Kawasaki Disease Coronary Artery Aneurysms Research Articles

Etiology and prognosis of non-Kawasaki disease induced coronary aneurysms in children: a retrospective case series study

While Kawasaki disease (KD) induced coronary artery aneurysms (KD CAAs) in children are well studied, the features and prognosis of non-KD induced CAAs (non-KD CAAs) in the pediatric population are poorly documented. This case series study is to analyze the etiology and prognosis of non-KD CAAs in children and compare the characteristics of non-KD CAAs and KD CAAs. Non-KD CAA and KD CAA cases at our department from January 2022 to December 2023 were retrospectively collected. Etiologies and prognosis of non-KD CAAs were analyzed. Furthermore, demographic data, biochemical parameters and outcomes between children with Non-KD CAAs and children with KD CAAs were comparatively studied. Fifteen children with non-KD CAAs with a median age of 6 years and 117 children with KD CAAs with a median age of 2.0 years (p = 0.022) were included in this study. The causes of non-KD CAAs include: unknown etiologies (2 cases), coronary artery structural abnormalities (4), Takayasu arteritis (2), virus infection (2), cardiomyopathy (2), aplastic anemia with agranulocytosis (1), ANCA-associated vasculitis (1), and mucopolysaccharidosis (1). In the non-KD CAA group, there were a total of 19 CAAs with 3 being giant, 5 medium, and 11 small; 4 patients had complete CAA regression; an infant with a fistula between the right coronary artery and the coronary sinus complicated with cardiac enlargement died of heart failure. The KD group had significantly higher levels of CRP, white cells counts and ESR with zero mortality. Non-KD CAA cases had a significantly lower regression rate than KD-CAA cases (26.7% vs 66.7%, p = 0.004), and the probability of CAA regression in non-KD patients was 0.341 of that in KD patients (p = 0.006, OR = 0.341, 95% CI: 0.179–0.647).Conclusions: Various etiologies for Non-KD CAAs are identified. Patients with Non-KD CAAs were observed to have lower inflammatory indexes but poorer recovery than patients with KD CAAs. Therapeutic strategies different than those for KD may be needed for non-KD CAAs.What is Known:• Coronary artery aneurysm (CAA) in children is most commonly induced by Kawasaki disease (KD CAA), with a 50 ~ 70% regression rate in 1 to 2 years.• CAA induced by diseases other than KD (non-KD CAA) in children is rare and its prognosis remains largely unknown.What is New:• Most non-KD CAA cases are caused by coronary artery structural malformations.• Non-KD CAA in children has poorer prognosis and lower regression rate compared with KD CAA.• In addition to guideline directed anti-platelet and anti-coagulant therapies, treatments targeting the causal factor are necessary for non-KD CAA.

Pharmacogenomics of coronary artery response to intravenous gamma globulin in kawasaki disease

Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The mechanism of coronary artery aneurysms (CAA) in KD despite intravenous gamma globulin (IVIG) treatment is not known. We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z ≥ 2.5 and large coronary aneurysm (CAA/L) (N = 92) as z ≥ 5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p < 6.32E–08 most significant). Variants in SMAT4, LOC100127, PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. Functional mapping and annotation (FUMA) analysis identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an area under the receiver operating characteristic curve (AUC) of 0.86. This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD and shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.

Advancing Risk Stratification of Coronary Artery Aneurysms Caused by Kawasaki Disease Using Hemodynamics Analysis and Computational Fluid Dynamics

This article reviews previous studies on the risk assessment of coronary artery aneurysms (CAA) caused by Kawasaki disease (KD) using the computational fluid dynamics (CFD) simulation. Patient-specific CFD is an emerging tool that provides detailed three-dimensional hemodynamic information, not available from current standard imaging techniques or invasive measures. The reviewed CFD studies on KD CAA used Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) images to reconstruct the three-dimensional anatomical geometry consisting of the aorta and coronary arteries. On the inlet and outlet of the anatomical model, physiologic boundary conditions were prescribed to match the measured patient-specific blood pressure or flow data, supplemented by physiologic rules informed by population studies. Hemodynamic variables such as the blood velocity, wall shear stress, oscillatory shear index, fractional flow reserve, and particle residence time, were then quantified from the simulation results. The studies reviewed revealed strong correlations between these hemodynamic parameters and clinical outcomes, suggesting that hemodynamic metrics could be useful for treatment planning for KD patients. We discuss the limitations of the reviewed studies including small sample sizes, a narrow focus on thrombosis, and the use of different imaging modalities. The article suggests future research directions for CFD studies of KD that address these limitations.

Multi-centre, randomised, open-label, blinded endpoint assessed, trial of corticosteroids plus intravenous immunoglobulin (IVIG) and aspirin, versus IVIG and aspirin for prevention of coronary artery aneurysms (CAA) in Kawasaki disease (KD): the KD CAA prevention (KD-CAAP) trial protocol

BackgroundKawasaki disease (KD) is an acute self-limiting inflammatory vasculitis affecting predominantly medium-sized arteries, particularly the coronary arteries. A number of recent studies conducted in different European countries have demonstrated alarmingly high coronary complications despite treatment with intravenous immunoglobulin (IVIG). These high complication rates now emphasize the need for an urgent reappraisal of IVIG as the sole primary therapeutic agent for KD. The Kawasaki disease CAA prevention (KD-CAAP) trial will test the hypothesis that immediate adjunctive corticosteroid treatment to standard of care IVIG and aspirin will reduce coronary artery aneurysm (CAA) rates in unselected KD patients across Europe.MethodsKD-CAAP is a multicentre, randomised, controlled, open-label, blinded endpoint assessed trial that will be conducted across Europe supported by the conect4children pan-European clinical trials network. Patients with KD who satisfy the eligibility criteria will be randomised (1:1) to receive either oral prednisolone 2 mg/kg/day plus standard of care therapy IVIG (2 g/kg) and aspirin (40 mg/kg/day); or IVIG and aspirin alone. Further management is dictated by temperature and C-reactive protein (CRP) responses. Co-primary outcomes are as follows: (i) any CAA within the 3 months of trial follow-up; (ii) average estimate of maximum coronary Z-score at weeks 1, 2 and 6 adjusting for rescue treatment. Additional outcomes will be assessed including cost effectiveness, quality of life, corticosteroid toxicity and other safety outcomes.DiscussionSeveral recent studies have indicated that coronary complications associated with KD across Europe are much higher than early trials of IVIG had initially suggested. KD-CAAP directly addresses this issue by exploring the therapeutic benefit of adjunctive corticosteroids in unselected KD cases. If we find that corticosteroids prevent CAA and are safe, this is a cheap and widely available intervention that could be implemented immediately for the benefit of children.Trial registrationISRCTN71987471- March 31, 2020; Eudract 2019–004433-17.

Histological studies shed new light on the initiation and characteristics of calcification of coronary artery aneurysms in Kawasaki disease

BackgroundCalcification of coronary artery aneurysms (CAAs) is common in the remote phase of Kawasaki disease (KD), but the detailed features of its development remain unclear. This study aimed to elucidate the histological characteristics of calcification in KD CAAs. Materials and MethodsThe study materials consisted of 24 coronary artery branches with aneurysms that were obtained from 14 Japanese patients who died during the period from 40 days to 3 years after the onset of KD. We first examined the CAAs for the presence of thrombi and calcification. When calcifications were observed, we determined their location and shape, and investigated the time-course of the changes based on the time-interval from KD onset until death. Then we measured the area of each calcification and examined for correlations between the calcified area, and (1) the disease duration, and (2) the aneurysm diameter. ResultsCalcification was observed in 14 of 24 CAAs (in 7 of 13 LCA and 7 of 11 RCA). Thrombi were also seen in 13 of 14 CAAs with calcification. Calcification showed two localizations: in the organized portion of the thrombus (seen in 12 CAAs) and deep in the thickened tunica of the intima (3 CAAs). The earliest observation of calcification was in an infant who died on the 49th disease day: it was a small, band-shaped calcified lesion in granulation tissue that had formed at the boundary between the thrombus and the blood vessel wall. As the duration of KD increased, the calcified lesion increased in size, and nodular shapes were formed. Moreover, the calcified area tended to increase as the diameter of the aneurysm increased. ConclusionHistologically, CAA calcification starts early in the remote phase of KD, and it is closely related to organization of thrombi.

Distribution of Kawasaki Disease Coronary Artery Aneurysms and the Relationship to Coronary Artery Diameter.

We investigated how the diameter of coronary artery aneurysm (CAA) relates to the distribution immediately after Kawasaki disease (KD). Two hundred and four pts (155 males and 49 females) who had undergone selective coronary angiography (CAGs) less than 100 days after the onset of KD were studied. We measured the maximum diameter of each artery segment in the initial CAGs. We analyzed the relationship between the maximum diameters and the distribution of CAA. We divided the patients into four groups based on the maximum CAA diameter in each patient (large(L) ≥8mm, medium(M) ≥6 and <8mm, small(S) ≥4 and <6mm, very small(VS) <4mm) and counted the affected segments. There were 87, 61, 36, and 20 patients in groups L, M, S, VS, respectively. The number of segments with CAA in each group was L 6 ± 2, M 4 ± 2, S 2 ± 2, VS 2 ± 1. The number of affected segments in L was significantly more than M, and a large value for L indicated that involvement was significantly more likely to be bilateral. The larger the maximum diameter of CAA, the more extensive disease involvement and the more likely to be bilateral. A large maximum CAA can also indicate coronary involvement in the longitudinal directions. It is an important charcteristic in distribution of CAA caused by KD vasculitis.

Cell Adhesion Molecule Expression in Coronary Artery Aneurysms in Acute Kawasaki Disease

The pathogenesis of coronary artery aneurysm (CAA) formation in acute Kawasaki disease (KD) remains unclear. Cell adhesion molecules mediate cell-cell and cell-matrix interactions and regulate leukocyte migration, angiogenesis and tissue remodeling. We hypothesized that cell adhesion molecules are expressed in acute KD CAA. : P-selectin, E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and integrin beta1 were immunolocalized in coronary arteries from 6 acute KD patients and 7 controls. In endothelial cells of adventitial neovasculature in KD CAA, P-selectin and integrin beta1 were expressed in all of 6 patients, and E-selectin and/or VCAM-1 were expressed in 4 of 6. Endothelial cells in controls and in nonaneurysmal KD coronary arteries expressed P-selectin and integrin beta1, but not E-selectin or VCAM-1. Integrin beta1 was expressed on infiltrating leukocytes in 5 of 6 KD CAA and on fibroblasts in 6 of 6; these findings were absent in controls and in nonaneurysmal KD coronary arteries. The lack of widespread expression of E-selectin or VCAM-1 on endothelial cells of acute KD coronary arteries was surprising and suggests that inflammatory cell infiltration into KD coronaries is not simply the result of widespread up-regulation of cell adhesion molecules on endothelial cells by circulating cytokines. Rather, inflammatory cells may be directed to specific areas of the coronary arteries targeted by a pathogen causing KD. Our results suggest that E-selectin and VCAM-1 expression on neovasculature may contribute to neoangiogenesis and prolonged CAA inflammation and that integrin beta1 might be involved in fibroblastic remodeling of acute KD CAA.

Advances in Kawasaki disease.

Recent studies have increased our understanding of the etiopathogenesis of Kawasaki disease (KD). The inflammatory infiltrate in KD coronary artery aneurysms has been shown to consist of CD8 T lymphocytes, macrophages, and IgA plasma cells, consistent with an immune response to an intracellular pathogen with a mucosal portal of entry. The identification of an oligoclonal IgA response in the vascular wall and the detection of a KD-associated antigen in inflamed KD tissues using a synthetic antibody derived from KD oligoclonal IgA antibodies have provided new approaches to identification of the etiologic agent. Highly effective therapy has evolved for KD, even in the absence of identification of the etiologic agent. The existence of incomplete KD cases remains a significant diagnostic dilemma for the clinician. The development of a diagnostic test, more specific therapy, and ultimate prevention of this potentially fatal illness of childhood are dependent upon continued advances in determining the etiopathogenesis of this fascinating disorder.

Matrix Metalloproteinases-2 and-9 in Areas of Extracellular Matrix Destruction and Angiogenesis in Coronary Artery Aneurysms in Kawasaki Disease

Coronary artery aneurysms (CAA) can complicate Kawasaki Disease (KD) and lead to rupture, coronary thrombosis or coronary stenosis. CAA are characterized histologically by destruction of extracellular matrix (ECM), most notably elastic tissue in the vascular media; inflammatory cell infiltrates; and neovascularization. Matrix metaloproteinases (MMP) are known to regulate degradation and remodeling of the ECM and angiogenesis. MMP-2 and-9 have been implicated in the pathogenesis of abdominal aortic aneurysms and atherosclerosis, and elevated plasma levels of MMP-9 have been demonstrated in acute KD. We hypothesized that MMP are important in the pathogenesis of CAA development and vascular remodeling in KD. To determine if MMP are present in KD CAA, we performed immunohistochemistry for MMP-2 and -9 on paraffin-embedded formalin-fixed coronary artery tissue from 11 fatal acute KD cases and from 7 children who died of other causes. Although there was no significant quantitative difference in MMP-2 in KD and non-KD coronary arteries, there was a qualitative difference in the pattern of MMP-2 expression. In control and non-aneurysmal KD arteries, MMP-2 was present only in vascular smooth muscle cells and endothelial cells, whereas in KD CAA, MMP-2 was prominent in the thickened neointima, in smooth muscle cells migrating from the media into the neointima, and in endothelial cells in areas of adventitial angiogenesis. In contrast, there was a significant difference in the expression of MMP-9 in KD CAA and control coronary arteries (p≤0.01). MMP-9 was prominently expressed by mononuclear inflammatory cells in CAA but was not expressed in non-aneurysmal KD coronary arteries or in control subject coronary arteries. We conclude that MMP-2 and -9 are differentially expressed in CAA of KD patients when compared to non-aneurysmal KD or control coronary arteries. Differential expression of MMP may contribute to ECM degradation, neointimal proliferation, and local angiogenesis in KD CAA.