating myocardium,and much higher than that of restTl and stressT1(AUC=0.631 and 0.685),both of which with p<0.05.The collagen volume fraction was correlated with ΔT1,δT1,δECV(r=-0.697,-0.701,-0.504,respectively,P<0.05).Conclusions:Using histopathologic validation in a swine model,non-invasive CMR stressT1 mapping has been proved high accuracy in detecting ischemic,hibernating and infarcted myocardium,without the need of contrast agents.Part 3Establishment of hypertension animal model and full quantitative dynamic evaluation by CMR.Objective:To combine cardiac magnetic resonance-feature tracking(CMR-FT)and T1 mapping to evaluate the changes in cardiac structure,function,and myocardial tissue characteristics in the early stages of hypertension using pathology as the gold standard.Materials and Methods:Eight healthy Chinese male miniature pigs aged 6-12 months were included in the prospective study.In the hypertension group(n=6),the left renal artery was ligated to obtain a chronic hypertension model,while the control group(n=2)did the laparotomy without ligation(Following the "3R" principle of animal research,this control group is shared with the first part).The two groups underwent cardiac MRI at baseline and 6 months after modeling.Strain,strain rate and cardiac function parameters were calculated by cine MRI and late gadolinium enhancement(LGE)was performed.After the second MRI,the animals were sacrificed for TTC staining and hematein eosin(HE),Masson and Picrosirius staining.Results:the mean systolic/diastolic blood pressure increased gradually from 102/71 mmHg to 145/86mmhg during 6 months after modeling.There was no significant difference in left ventricular ejection fraction between different periods of hypertension(P=0.34).No LGE was found in the baseline and 6 months after modeling.In the hypertensive group,the radial strain(RS),longitudinal strain(LS),circumferential early diastolic strain rate(CSRE)and the longitudinal early diastolic strain rate(LSRE)were significantly decreased(p<0.05).HE,Masson and Picrosirius staining sections showed obvious interstitial fibrosis in myocardium 6 months after modeling.There was a good correlation between CVF and RS(r=-0.61,p=0.03).Conclusion:CMR-FT is more sensitive than ejection fraction in assessing the degree of impaired cardiac function in early hypertension.Strain and strain rates can sensitively reflect the decrease in left ventricle function before the occurrence of cardiac dysfunction and LGE,and this change is associated with increased cardiac interstitial fibrosis.Part 4Evaluation of hypertensive heart disease based on CMR T1 mapping and ECVBackground:Recent studies have shown that extracellular interstitial fibrosis plays an important role in left ventricular hypertrophy in hypertension.We aim to quantitatively evaluate the dynamic changes of extracellular volume(ECV)and native T1 in hypertensive swine over time using histology as gold standard.Materials and Methods:Eighteen hypertensive(hypertension group)and six normal(control group)swine aged 6-12 months were studied.Both groups underwent cardiac MBI including pre-and post-contrast T1 mapping,and late gadolinium enhancement imaging(LGE)at three time points:baseline,1 month-and 3 months-after hypertensive model induction.The LV function was also calculated using the cine images.Animals were put to execution after the last examination of MRI.Histopathologic examination of heart was performed later.Analysis of the relationship between strain,ECV,and native T1 was carried out by Pearson’s correlation and linear regression models.Results:The mean systolic/diastolic pressure were increased from 111/68mm Hg to 160/97mmHg over 3 months during developing hypertension(p=0.03,0.02,respectively).There was no LGE detected at three imaging times.The ECV and native T1 value of myocardium in the hypertension group increased over 3 months(ECV:increased from 21.5±4.4%to 27.3±5.4%;Native T1:increased from 1056±32ms to 1218±66ms,mean±SD,all p<0.001).The collagen volume fraction(CVF)was calculated and correlated with ECV(r=0.63,p=0.01)and native T1(r=0.80,p<0.001).Conclusions:Native T1 and ECV correlated significantly with the CVF,reflecting early myocardial interstitial fibrosis exist in hypertensive heart disease.As the hypertensive progresses,the value of ECV fraction and T1 native increases. |
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