The Correlation Of C1q/tumor Necrosis Factor-related Protein Family With Acute Coronary Syndrome

Objective:Acute coronary syndrome(ACS),the most common critical type of cardiovascular disease,remains the leading cause of cardiovascular death worldwide.Coronary artery atherosclerosis,plaque rupture and thrombosis are speculated to be the common pathogenesis of ACS.Epicardial adipose tissue(EAT)is a fat tissue located between the myocardium and visceral layer of the epicardium,which affects the development of ACS via secreting various adipocytokines to involve in the formation of coronary atherosclerotic plaques.Clq/tumor necrosis factor-related protein(CTRP),a family of adiponectin(ADP)paralogs,including CTRP1 to CTRP15,show the highest expression in adipose tissue around the heart.Recently,increasing evidence suggests that CTRP family have a role in inflammation regulation,energy metabolism,insulin signaling,and cardiovascular disease.In the present study,we aimed to investigate the relationship between serum CTRP family and the prevalence of ACS patients,and to compare the diagnostic performance of different CTRP family members for ACS.Methods:A total of 289 eligible inpatients with suspected ACS undergoing coronary angiography(CAG)were consecutively enrolled in our study from October 2020 to December 2021.They were divided into the ACS(n=210)and Control(n=79)groups according to the diagnostic criteria of ACS.The demographics and clinical characteristics were collected by our research team.The severity of coronary artery stenosis was quantitated using the Gensini score,and the serum levels of CTRP family members(CTRP1,CTRP2,CTRP3,CTRP5,CTRP9,CTRP12,CTRP13,CTRP15),TNF-α(tumor necrosis factor-α),and ADP were measured using enzyme-linked immunosorbent assay(ELISA)kit.Receiver operating characteristic(ROC)curve analysis was used to calculate the cutoff value of CTRP family members for diagnosing ACS.Multivariate logistic regression models were constructed to evaluate the association between serum CTRP family and ACS in the general population and different subgroups.Testing for trend was used to analyze the linear trend between the serum levels of CTRP family members and the risk of ACS.Spearman correlation and Kruskal-Wallis H test were used to analyze the correlations between CTRP family members and the severity of coronary artery stenosis.Results:1.Baseline clinical characteristicsThe proportion of male,smoker,dyslipidemia,hypertension and diabetes mellitus patients was higher in the ACS group than those in the Control group[67.6%(142/210)vs.45.6%(36/79),57.1%(120/210)vs.40.5%(32/79),67.6%(142/210)vs.43.0%(34/79),60.5%(127/210)vs.41.8%(33/79),39.5%(83/210)vs.10.1%(8/79)and 37.6%(79/210)vs.13.9%(11/79),all P<0.05].2.The serum levels of CTRP family membersThe serum CTRP1,CTRP5,and TNF-α levels were significantly higher in the ACS group than in the Control group:654.50(584.00,737.50)vs.591.50(503.25,669.67)pg/mL,183.30(145.73,231.68)vs.176.88(104.65,210.28)pg/mL,391.35(330.83,440.83)vs.351.55(265.13,437.55)pg/mL,respectively(all P<0.05).The serum CTRP2,CTRP3,CTRP9,CTRP 12,CTRP13,CTRP15,and ADP levels were significantly lower in the ACS group than in the Control group:342.85(292.34,404.74)vs.382.00(337.20,453.58)pg/mL,696.50(604.75,826.25)vs.896.00(659.75,1132.25)pg/mL,119.75(102.50,135.10)vs.124.53(110.26,171.74)pg/mL,433.95(333.93,497.03)vs.468.45(390.95,565.63)pg/mL,493.05(443.75,554.75)vs.550.00(491.98,645.25)pg/mL,65.95(58.13,74.45)vs.75.83(60.76,104.08)pg/mL,1543.75(1273.88,1878.13)vs.1685.50(1482.50,2374.50)pg/mL,respectively(all P<0.05).3.ROC curve analysis of CTRP family members for diagnosing ACSThe area under the curve(AUC)of CTRP1,CTRP15,and TNF-α were 0.606[95%confidence interval(CI):0.521,0.690],0.661(95%CI:0.577,0.744),0.641(95%CI:0.553,0.729),respectively.The optimal cut-off values for the diagnosis of ACS were 642.75 pg/mL,121.80 pg/mL,285.60 pg/mL.The AUC of CTRP1 combined with CTRP5 was 0.684(95%CI:0.598,0.770).The diagnostic performance for ACS improved after values for CTRP1 and 5 were combined(all P<0.05).The AUC of CTRP2,CTRP3,CTRP9,CTRP12,CTRP13,CTRP15,and ADP were 0.810(95%CI:0.732-0.888),0.800(95%CI:0.715-0.886),0.706(95%CI:0.608-0.804),0.740(95%CI:0.643-0.837),0.794(95%CI:0.711-0.877),0.748(95%CI:0.651-0.845),and 0.704(95%CI:0.603-0.805),respectively.The optimal cut-off values for the above adipocytokines were 328.55 pg/mL,785.25 pg/mL,160.08 pg/mL,366.58 pg/mL,543.50 pg/mL,76.23 pg/mL,1479.75 pg/mL,respectively.The diagnostic performance for ACS also improved after data for CTRP2,CTRP3,CTRP9,CTRP12,CTRP13,and CTRP15 were combined[AUC:0.864(95%CI:0.798-0.929);all P<0.05].4.The correlation of CTRP family members with ACS4.1 Logistic regression analysis for the effect of CTRP family members in ACSIn logistic regression analysis,the increasing of serum CTRP1 and CTRP5 levels were independent risk factors for ACS,and the increasing of serum CTRP2,CTRP3,CTRP9,CTRP12,CTRP13,CTRP15 levels were independent protective factors for ACS.The odds ratio(OR)of above CTRP family members were 2.351(95%CI:1.304-4.236),1.756(95%CI:1.147-2.688),0.649(95%CI:0.500-0.843),0.502(95%CI:0.370-0.681),0.611(95%CI:0.458-0.816),0.730(95%CI:0.571-0.934),0.735(95%CI:0.577-0.937),0.635(95%CI:0.486-0.829),which were determined based on 1 standard deviation(1-SD)increases of serum CTRP family levels(all P<0.05).After adjusting for confounding factors in multivariate logistic regression analysis,CTRP family were independently associated with ACS.The OR of CTRP1,CTRP2,CTRP3,CTRP5,CTRP9,CTRP12,CTRP13,and CTRP15 expression levels per 1-SD increase were 2.692(95%CI:1.324-5.471),0.668(95%CI:0.471-0.947),0.350(95%CI:0.201-0.609),1.858(95%CI:1.089-3.171),0.661(95%CI:0.449-0.973),0.653(95%CI:0.468-0.910),0.716(95%CI:0.514-0.999),0.696(95%CI:0.498-0.972)(all P<0.05).4.2 Subgroup analysis for the effect of CTRP family members in ACSThe independent association between CTRP family and ACS was not significantly affected by sex(male or female),age(≥65 or<65 years),diabetes mellitus and dyslipidemia status(with or without).The CTRP3 expression level exhibited a higher protective role against ACS in male than in female patients[OR(95%CI)per 1-SD:0.355(0.215-0.586),P<0.001 vs.0.400(0.202,0.795),P=0.009,respectively;P for interaction<0.05].The CTRP5 expression level was an independent risk factor for ACS in patients without,however,not in those with diabetes mellitus[OR(95%CI)per 1-SD:1.983(1.225-3.209),P=0.005 vs.1.587(0.533-4.724),P=0.406,respectively;P for interaction<0.05].4.3 The linear trend between CTRP family members and ACSAfter adjusting for confounding factors in the linear trend test,the risk of ACS increased gradually with rising serum CTRP1 levels[OR(95%CI):T2 vs.T1:1.828(0.849-3.939),P=0.123;T3 vs.T1:3.375(1.432-7.956),P=0.005;P for trend<0.05].In contrast,the risk of ACS showed a downward trend with increasing serum CTRP2,CTRP12,and CTRP13 expression levels[OR(95%CI):T2 vs.T1:0.412(0.174-0.975),P=0.044;T3 vs.T1:0.231(0.095-0.561),P=0.001;Pfor trend<0.05];[OR(95%CI):T2 vs.T1:0.416(0.179-0.969),P=0.042;T3 vs.T1:0.174(0.075-0.403),P<0.001;P for trend<0.05];[OR(95%CI):T2 vs.T1:0.308(0.126-0.754),P=0.010;T3 vs.T1:0.120(0.049-0.293),P<0.001;P for trend<0.05].The protective role of serum CTRP3 and CTRP 15 expression for ACS exhibited a U-shaped trend(decrease before increase)with increasing levels[OR(95%CI):T2 vs.T1:1.306(0.493-3.457),P=0.591;T3 vs.T1:0.155(0.060-0.401),P<0.001;P for trend<0.05];[OR(95%CI):T2 vs.T1:1.559(0.646-3.766),P=0.323;T3 vs.T1:0.360(0.159-0.818),P=0.015;P for trend<0.05].5.The correlations between CTRP family members and the severity of coronary artery stenosisThe serum levels of CTRP1 were positively correlated,whereas those of CTRP2,CTRP13,and CTRP15 were negatively correlated with the Gensini score,the correlation coefficient r was 0.224,-0.179,-0.153,and-0.217,respectively(all P<0.05).Patients were divided into four quartiles according to the Gensini score,Q1(n=81,Gensini score ≤26.5),Q2(n=64,26.5<Gensini score ≤39),Q3(n=73,39<Gensini score ≤62.5),and Q4(n=71,Gensini score>62.5).The expression level of CTRP1 was increased across the quartiles of the Gensini score.In addition,CTRP2,CTRP3,CTRP12,CTRP13,and CTRP15 levels showed a decreasing trend across the quartiles of Gensini score(all P<0.05).Conclusions:1.CTRP family members,as pro-inflammatory or anti-inflammatory adipokines,were independent predictors for ACS,and the association between them was not significantly affected by sex,age,diabetes mellitus,and dyslipidemia status.CTRP family members may be used as novel biological markers for the diagnosis of ACS.2.The serum levels of CTRP1,CTRP2,CTRP12,and CTRP13 showed a linear trend with the risk of ACS,which may be used for early risk assessment of ACS.3.The serum levels of CTRP1,CTRP2,CTRP13,and CTRP15 showed a certain correlation with the severity of coronary artery stenosis,which may be used as reference biomarkers to evaluate the severity of coronary artery lesions.