Serum Metabolic Profiling Of Different Vascular Endothelial Function Under The Predicted Cardiovascular Risk Classification

ObjectiveThis study was aimed to evaluate the relationship between Framingham risk scores(FRS)and brachial artery blood flow-mediated dilation(FMD),and further explore the serum metabolic profiling of the different status of vascular endothelial function based on the predicted cardiovascular risk classifications,increasing an understanding of the underlying mechanisms for the early pathological changes of cardiovascular system from a metabolic standpoint.MethodsIn this study,a convenience sampling method was used to recruit residents in Rongan County and Rongshui County,Guangxi.Information of sociodemographic factors,smoking history,drinking history,physician diagnosis of disease,as well as use of medication were collected by a self-reported questionnaire.And the height,weight,blood pressure,and FMD of the subjects were measured during the physical examinations.Blood samples of the study subjects were collected to measure the serum glucose,serum total cholesterol,serum high-density lipoprotein cholesterol,serum low-density lipoprotein cholesterol,serum triglyceride,and serum C-reactive protein.A total of 680 subjects without cardiovascular disease(CVD)were included,and the basic characteristics of the subjects were described according to the low,medium and high classification of FRS,and the linear dose-response relationship between FRS and FMD was analyzed using multiple linear regression.Second,according to the combination of low,middle and high classification of FRS and bad,general and good of endothelial function states,we selected 103 subjects based on the balanced of age and gender.The specific grouping was as follows: group A: subjects has low FRS and better vascular endothelial function(n=30),group B: subjects has high FRS but better endothelial function(n=25),group C: subjects has low FRS but endothelial dysfunction(n=30),group D: subjects has high FRS and endothelial dysfunction(n=18).And we set group CVD: this group was consisted with 12 CVD patients to verify the reliability of this experiment.Group A as a control,and the other four groups were compared with it for metabolic profiling detection.Combined with principal component analysis(PCA),orthogonal partial least squares-discriminant analysis(OPLS-DA)and t test,the differential metabolites were found among the comparison groups.Third,according to the differential metabolites,we further searched for relevant metabolic pathways.In addition,ROC curves were used to analyze the distinguishing ability of differential metabolites for each comparison group.Results1.A total of 680 subjects were included in the study,with an mean age of 54.4±10.4 years.The median FMD and Framingham risk scores were 8.7% and 8.9%,respectively.Multiple linear regression analysis of the linear dose-response relationship between FRS and FMD showed that FMD of subjects in the Framingham high-risk score were decreased by 15%(95% CI: 3%-26%)compared with the Framingham low-risk score,and there was a linear dose-response relationship between the Framingham risk score and FMD in this model(linear trend P = 0.01).2.A total of 115 subjects were used for metabolic analysis,including 30 subjects in group A,with a mean age of 55.3±6.0 years,a median FMD of 12.2%,and a median FRS of 5.5%..25 subjects in group B,with a mean age of 59.4±6.3 years,a median FMD of 11.1%,and a median FRS of 27.7%.30 subjects in group C,with a mean age of 55.9±6.2 years,a median FMD of 4.4%,a median FRS of 5.3%.And 18 subjects in group D,the mean age was 58.4±7.9 years,the median FMD was 4.8%,and the median FRS was 27.2%.And 12 subjects in the E group,with a mean age of 63.1±9.7 years,and the median FMD was 9.9%.The current number of smokers,BMI,systolic blood pressure,heart rate and the levels of blood lipid,CRP and eGFR were different among the groups.3.Compared with group A,metabolic profile analysis showed that the contents of 7 metabolites such as tagatose increased(Fold change >1)and the contents of 10 metabolites such as galacturic acid decreased(Fold change <1)in group B.And the area under the ROC(AUC)was above 0.650 for each differential metabolite.The contents of 9 metabolites such as thymol increased,and the contents of 13 metabolites such as tryptophan decreased,and the AUC of each differential metabolite were Above 0.620 in group C.The contents of 6 metabolites such as 2-pentanone increased,and the contents of 11 metabolites including 3-aminoisobutyric acid decreased in group D,and the AUC of each metabolite were above 0.640.In the CVD group,the urea content increased,and the contents of 12 metabolites such as lactic acid decreased,and the AUC of each differential metabolite were above 0.680.4.Metabolic pathway analysis showed that 3 differential metabolites compared with group B and group A were enriched in galactose metabolism;8 different metabolites compared with group C and group A were enriched in 4 pathways.That is,pyrimidine metabolism,pantothenic acid and CoA biosynthesis,nitrogen metabolism and methyl butyrate metabolism;five differential metabolites compared with group D and group A were enriched in two pathways,namely pyrimidine metabolism and starch and sucrose metabolism;9 differential metabolites between CVD group and Group A were enriched in seven pathways: pyrimidine metabolism,alanine,aspartate and glutamate metabolism,pyruvate metabolism,starch and sucrose metabolism,and aminoacyl-tRNA Biosynthesis,arginine and valine metabolism,and D-glutamine and D-glutamate metabolism.The combined diagnosis of the differential metabolites involved in the abnormal metabolic pathways associated with each of the control groups had an AUC value between 0.734 and 1.000,and the AUC values did not change significantly after adjustment for age and sex in the model.Conclusion1.In this study,the increased FRS was associated with the decreased of endothelial function.Metabolomic analysis can screen out serum metabolites associated with increased FRS and vascular endothelial dysfunction,and can also be useful in identifying serum metabolites associated with protected endothelial function in the condition of high FRS,as well as associated with impaired endothelial function in the condition of low FRS2.In the process of promoting endothelial dysfunction by high FRS involves in the changes of pyrimidine metabolism,starch and sucrose metabolism.Changes in galactose metabolism may be related to endothelial protection in high FRS conditions.And in the low FRS condition,Changes in pantothenate and CoA biosynthesis and methyl butyrate metabolism may be related to the promotion of endothelial dysfunction.