Coronary Lesions in Patients with Kawasaki Disease -- from High-risk Genetic Factors to Remodeling of Coronary Arterial Lesions
Date Issued
2011
Date
2011
Author(s)
Lin, Ming-Tai
Abstract
Kawasaki disease (KD) is an acute systemic vasculitis that occurs predominantly in infants and young children. KD is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develop in 5% to 10% of affected children even after the recommended intravenous immunoglobulin therapy. With an ever increasing incidence almost worldwide, KD is now the leading cause of acquired heart disease in children. The annual incidence of KD in Taiwan has increased steadily since 1976 and is now 66-69 patients per 100,000 children <5 years old, the third highest rate in the world.
The etiology and pathogenesis of KD are still uncertain. It is generally agreed that KD is related to ubiquitous infectious agents that cause the disease in genetically predisposed individuals. In the present doctoral thesis, we first sought to examine the seasonality of KD in Taiwan by using the epidemiologic data of KD in Taiwan between 1996 and 2002. Basically, the database came from the National Health Insurance data and hospitalized patients who were under 18 years old and met criteria listed for KD (ICD-9-CM code: 446.1) were selected. The data were transformed and analyzed in the form of cumulative distribution curve. Kuiper’s test was applied to test the seasonality, and we found the results of Kuiper’s test for seasonality in each year between 1996 and 2002 showed statistical significance for all years examined, (p <0.01) and ascertained the presence of seasonality for KD. This will support the theory that certain infectious agents may cause KD. The most interesting is the peak rmonth of patient numbers is April to June in Taiwan, rather than January (in Japan). The reasons for such differences between Japan and Taiwan remain unclear. But, the possibility that different interaction between infectious agents and genetic predisposing factors may be elucidated in the future studies.
The highest incidences of KD are found in three countries in Japan. The risk of KD in siblings of affected children is ten times higher as compared to the general population, while it is twice as high in children born to parents with a history of KD compared to the general population. Echoing these epidemiological data, previous studies have demonstrated the associations of genetic markers with a susceptibility to KD and/or increased risk of developing CAL in KD patients. Of the studied genetic markers, we picked up the functional single nucleotide polymorphism (SNP) rs28493229 of ITPKC (inositol 1,4,5-trisphosphate 3-kinase C) gene as the candidate and studied its association with susceptability to KD. Furthermore, if the C allele of ITPKC may lead to immune hyper-reactivity and susceptibility to KD, its presence may be also associated with different clinical manifestations (ex: erythema at BCG scar) during the acute phase of KD. Based on a Taiwanese KD cohort with complete medical data, we sought to define the role of the C allele of ITPKC rs28493229 polymorphism played in the disease susceptibility, clinical manifestation and the development and severity of CAL in KD patients.
We enrolled 280 unrelated Taiwanese children with KD and 492 healthy ethnically and gender-matched controls. Genotyping for the ITPKC polymorphism was conducted and the clinical manifestations and laboratory data were systemically collected. We found that the GC and CC genotypes of ITPKC gene SNP rs28493229 were over-represented in KD patients (GG:GC:CC was 236:43:1, C allele frequency: 8.04%) than in the controls (GG:GC:CC was 454:37:1, C allele frequency: 3.96%; OR:2.23, p=0.001). In KD patients, patients with GC or CC genotypes of SNP rs28493229 (19/44) were more likely to have reactivation at the Bacille Calmette-Guérin (BCG) inoculation site than those with GG genotypes (66/236; OR= 1.96, p=0.044). Such association was particularly strong in patients aged < 20 months (OR= 3.26, p=0.017). The other clinical manifestations were not related to this SNP. In this cohort, there were 160 (57.1%) patients with coronary arterial lesions (CAL). The development and the severity of CAL was not associated with this SNP either. Comparison between patients with and without BCG reactivation revealed only one difference: patients with reactivation were younger. Therefore, we concluded, in a cohort from a population with the world’s third highest incidence of KD, the C-allele of ITPKC SNP rs28493229 is associated with KD susceptibility and BCG scar reactivation during the acute phase, though its frequency is lower than that in Japanese cohort (22.6%), suggesting this SNP contributes to KD susceptibility via induced hyperimmune function reflected in the BCG reactivation.
The final part of the doctoral thesis is regarding to the research on matrix remodeling of coronary lesions in KD patients. Pathological data from the hearts of KD patients who suffered from sudden death showed thickening of coronary arteries and arterioles as well as perivascular and myocardial fibrosis. Alterations in the build-up and breakdown of arterial extracellular matrix are key features in vascular remodeling. Therefore, serum biomarkers of fibrosis may be sensitive indices for late cardiac complications of KD. We studied a cohort of 60 adolescents and young adults, which comprised 10 KD patients with persistent coronary artery lesions (CAL) 14.5 ± 4.4 years since onset, 25 KD patients with no CAL since onset and 25 healthy age-matched volunteers. The lipid profile, liver function, amino-terminal propeptide of type III procollagen (PIIINP), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and the MMP-9/TIMP-1 ratios were compared. Severity of CAL was based on computer tomography determinations of the frequency of aneurysms, the extent of coronary stenosis/occlusion, thrombosis and calcification.
We found elevated PIIINP, and decreased MMP-9, TIMP-1 and MMP-9/TIMP-1 ratios not only in KD patients with persistent CAL but also in those without, although to a lesser extent in the latter group. In KD patients, the concentrations of PIIINP were positively associated with the severity of coronary stenosis/occlusion (r=0.72, p= 0.011) and with the extent of coronary thrombus (r=0.64, p=0.014). The concentrations of high sensitivity C reactive protein, however, were not found different across groups. This is the first study of profiling for biomarkers of the extracellular matrix in KD adult patients more than ten years after disease onset. We report the following novel findings: (1) the index of collagen synthesis, PIIINP, was elevated and the concentrations of MMP-9, TIMP and the MMP-9/TIMP ratio were diminished in KD adolescents and young adults, especially in patients with persistent CAL. (2) In patients with KD, the concentrations of PIIINP were closely associated with quantifiable characteristics of severity of CAL (coronary stenosis/occlusion and coronary thrombosis). (3) In patients without gross coronary complications, the collagen turnover was still abnormal. Together these findings suggest that late after the onset of KD, the collagen turnover is still far from normal and may be related to the severity of CAL, microangiopathy or myocardial fibrosis.
In conclusion, the present doctoral thesis first confirmed the seasonality of KD in Taiwan. With the genetic analysis, we then demonstrated the ITPKC-realted T cell activation were associated with the development of KD and BCG scar reactivation. Finally, in adolescents and young adults late after the onset of KD, we novelly found alterations in biomarkers of extracellular matrix and turnover of collagen, not only echoing to the previous pathology reports, but also opening a new direction for the future monitoring and treatment of Kawasaki disease.
Subjects
Kawasaki disease
coronary arterial lesions
seasonality
genetic polymorphisms
matrix remodeling
Type
thesis
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