Clinical And Basic Study Of Abnormal Myocardial Glucose Metabolism Based On ¹⁸F-FDG PET Myocaidial Metabolic Imaging In Diabetes

Diabetes mellitus(DM)is a major health problem threatening the health of urban residents in China.Coronary artery disease and heart failure are common cardiac complications in diabetic patients,accompanied by obvious abnormality of myocardial metabolism,and there is still a lack of effective imaging tools.18F-FDG PET myocardial metabolic imaging(MMI)targets the metabolic process of myocardial energy substratesglucose,which is noninvasive,sensitive and quantitative.However,there are still many doubts and difficulties in the application of this technique in diabetic myocardial glucose metabolism abnormalities that have not been completely solved.For this reason,we intend to carry out the following study.Part Ⅰ Clinical study of myocardial glucose metabolism in diabetic patients without cardiovascular symptomsObjective:Diabetes mellitus is a metabolic disorder syndrome characterized by hyperglycemia,hyperlipidemia,and insulin resistance,which is the risk factor of cardiovascular disease.However,it is unknown whether abnormal myocardial glucose metabolism is present in DM patients without cardiovascular symptoms.PET myocardial dynamic imaging after hyperinsulinemic-euglycemic clamp to determine myocardial glucose metabolic rate is a classical method,but the process is relatively cumbersome.Fasting whole-body 18F-FDG PET/CT imaging is simple and easy,but the traditional view is that the 18F-FDG uptake by the myocardium is non-specific and has no clinical significance.This study intends to elucidate the changes of abnormal myocardial glucose metabolism and related influencing factors in DM patients without cardiovascular symptoms based on whole-body 18F-FDG PET/CT imaging.Methods:A total of 191 subjects without cardiovascular symptoms who required 18F-FDG PET/CT for a variety of reasons(elevated unexplained tumor biomarkers,family genetic history of tumors,history of exposure to suspected carcinogens,etc.)were retrospectively analyzed.The levels of FDG uptake in myocardium were visually divided into 4 grades(Grade 0-3,from low to high).The differences in clinical and metabolic parameters among DM,impaired fasting glucose(IFG),and normal fasting glucose(NFG)groups were analyzed,as well as their associations with myocardial FDG uptake.Results:Compared with NFG and IFG groups,DM group had more cardiovascular-related risk factors.The degree of myocardial FDG uptake was significantly decreased in DM group;when myocardial FDG uptake ≤Grade 1,the sensitivity of DM prediction was 84.0%,and the specificity was 58.4%.Univariate analysis showed that the myocardial FDG uptake was weakly and negatively correlated with multiple metabolic-related parameters(r=-0.173～-0.365,P<0.05).Multivariate logistic regression analysis showed that male,HOMA-IR and nonalcoholic fatty liver disease were independent risk factors for poor myocardial FDG uptake.By screening and adjusting for potential confounders between HOMA-IR and myocardial SUVmean,curve fitting revealed that myocardial SUVmean gradually decreased with increasing HOMA-IR,and there was an approximately linear association between the two(P=0.003).Conclusion:Diabetes is associated with decreased myocardial glucose metabolism,which is mediated by multiple metabolic abnormalities.Part Ⅱ Analysis of factors influencing myocardial glucose metabolism imaging in diabetic patients with coronary artery diseaseObjective:18F-FDG myocardial metabolic imaging is the "gold standard" for evaluating viable myocardium.The presence and number of viable myocardium are important indicators forjudging whether they can benefit from revascularization.Therefore,the success of imaging and the quality of images are essential for the accuracy of qualitative and quantitative evaluation of viable myocardium.This study intends to retrospectively analyze the influencing factors of images quality of 18F-FDG PET MMI in different populations,and provide a reference for clinical optimization of imaging process.Methods:Patients with viable myocardium evaluated by 99mTc-MIBI rest-gated myocardial perfusion imaging(GMPI)and 18F-FDG PET MMI in the Department of Nuclear Medicine of our hospital were retrospectively analyzed.According to visual analysis,the images were divided into good,moderate and uninterpretable.Univariate and multivariate logistic regression were used to analyze the influencing factors of image quality in the overall and non-diabetic coronary artery disease(CAD)population,and the key factors affecting the success or failure of imaging in the CAD population with diabetes were analyzed.Results:Of the 161 patients,grades of good,moderate,and uninterpretable were observed in 65.2%(105/161),19.3%(31/161)and 15.5%(25/161)patients,respectively.Among CAD patients with diabetes(n=52),moderate,and uninterpretable were observed in 25.0%and 28.8%patients,and only 16.5%and 9.2%in CAD patients without diabetes(n=109);the difference was statistically significant(χ2=14.370,P=0.001).By univariate and multivariate logistic regression analysis:for the overall population,body mass index(BMI,OR=1.212,95%CI:1.063～1.383,P=0.004)and diabetes(OR=4.402,95%CI:1.678～11.551,P=0.003)were independent factors for 18F-FDG PET MMI images quality;for CAD patients without diabetes,BMI(OR=1.235,95%CI:1.056～1.444,P=0.008)and insulin dose injected during blood glucose regulation(OR=1.426,95%CI:1.047～1.941,P=0.024)were independent factors for 18F-FDG PET MMI images quality;for CAD patients with diabetes,dyslipidemia(OR=12.156,95%CI:1.489～99.217,P=0.020)was the independent factor leading to 18F-FDG PET MMI imaging failure.Conclusion:The influencing factors of the success or failure of 18F-FDG PET MMI and the images quality are not completely consistent for different populations.In clinical work,we should not only follow the guidelines,but also embody the principle of individuality,maximize the imaging success rate and improve image quality to achieve accurate evaluation of viable myocardium.Part Ⅲ Feasibility and application of trimetazidine in 18F-FDG PET myocardial metabolic imaging of diabetic mellitus patients with ischemic cardiomyopathy:a prospective,self-controlled studyObjective:18F-FDG PET myocardial metabolic imaging is sometimes uninterpretable due to background activity from uncontrolled glucose homeostasis in diabetic mellitus patients.Trimetazidine is an oral medication that promotes the transformation of myocardial energy supply from free fatty acids to glucose.We aimed to investigate the feasibility and application of trimetazidine in 18F-FDG PET MMI of DM patients.Methods:Diabetic patients with ischemic cardiomyopathy serving as self-controls,the effects of trimetazidine on PET MMI image quality,myocardial viability assessment,quantitative analytical parameters,and 18F-FDG uptake of different myocardial segments were elucidated.Registration No:ChiCTR2000038559.Results:The image quality of 18F-FDG MMI was graded visually as good,moderate,and uninterpretable.After trimetazidine,grades of good,moderate,and uninterpretable were observed in 14(60.9%),8(34.8%),and 1(4.3%)patients,respectively,and in 4(17.4%),15(65.2%),4(17.4%)patients without trimetazidine.The myocardial SUV and myocardial to blood pool SUV ratio(M/B ratio)were significantly higher after trimetazidine administration than those before(3.11 ± 1.07 vs.2.32±1.00,2.67±1.41 vs.1.81±0.75,P all<0.01).6(3,7)viable myocardium segments were detected with a mismatch score of 10(6,17)after trimetazidine,significantly higher than those before trimetazidine[5(2,7)and 8(2,17),P<0.05].Meanwhile,the 18F-FDG uptake in myocardial segments with decreased and normal perfusion showed different ranges of increase(by 15.30-57.77%).Conclusion:Trimetazidine is feasible and effective in DM patients with ischemic cardiomyopathy before 18F-FDG PET MMI,which can significantly improve the image quality and increase the number of viable myocardium segments detected.Part Ⅳ Dynamic observation and preliminary mechanism of abnormal myocardial glucose metabolism in diabetes based on microPET myocardial dynamic imagingObjective:Cardiac dysfunction and heart failure are serious complications in diabetic patients and seriously affect their prognosis.There are many mechanisms to elucidate the causes of abnormal cardiac function caused by diabetes,and abnormal metabolism of myocardial energy substrates is one of the numerous mechanisms.However,how glucose metabolism(one of the myocardial energy substrates)changes during the progression of diabetes,how it is related to cardiac function,and how its underlying mechanism is currently controversial.This study intends to preliminarily elucidate the changes of myocardial glucose metabolism,the relationship with cardiac function and the preliminary mechanism in the progression of diabetes using microPET myocardial dynamic imaging.Methods:Diabetic mice(BKS-db)and their controls were used to verify and group them using myocardial histopathology(Masson staining,PAS staining,transmission electron microscopy),and the differences in myocardial glucose metabolism levels and cardiac function between each group(control group,early and advanced stage of diabetic myocardial injury)were observed using 18F-FDG microPET myocardial dynamic imaging and cardiac ultrasound to elucidate the relationship between the two;the expression of key proteins of myocardial glucose metabolism signaling pathway(GLUT-1,GLUT-4,AMPK/p-AMPK)was analyzed by Western immunoblotting to preliminarily elucidate the mechanism of abnormal glucose metabolism in diabetic myocardium.Results:The differences in myocardial Masson staining,PAS staining,and myocardial ultrastructure under transmission electron microscope between BKS-db mice and their controls at 8,12,16,and 20 weeks of age were compared,respectively.It was found that with increasing age,myocardial fibrosis was gradually aggravated,PAS-positive substance deposition was increased,and myocardial ultrastructure,especially mitochondrial injury,was aggravated in BKS-db.The experimental animals were divided into control group(BKS,n=8),w8～12 group(BKS-db,n=8,early stage)and w16～20 group(BKS-db,n=8,advanced stage).E/e’ of w8～12 group was significantly higher than that in control group(P=0.033),but there was no significant difference in LVEF(P=0.075);LVEF and E/e’ of w 16～20 group were significantly abnormal compared with control group and w8～12 group(P<0.05).The levels of myocardial glucose metabolism(MRglu,Ki,SUV)of w8～12 group or w 16～20 group were significantly lower than those of the control group(P<0.05),while there was no significant difference in w8～12 and w16～20 group.Fasting blood glucose was moderately correlated with systolic function(LVEF),diastolic function(E/e’ ratio),and myocardial glucose metabolism levels(MRglu,Ki,SUV).By adjusting fasting blood glucose,there was no significant correlation between MRglu and SUV and E/e’ ratio,with correlation coefficients of-0.327 and-0.294,respectively,and P of 0.128 and 0.174.Compared with the control group,myocardial GLUT-4 expression was significantly reduced in the w8～12 group(P=0.001),but GLUT-1 changes were not significant(P=0.788);GLUT-1 and GLUT-4 expression were significantly reduced in diabetic mice in the w16～20 group(P=0.027 and<0.001);compared with the w8～12 group,GLUT-1 was significantly reduced in the w16～20 group(P=0.045),but GLUT-4 changes were not significant(P=0.125).Myocardial MRglu,Ki,and SUV were positively correlated with myocardial GLUT-4 expression(MRglu:r=0.537;Ki:r=0.818;SUV:r=0.491;P=0.000～0.046),but not significantly correlated with myocardial GLUT-1 expression(P=0.238～0.780).Meanwhile,myocardial p-AMPK protein expression was reduced in the w8～12 group compared with the control group,but the difference was not statistically significant(P=0.115);myocardial p-AMPK protein expression was significantly reduced in the w16～20 group compared with the control group(P=0.002).Conclusion:Abnormal myocardial glucose metabolism and diastolic function may occur in the early stage of diabetic myocardial injury,and both of them are earlier than abnormal systolic function.Hyperglycemia is the key cause of abnormal myocardial glucose metabolism and cardiac function.Quantitative parameters of myocardial glucose metabolism measured by microPET were significantly correlated with GLUT-4.Inhibition of AMPK phosphorylation and decreased activity in myocardium,and decreased expression of GLUT-1 and GLUT-4 may be the underlying mechanism of reduced glucose metabolism.18F-FDG microPET dynamic imaging is an important imaging tool for monitoring myocardial metabolic remodeling in diabetes.