An update on understanding the pathophysiology in Kawasaki disease: Possible role of immune complexes in coronary artery lesion revisited.

Kawasaki disease (KD) is an acute self-limiting systemic vasculitis of unknown etiology affecting predominantly the coronary arteries. The role of circulating immune complexes (ICs) in the pathogenesis of KD has been studied using the sera of patients with KD. It has been proposed that ICs are triggered by single or multiple unknown causative agents as well as vasculitis. The outbreak of severe acute respiratory syndrome coronavirus 2 infections caused similar pathophysiology in producing vasculitis, and the RNA virus may have triggered signs and symptoms similar to KD. For clinicians and researchers alike, detecting the causative agents of KD remains a challenge. According to studies in animal models, type III hypersensitivity reactions caused by serum sickness are a prototype for IC vasculitis. The signs and symptoms of coronary artery dilation in swine are similar to those of KD. These models may be used to evaluate new pharmacological agents for KD. The pathogenesis of KD is complex and remains inadequately understood at present. However, circulating ICs may play a key role in the pathophysiology of KD and coronary artery vasculitis. Various therapeutic agents are being explored in the management of KD and these agents act at various stages of the production of pro-inflammatory cytokines and chemokines. In this review, we discuss recent developments in the pathogenesis of KD and provide insights into the innate immune response and mechanisms behind coronary artery damage in KD. We specifically explore the potential role of ICs in the pathogenesis of KD.

Characteristics of coronary artery ectasia and accompanying plaques: an optical coherence tomography study.

Coronary artery ectasia (CAE) in adults is often caused by atherosclerotic plaques. CAE can affect atherosclerotic plaques through hemodynamic changes. However, no study has evaluated the characteristics of CAE with atherosclerotic plaques. Therefore, we aimed to disclose the characteristics of atherosclerotic plaques in patients with CAE using optical coherence tomography (OCT). We evaluated patients with CAE, confirmed by coronary angiography, who underwent pre-intervention OCT between April 2015 and April 2021. Each millimeter of the OCT images was analyzed to assess the characteristics of CAEs, plaque phenotypes, and plaque vulnerability. A total of 286 patients (344 coronary vessels) met our criteria, 82.87% of whom were men. Right coronary artery lesions were the most common, comprising 44.48% (n = 153) of the total. We found 329 CAE vessels with plaques, accounting for 95.64% of the coronary vessels. After grouping CAEs and plaques by their relative positions, we found that the length of plaques within CAE lesions was longer than that of plaques in other sites (P < 0.001). Plaques within CAE lesions had greater maximum lipid angles and lipid indexes (P = 0.007, P = 0.004, respectively) than those on other sites. This study revealed the most common vascular and morphological characteristics of CAE. While the accompanying plaques were not affected by the location or morphology of the CAE vessels, they were affected by their position relative to the CAE lesion.

Immune and non-immune mechanisms that determine vasculitis and coronary artery aneurysm topography in Kawasaki disease and MIS-C.

The overlap between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) including coronary artery aneurysms (CAA) and broadly shared gastrointestinal and mucocutaneous disease is poorly defined. In this perspective, we highlight common age-related extravascular epicardial microanatomical and immunological factors that might culminate in CAA expression in both MIS-C and KD. Specifically, the coronary vasa vasorum originates outside the major coronary arteries. Widespread inflammation in the epicardial interstitial compartment in shared between KD and MIS-C. Age-related changes in the neonatal and immature coronary vasculature including the impact of coronary artery biomechanical factors including coronary vessel calibre, age-related vessel distensibility, flow, and vessel neurovascular innervation may explain the decreasing CAA frequency from neonates to older children and the virtual absence of CAA in young adults with the MIS-C phenotype. Other KD and MIS-C features including mucocutaneous disease with keratinocyte-related immunopathology corroborate that disease phenotypes are centrally influenced by inflammation originating outside vessel walls but a potential role for primary coronary artery vascular wall inflammation cannot be excluded. Hence, common extravascular originating tissue-specific responses to aetiologically diverse triggers including superantigens may lead to widespread interstitial tissue inflammation characteristically manifesting as CAA development, especially in younger subjects. Given that CAA is virtually absent in adults, further studies are needed to ascertain whether epicardial interstitial inflammation may impact on both coronary artery physiology and cardiac conduction tissue and contribute to cardiovascular disease- a hitherto unappreciated consideration.

An autopsy case of hyperimmunoglobulin E syndrome with coronary fibrinoid necrotizing arteritis and an aneurysm.

We report a case of hyperimmunoglobulin (Ig) E syndrome (HIES) with a coronary artery aneurysm (CAA) in a 25-year-old Japanese man. He died suddenly due to chronic heart failure associated with HIES. We noted a CAA at the trunk of the left coronary artery and granulomatous and fibrinoid necrotizing arteritis of the middle portion of the left anterior descending during the autopsy. We speculate herein on the relationship between the aneurysm and arteritis. These findings facilitate a better understanding of the pathogenesis underlying HIES.

Exploring the relationship between pyroptosis, infiltrating immune cells and Kawasaki disease with resistance to intravenous immunoglobulin (IVIG) via bioinformatic analysis.

BACKGROUND: Kawasaki disease (KD) is a kind of vasculitis predominantly afflicting children younger than five. Although intravenous immunoglobulin (IVIG) has been regarded as the first-line therapy, there are some children unresponsive to it, resulting in higher risk of coronary artery aneurysms (CAA), the most severe complication of KD. Pyroptosis is an inflammatory apoptosis, which resembles the traits of IVIG-resistance. Therefore, our research aims to find relationships between KD with IVIG-resistance and pyroptosis, and provide the underlying mechanisms of IVIG-resistance. METHODS: The transcriptome data of three datasets were downloaded from Gene Expression Omnibus (GEO) database. CIBERSORTx and WGCNA were combined to identify the coexpression gene network correlated with the up-regulated immune cells in KD, using differentially expressed genes (DEGs) overlapped in GSE68004 and GSE73461. The key genes in hub module were intersected with pyroptosis-related genes (PRGs). Then KD patients were divided into subgroups according to the expression of remaining genes, along with the construction of risk score (RS) based on the least absolute shrinkage and selection operator (LASSO) regression analysis. Besides, we explored the clinical value of RS between IVIG-responsive and -resistant KD patients in GSE16797. In addition, the biological pathways between subgroups were evaluated using Gene Set Variation Analysis (GSVA). RESULTS: A total of 4246 DEGs and three immune cells, including Monocytes, M0 macrophage, and neutrophils, were analyzed with P < 0.05 between KD and healthy controls (HCs). The lightcyan module was the hub module based on WGCNA, and only NLRC4, CASP1, CASP4, GSDMD, IL1B and PYCARD in the hub module were overlapped with PRGs. Then KD patients in GSE68004 were stratified into two clusters on the basis of the expression levels of six genes. RS was built with five out of six genes (exclude PYCARD) according to the LASSO analysis, which could differentiate C1 from C2, IVIG-responsive from -resistant KD patients. Besides, the high-risk group (C1) tended to be with increased levels of inflammation, immune responses and infiltration of neutrophils according to the analysis of GSVA and CIBERSORTx. CONCLUSION: We built a pyroptosis-related RS to evaluate the degree of pyroptosis and infiltrating immune cells in subgroups of KD, and associated it with the responsiveness to IVIG, which might help us to further understand the pathological process during IVIG-nonresponse.

The relationship between TNF-like protein 1A and coronary artery aneurysms in children with Kawasaki disease.

Kawasaki disease (KD) is an acute, systemic vasculitis of unknown etiology that occurs predominantly in infants and children, and the most crucial complication of KD is coronary artery aneurysm (CAA). Tumor necrosis factor (TNF)-like protein 1A (TL1A) is a member of the TNF superfamily, which possesses the ability of maintaining vascular homeostasis and regulating immune responses. This study aimed to examine serum TL1A levels in KD patients, and to investigate the relationship between TL1A and CAAs in children with KD. Blood samples were recruited from 119 KD patients, 35 febrile controls (FCs), and 37 healthy controls (HCs). The KD group was further divided into KD with CAAs (KD-CAAs) and KD non-CAAs (KD-NCAAs) groups. Serum TL1A levels were measured using enzyme-linked immunosorbent assays, and clinical parameters were collected from KD patients. Serum TL1A levels of KD patients in the acute phase of KD were significantly higher than in the FC and HC groups. In particular, serum TL1A levels were substantially increased in the KD-CAA group compared with the KD-NCAA group. Furthermore, TL1A levels in the KD group were positively correlated with the duration of fever and the time point of IVIG and WBC levels, but negatively correlated with levels of RBC, Hb and albumin. TL1A might be involved in KD-associated vasculitis and in the development of CAAs.

Cardiac pathology and outcomes vary between Kawasaki disease and PIMS-TS.

Overlapping clinical features promoted the discussion of whether Kawasaki disease (KD) and PIMS-TS share pathophysiological features and disease outcomes. Medical records from English patients with KD (2015-02/20, N = 27) and PIMS-TS (02/2020-21, N = 34) were accessed to extract information. Children with PIMS-TS were older and more frequently of minority ethnicity background. They patients more commonly exhibited cytopenias and hyperferritinemia, which associated with diffuse cardiac involvement and functional impairment. In some PIMS-TS cases, cardiac pathology developed late, but outcomes were more favorable. In both, KD and PIMS-TS, baseline coronary diameter was a predictor of outcomes. PIMS-TS treatment more frequently included respiratory and cardiovascular support, and corticosteroids with IVIG. Cardiac involvement in PIMS-TS may be the result of a cytokine storm. Though more severe and diffuse when compared to KD, cardiac involvement of PIMS-TS has a more favorable prognosis, which may, after recovery, mitigate the need for long-term follow up.

A Large Mediastinal Mass in a Young Woman: A Case of Giant Coronary Artery Aneurysm.

We report the case of a 23-year-old female patient with recurrent episodes of chest and back pain. A cardiac mass of uncertain etiology was discovered and she was referred to our multidisciplinary cardiac tumor team. Pathologic analysis from the surgical specimen confirmed this mass was a giant aneurysm of the left anterior descending artery.

A Pediatric Case Report of Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis With Pericardial Effusion and Multiple Coronary Artery Aneurysms.

Pediatric coronary artery aneurysms (CAAs) are mainly detected in Kawasaki disease and in chronic active Epstein-Barr virus (EBV) infection sometimes, and cardiac complications are rare in viral-associated hemophagocytic lymphohistiocytosis (HLH) patients. Here, we report a pediatric case of EBV-associated HLH with pericardial effusion and multiple CAAs, whereas the patient did not fulfill the diagnostic criteria of Kawasaki disease or chronic active EBV. The case indicates that CAAs may occur in EBV-HLH. Specifically, in a patient with a long-term fever and a high EBV DNA copy number, the detection of cardiac complications may help signal the possible occurrence of HLH, and CAAs may affect the prognosis for high risk of cardiac events.

Myocarditis and coronary aneurysms in a child with acute respiratory syndrome coronavirus 2.

A 6-year-old African boy with multi-viral infection including parvovirus B19 and severe acute respiratory syndrome coronavirus 2 was admitted for persistent fever associated with respiratory distress and myocarditis complicated by cardiogenic shock needing ventilatory and inotropic support. Coronary aneurysms were also documented in the acute phase. Blood tests were suggestive of macrophage activation syndrome. He was treated with intravenous immunoglobulins, aspirin, diuretics, dexamethasone, hydroxychloroquine, and prophylactic low molecular weight heparin. Normalization of cardiac performance and coronary diameters was noticed within the first days. Cardiac magnetic resonance imaging, performed 20 days after the hospitalization, evidenced mild myocardial interstitial oedema with no focal necrosis, suggesting a mechanism of cardiac stunning related to cytokines storm rather than direct viral injury of cardiomyocytes.

Time Course of Coronary Artery Aneurysms in Kawasaki Disease.

OBJECTIVES: To determine the timeframe in which coronary artery aneurysms (CAAs) caused by Kawasaki disease reach their maximum diameter, the timeframe in which they regress to normal size, and the cutoff point of the diameter for CAA regression. STUDY DESIGN: We reviewed 195 CAAs of the right coronary artery, left anterior descending artery, and left coronary artery measured by 2-dimensional echocardiography ≥5 times for 1 year after Kawasaki disease in 84 patients using medical records from 1995. The maximum diameters of CAAs were investigated retrospectively. The time to CAA regression using both absolute diameter and Z score were investigated. The cutoff points of the diameter of CAA regression in the 2 classifications were identified using receiver operator characteristic curve analysis. One year after Kawasaki disease, a CAA of <3.0 mm in absolute diameter and a Z score of <2.5 were defined as CAA regression. RESULTS: The time when CAAs reached their maximum diameter ranged from 11 days to 87 days, with a median of 35 days (n = 195). The time to CAA regression ranged from 41 to 386 days, with a median of 136 days in the absolute diameter classification (n = 92); 78% of CAA regression regressed by 200 days. The cutoff point for CAA regression at one year was 5.7 mm for the absolute diameter (area under the curve, 0.887; P < .0001; n = 190) and 9.5 for the Z score (area under the curve, 0.815; P < .0001; n = 195). CONCLUSIONS: CAAs with a smaller diameter regressed earlier, and most CAAs of <6 mm regressed by 6 months after Kawasaki disease.

[Giant coronary aneurysms in infant with Kawasaki disease shock syndrome]. / Aneurismas coronarios gigantes en lactante con síndrome de choque por enfermedad de Kawasaki.

BACKGROUND: Kawasaki disease shock syndrome is a rare presentation of Kawasaki disease, in which cardiovascular manifestations associated with elevated inflammation biomarkers that develop hypotension are observed. It is preceded by gastrointestinal and neurological manifestations, with an increased risk of coronary lesions and resistance to intravenous immunoglobulin. CASE REPORT: A 5-month-old male patient with a fever that had developed in the last week, gastrointestinal and neurological symptoms with hypotensive shock, urticarial rash, BCG lymphadenitis, and edema of palms and soles. Giant coronary aneurysms were evident, so Kawasaki disease shock syndrome was diagnosed, which was treated with corticosteroid pulse and intravenous immunoglobulin. CONCLUSIONS: Clinicians must suspect Kawasaki disease shock syndrome when there is hypotensive shock, and the gastrointestinal, neurological and mucocutaneous symptoms that are characteristic of the disease, especially in infants under one year of age. The timely treatment of this disease reduces severe complications.

Antecedentes: El síndrome de choque es una presentación poco habitual de la enfermedad de Kawasaki en el que se observan manifestaciones cardiovasculares asociadas con niveles elevados de marcadores de inflamación, que llevan a hipotensión. Es precedido por manifestaciones gastrointestinales y neurológicas y existe mayor riesgo de lesiones coronarias y resistencia a inmunoglobulina intravenosa. Caso clínico: Varón de cinco meses de edad con fiebre de una semana de evolución, síntomas gastrointestinales y neurológicos con choque hipotensivo, erupciones urticariforme, linfadenitis por vacunación con bacilo de Calmette-Guérin, así como edema de manos y pies. Se evidenciaron aneurismas coronarios gigantes, por lo que se diagnosticó síndrome de choque por enfermedad de Kawasaki, el cual fue tratado con pulso de corticoesteroide e inmunoglobulina intravenosa. Conclusiones: El diagnóstico de síndrome de choque por enfermedad de Kawasaki se debe sospechar por choque hipotensivo, síntomas gastrointestinales, neurológicos y mucocutáneos propios de la enfermedad, especialmente en menores de un año. El tratamiento oportuno reduce las complicaciones graves.

Medium-Term Complications Associated With Coronary Artery Aneurysms After Kawasaki Disease: A Study From the International Kawasaki Disease Registry.

Background Coronary artery aneurysms (CAAs) may occur after Kawasaki disease (KD) and lead to important morbidity and mortality. As CAA in patients with KD are rare and heterogeneous lesions, prognostication and risk stratification are difficult. We sought to derive the cumulative risk and associated factors for cardiovascular complications in patients with CAAs after KD. Methods and Results A 34-institution international registry of 1651 patients with KD who had CAAs (maximum CAA Z score ≥2.5) was used. Time-to-event analyses were performed using the Kaplan-Meier method and Cox proportional hazard models for risk factor analysis. In patients with CAA Z scores ≥10, the cumulative incidence of luminal narrowing (>50% of lumen diameter), coronary artery thrombosis, and composite major adverse cardiovascular complications at 10 years was 20±3%, 18±2%, and 14±2%, respectively. No complications were observed in patients with a CAA Z score <10. Higher CAA Z score and a greater number of coronary artery branches affected were associated with increased risk of all types of complications. At 10 years, normalization of luminal diameter was noted in 99±4% of patients with small (2.5≤Z<5.0), 92±1% with medium (5.0≤Z<10), and 57±3% with large CAAs (Z≥10). CAAs in the left anterior descending and circumflex coronary artery branches were more likely to normalize. Risk factor analysis of coronary artery branch level outcomes was performed with a total of 893 affected branches with Z score ≥10 in 440 patients. In multivariable regression models, hazards of luminal narrowing and thrombosis were higher for patients with CAAs of the right coronary artery and left anterior descending branches, those with CAAs that had complex architecture (other than isolated aneurysms), and those with CAAs with Z scores ≥20. Conclusions For patients with CAA after KD, medium-term risk of complications is confined to those with maximum CAA Z scores ≥10. Further risk stratification and close follow-up, including advanced imaging, in patients with large CAAs is warranted.

Frequency of risk factors in patients of acute coronary syndrome due to coronary ectasia.

BACKGROUND: Coronary artery ectasia is a relatively common entity characterized by inappropriate dilatation of the coronary vasculature. In some cases of acute coronary syndrome without obstructive coronary lesions, coronary ectasia is the sole cause. The exact mechanism of its development is unknown but evidence suggests a combination of genetic predisposition, common risk factors for coronary artery disease, and abnormal vessel wall metabolism. As there are few data regarding the pattern of coronary risk factors in patients with coronary ectasia, the objective of the study was to determine the frequency and distribution of coronary risk factors in patients with acute coronary syndrome solely due to coronary ectasia. METHODS: The study included 155 patients over a period of 6 months, with coronary angiographic evidence of coronary ectasia as the sole cause of acute coronary syndrome. There were 79 (51%) men and 76 (49%) women with a mean age 51.92 ± 7.83 years; 73 (47.10%) were aged 20-50 years and 82 (52.90%) were 51-80 years of age. The frequencies of coronary risk factors were stratified according to sex and the two age groups. RESULTS: Seventy-one patients (45.80%) had diabetes mellitus, 83 (53.54%) had hypertension, 55 (35.48%) were smokers, 46 (29.68%) had dyslipidemia, and 47 (30.3%) were obese. CONCLUSION: Hypertension is the leading coronary risk factors in patients with acute coronary syndrome solely due to coronary ectasia, followed by diabetes mellitus and smoking.

Sudden death of a young adult with coronary artery vasculitis, coronary aneurysms, parvovirus B19 infection and Kawasaki disease.

We present a case of a 20-year-old man who suffered from Kawasaki disease (KD) associated with a florid parvovirus infection, and who died suddenly from thrombotic occlusion of the coronary arteries. The autopsy revealed several aneurysms of the coronary arteries, a chronic vasculitis and a myofibroblast proliferation leading to focal luminal narrowing. The inflammatory response as well as the detection of the viral particles by PCR in blood and in the lesional tissue demonstrated a possible cause by Parvovirus infection. The expression of endoglin on endothelial cells of neoangiogenesis indicates the involvement of the TGF-beta pathway, necessary for maintaining chronic inflammation. In addition, a possible connection between the intake of methylphenidate, arteritis and a possible pre-existing heart disease must be discussed. Furthermore, KD must also be considered as a cause of sudden death in the adult population.

Two females with coronary artery occlusion caused by presumed Kawasaki disease would have delivered without recognition of ischaemic heart disease.

We report two females with coronary artery occlusion caused by presumed Kawasaki disease that delivered children without any special treatment. After a 58-year-old female had ventricular tachycardia, a giant coronary artery aneurysm with calcification at the bifurcation of the left coronary artery and segmental stenosis of the right coronary artery were pointed out by CT angiography. She had an episode of sepsis when 3 years old. Further, she remembered chest pain during sleep after that episode. She had delivered twice without any complication during her 20s. Her diagnosis was undiagnosed coronary artery lesions caused by presumed Kawasaki disease and a previous myocardial infarction, and she underwent radiofrequency catheter ablation and implantable cardioverter defibrillator implantation. The other 48-year-old female was accidentally discovered to have coronary artery calcification on CT, while experiencing pneumonia. Her CT angiograms revealed a right coronary artery occlusion and coronary artery calcification at segments 1, 6, and 11. She had a history of "scarlet fever" before 12 months. Premature ventricular contractions were detected, while delivering her first child when 31 years old. However, she was not diagnosed as ischaemic heart disease and delivered twice by a vaginal delivery without any complication. Current guidelines recommend systemic anti-coagulation and anti-platelet therapy for all patients with giant aneurysms resulting from Kawasaki disease in childhood. The two women reported here were fortunate not to have had complications during pregnancy and delivery despite their severe coronary artery aneurysms, which were unrecognised clinically until later in life. They were lucky cases.

Giant Right Coronary Artery Aneurysms.

Described herein are 2 adults with right coronary artery aneurysms measuring ≥4.0 cm in maximal diameter. Each aneurysm contained huge intra-aneurysm thrombus and each coronary artery contained atherosclerotic plaques diffusely. Each aneurysm was resected without complication and each patient has resumed preoperative level of activities without limitations.

An unknown mass on the cardiac surface with huge coronary aneurysm and fistula: A case report.

Cardiac mass is rare in the clinic and can be primary or secondary. It is quite rare to find a mass only on the cardiac surface. Today we report a patient with a cardiac mass grown on the cardiac surface and also had a coronary aneurysm combined a coronary fistula, pathology examination showed that the mass was not a tumor but an aneurysm with thrombosis. This is the first time that a primary thrombus discovered on the surface of the heart.