Risk Factors Of Vascular Lesions In Late Convalescence Period Of Kawasaki Disease

Kawasaki disease (KD) is an acute inflammatory syndrome that takes the form of systemic vasculitis. Cardiovascular lesions, especially coronary artery lesion are the main complication of KD. It has been determined that KD is a chronic low grade inflammation and may be closely associated with atherosclerosis. Therefore, to investigate underlying mechanism of KD and vascular lesions in long term of KD would be very important for establishing the project for individual therapy, evaluating the prognosis, preventing vascular lesions from atherosclerosis in this population.PartⅠThe ultrasound study of vascular lesions in late convalescenceperiod of Kawasaki diseaseObjective:To explore weather the functional and structural changes in vascular bed persist for years after acute KD; to search a feasible project, which can evaluate better the prognosis of vascular lesions with KD.Methods:A cohort of 174 children was studied, which comprised 51 patients with KD with coronary artery lesions (CAL), 50 patients with KD with normal coronary arteries (non-CAL), and 103 healthy age-matched children (control group). Flow-mediated dilation of the brachial artery (FMD%), carotid arterial stiffness index (stiffness) and carotid arterial intima-media thickness (IMT) were evaluated.Results:1,FMD% in CAL group, non-CAL group and control group were 5．2%±1．9%, 6．8%±2．0% and 13．2%±4．1% respectively. FMD% in CAL group and non-CAL group was lower than that in control group (CAL group vs non-CAL, p=0．036; CAL group vs control group, p<0．01; non-CAL group vs control group, p<0．01) .2,Stiffness in CAL group, non-CAL group and control group were 3．96±0．59, 3．64±0．61 and 3．42±0．49 respectively. Stiffness in CAL group was increased as compared to non-CAL and control group (p=0．012, p<0．01) .3,IMT in CAL group, non-CAL group and control group were 0．447±0．024mm, 0．426±0．016mm and 0．424±0．016mm respectively. IMT in CAL group was larger than those in non-CAL group and control group (p<0．01, p<0．01) .4,There were significant correlations between stiffness, FMD% and IMT in both healthy group and KD group after adjustment of age. Age and patient grouping were significant determinants of stiffness, FMD% and IMT, which were shown by multiple linear regression analysis.Conclusions:1,There were endothelial dysfunction and increased systemic arterial stiffness and IMT late after the acute phase of Kawasaki disease.2,FMD%, stiffness and IMT are practical indices for evaluating the prognosis of vascular lesions in long term of KD.PartⅡAssociation of the number of circulating endothelial progenitor cells with vascular lesions in the late convalescence period ofKawasaki diseaseObjectiveTo investigate if circulating endothelial progenitor cells (EPCs) are involved in vascular lesions in the late convalescence period of KD.MethodsA cohort of 63 children was studied. Participants were categorized into three groups: CAL group (n=21) , non-CAL group (n=20) , and control group (n=22) . EPCs count and FMD%, stiffness and IMT were measured and analyzed.Results1,The number of EPCs/ul in CAL group, non-CAL group and control group were 2．0±0．6/ul, 3．9±1．7/ul and 3．9±1．1/ul respectively. EPCs/ul in CAL group was decreased as compared to non-CAL and control group (p<0．01, p＜0．01) .2,The number of EPCs had significant correlations with FMD%, stiffness and IMT (r=0．39, r=-0．51, r=-0．46) .ConclusionsEPCs is decreased in patients with CAL in late convalescence period of KD, and the number of EPCs is closely associated with the degree of vascular lesions. Thus, the number of EPCs can be considered as one of the predictors for vascular lesions in patients with KD.PartⅢThe association of polymorphisms of CRP and TNF-αgenes withvascular lesions in Kawasaki diseaseObjective:To investigate the correlation among single nucleotide polymorphisms (SNPs) of CRP gene and susceptibility of KD, serum hs-CRP levels and vascular lesions; and to explore if SNPs of TNF-αgene affected susceptibility of KD and vascular lesions in the late convalescence period of KD.Method:PCR and genotyping were performed for the detection of SNP at positions-286, +1059 and +1444 of CRP gene and-308 of TNF-αgene in 101 KD patients and 173 healthy children. The serum hs-CRP levels were measured by enzyme-linked immunosorbent assay (ELISA). The correlations of SNPs of CRP gene and susceptibility of KD, serum hs-CRP levels and vascular lesions as well as the affection of SNPs of TNF-αgene to susceptibility of KD and vascular lesions in the late convalescence period of KD were analyzed.Results:1,Analysis of polymorphisms of CRP gene(1) frequencies of genotypes of A and/or T at position-286 of CRP gene were 45．1% in CAL group and 28．9% in control group (χ~2=5．491, P=0．019, OR=2．003, 95%CI, 1．116～3．594) . The allele frequencies of the less common A+T variant were 26．5% in CAL group and 14．7% in control group (χ~2=4．185, P =0．041, OR=2．068, 95%CI为1．023～4．180) .(2) Both GG, GC, CC genotype frequencies and G/C allele frequencies at position +1059 had no difference between CAL group, non-CAL group and control group.(3) Frequencies of CT/TTgenotype at position +1444 of CRP gene were 19．6% in CAL group, 8．0% in non-CAL group and 8．1% in control group, respectively (χ~2＝5．980, P=0．014, OR=2．875, 95%CI, 1．201～6．883) . The allele frequencies of rare T variant were 11．8% in CAL group and 4．0% in non-CAL group (χ~2=4．348, P = 0．037, OR=3．273, 95%CI, 1．018～10．523) .(4) The serum of hs-CRP levels in CAL group, non-CAL group and control group were 3．42±1．66mg/l, 2．63±1．27mg/l and 2．61±1．27mg/l, respectively (p<0．05, p<0．01) .(5) The serum of hs-CRP levels with CC, CA, CT, AT/AA/TT genotype at position-286 of CRP gene were 2．31±1．03mg/l, 3．55±1．59 mg/l, 3．28±1．56 mg/l and 3．85±1．69 mg/l, respectively (p<0．01) , while the stiffness were 3．47±0．05, 3．73±0．07, 3．84±0．08 and 3．98±0．20, respectively (p<0．05) .(6) The serum of hs-CRP level, and the stiffness had no difference between GG, GC and CC genotype at position +1059 of CRP gene.(7) The serum of hs-CRP level with CC and non-CC genotype at position +1444 of CRP gene were 2．65±0．12mg/l and 3．56±0．25 mg/l (p＜0．01) , while the stiffness were 3．53±0．04 and 3．88±0．07, respectively (p＜0．01) .2,Analysis of polymorphism of TNF-αgene(1) Frequencies of GA/AAgenotype at position-308 of TNF-αgene were 29．4% in CAL group, 15．0% in control group (χ~2=5．711, p=0．017, OR=2．315, 95%CI, 1．151～4．654) . The allele frequencies of rare A variant were 17．6% in CAL group and 7．8% in control group (χ~2=4．421, P=0．036, OR=2．524, 95%CI, 1．042～6．113) .(2) Stiffness with GG and GA/AA genotype at position-308 of TNF-αgene were 3．71±0．57 and 4．07±0．68 (p=0．012) .Conclusions:1,SNP at position-286 C/A/T of CRP gene is associated with the susceptibility of KD. A and/or T alleles are susceptible alleles to the vascular lesions in KD.2,The SNP at position +1444 C/T of CRP gene is associated with the susceptibility of KD. T allele was susceptible allele to KD and the vascular lesions.3,A and/or T alleles at position-286 and T allele at position +1444 of CRP gene might be regarded as genetic markers of risk factors for vascular lesions in late convalescence period of KD.4,The SNP at position +1059 G/C of CRP gene has no association with the susceptibility of KD, the sersum hs-CRP level and the stiffness.5,The serum hs-CRP level has a significant increase in CAL group, serum hs-CRP level might serve as a predictor of vascular lesions in late convalescence period of KD. 6 The SNP at position-308 G/A of TNF-αgene is associated with the susceptibility of the vascular lesions in KD. A allele is susceptible allele to the vascular lesions in KD. A allele at position-308 of TNF-αgene might be regarded as genetic marker of risk factors for vascular lesions in late convalescence period of KD.