Original articleRegression of aneurysms in Kawasaki disease: A pathological study
The pathology of five aneurysms resected from four patients with Kawasaki disease was examined to elucidate the mechanisms of regression. (1) Marked intimal thickening was present in all five aneurysms. (2) Two patients treated with aspirin early in their course showed well-regenerated endothelium and marked thickening of the intima without massive thrombus; the thickened intima was rich in smooth muscle cells. These aneurysms maintained an adequate lumen of similar diameter to normal arteries, and some regressed angiographically. (3) Two patients untreated with aspirin in the acute phase had intial thickening associated with massive thrombus formation and calcification. The pathologic appearances were similar to those of early atherosclerosis. One patient died suddenly of myocardial infarction. We conclude that the angiographically demonstrated phenomenon of aneurysm regression may result from intimal thickening mainly caused by the proliferation of smooth muscle cells not associated with massive thrombus. The thickened intima associated with massive thrombus may cause ischemic heart disease and simulate atherosclerosis. It is possible that the administration of aspirin may prevent massive thrombus formation. We hypothesize that Kawasaki disease may be an etiologic factor in some cases of early atypical coronary atherosclerosis.
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Cited by (192)
Time Course of Coronary Artery Aneurysms in Kawasaki Disease
2021, Journal of PediatricsTo 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.
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.
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).
CAAs with a smaller diameter regressed earlier, and most CAAs of <6 mm regressed by 6 months after Kawasaki disease.
Pattern of organ remodeling in chronic non-communicable diseases is due to endogenous regulations and falls under the category of Kauffman's self-organization: A case of arterial neointimal pathology
2020, Medical HypothesesClinical diagnosis is based on analysis of pathologic findings that may result in perceived patterns. The same is true for diagnostic pathology: Pattern analysis is a foundation of the histopathology-based diagnostic system and, in conjunction with clinical and laboratory findings, forms a basis for the classification of diseases. Any histopathology diagnosis is based on the explicit assumption that the same diseased condition should result in formation of the same (or highly similar) morphologic patterns in different individuals; it is a standard approach in microscopic pathology, including that of non-communicable chronic diseases with organ remodeling. During fifty years of examining diseased tissues under microscopy, I keep asking the same question: Why is a similarity of patterns expected for chronic organ remodeling? For infection diseases, xenobiotic toxicity and deficiencies forming an identical pathologic pattern in different individuals is understandable and logical: The same infection, xenobiotic, or deficiency strikes the same target, which results in identical pathology. The same is true for Mendelian diseases: The same mutations lead to the same altered gene expressions and the same pathologic pattern. But why does this regularity hold true for chronic diseases with organ remodeling? Presumable causes (or risk factors) for a particular chronic disease differ in magnitude and duration between individuals, which should result in various series of transformations. Yet, mysteriously enough, pathological remodeling in a particular chronic disease always falls into a main dominating pattern, perpetuating and progressing in a similar fashion in different patients. Furthermore, some chronic diseases of different etiologies and dissimilar causes/risk factors manifest as identical or highly similar patterns of pathologic remodeling.
I hypothesize that regulations governing a particular organ’s chronic remodeling were selected in evolution as the safest response to various insults and physiologic stress conditions. This hypothesis implies that regulations directing diseased chronic remodeling always preexist but normally are controlled; this control can be disrupted by a diverse range of non-specific signals, liberating the pathway for identical pathologic remodeling. This hypothesis was tested in an analysis of arterial neointimal formation, the identical pathology occurring in different diseases and pathological conditions: graft vascular disease in organ transplantation, in-stent restenosis, peripheral arterial diseases, idiopathic intimal hyperplasia, Kawasaki disease, coronary atherosclerosis and as reaction to drugs. The hypothesis suggests that arterial intimal cells are poised between only two alternative pathways: the pathway with controlled intimal cell proliferation or the pathway where such control is disrupted, ultimately leading to the progressive neointimal pathology. By this property the arterial neointimal formation constitutes a special case of Kauffman’s self-organization. This new hypothesis gives a parsimonious explanation for identical pathological patterns of arterial remodeling (neointimal formation), which occurs in diseases of different etiologies and due to dissimilar causes/risk factors, or without any etiology and causes/risk factors at all. This new hypothesis also suggests that regulation facilitating intimal cell proliferation cannot be overwritten or annulled because this feature is vital for arterial differentiation, cell renewal, and integrity. This hypothesis suggests that studying numerous, and likely interchangeable, non-specific signals that disrupt regulation controlling intimal cell proliferation is unproductive; instead, a study of the controlling regulation(s) itself should be a priority of our research.
Outcomes in Kawasaki disease patients with coronary artery abnormalities at admission
2020, American Heart JournalPrevious studies demonstrated that coronary artery lesions (CALs) resulting from Kawasaki disease (KD) can improve over time. However, limited information is available on sub-acute outcomes of CALs detected at admission during KD illness.
The nationwide Japanese KD survey contained substantial information on KD patients with CALs detected at admission and who received standard IVIG treatment within 10 days of disease onset. Coronary outcomes were evaluated by changes in CALs from admission to the first assessment at 30 days from disease onset in three categories: improved, unchanged, and progressed. Ordinal logistic regression analysis was performed to evaluate factors associated with the outcomes.
Of 2024 patients with CALs detected at admission, improved, unchanged, and progressed outcomes were found in 1548 (76.5%), 390 (19.3%), and 86 (4.2%), respectively. Over 80% of patients with coronary artery (CA) dilatations had improved outcome. Independent factors associated with worse outcomes were larger-size CALs (adjusted ORs [95% CIs]: CA aneurysm = 5.13 [3.65-7.22] and giant CA aneurysms = 7.49 [3.56-15.72] compared with CA dilatation, respectively), age ≥ 60 months (1.45 [1.08-1.94] compared with 12-59 months), recurrent KD (1.57 [1.07-2.29]), parental history of KD (2.23 [1.02-4.85]), and delayed admission (8-10 days from disease onset: 1.76 [1.21-2.57] compared with 1-4 days).
KD patients with larger CALs, ≥60 months old, and with recurrent status or parental history may require more rigorous treatment. In addition, delayed admission may result in worse coronary outcome, indicating that prompt diagnosis and treatment are required.
Virtual histology intravascular ultrasound evaluation of coronary artery lesions within 1 year and more than 10 years after the onset of Kawasaki disease
2020, Journal of CardiologyCoronary artery evaluation by virtual histological intravascular ultrasonography (VH-IVUS) late in Kawasaki disease (KD) shows intimal thickening, calcification, fatty components, and necrosis of regressed coronary artery lesions (CALs). However, it is not clear when these VH-IVUS findings start to occur. Therefore, we evaluated coronary arteries using VH-IVUS in patients with early-stage KD and tried to determine whether these atherosclerotic findings on VH-IVUS were different from that in patients with late-stage KD.
Eighteen patients with KD aged between 1 and 32 years who had CALs and underwent cardiac catheterization between January 1, 2008 and December 31, 2014 were included. They were divided into 2 groups—those with the disease for <1 year (group A) and those with it for >10 years (group B). VH-IVUS findings were compared between the groups. The coronary arteries were divided based on coronary angiography findings into normal, regressed (dilated CALs regressed to a normal size), and aneurysmal lesions. The Wilcoxon signed-rank test was used in the statistical analysis.
In both regressed and aneurysmal lesions, marked intimal proliferation and atherosclerotic findings (fibro-fatty and necrotic core lesions) were observed. In addition, there was no difference in the area percentage of atherosclerosis between the groups.
VH-IVUS revealed that atherosclerotic-like findings exist in CALs in patients with KD, even within a year of onset. The findings were almost the same in those with the disease for >10 years. Because there is no histological evidence of atherosclerosis in KD, these VH-IVUS findings may indicate complex histological findings of KD. Nevertheless, early interventions to help reduce the risk factors of atherosclerosis may be required in these patients.
Effective infliximab therapy for the early regression of coronary artery aneurysm in Kawasaki disease
2018, International Journal of CardiologyThere is limited information available regarding the role of infliximab (IFX) following the acute phase of Kawasaki disease (KD). We aimed to evaluate whether IFX is associated with coronary artery aneurysm (CAA) regression.
Between 2005 and 2016, we identified 971 consecutive patients with KD from 3 tertiary institutions, and 49 (5%) with CAAs were enrolled in our study. Patients were divided into 2 groups: 27 who received IFX and 22 who did not. The persistence rate of CAAs was compared between the groups.
Age, sex, and duration of the febrile period did not significantly differ between the groups. The maximum value of C-reactive protein was higher in the IFX- than in the non-IFX group. The maximum z-score of CAAs did not differ between the groups. The 2-, 4- and 6-year cumulative persistence rate of CAA was 24%, 24% and 24% in IFX-group, whereas 67%, 52% and 33% in non-IFX group, respectively (P = 0.03). The median duration of CAA regression was 1.1 vs. 4.6 years. Among those who developed medium- or large-sized CAAs, the 2-, 4- and 6-year cumulative persistence rate of CAA was 33%, 33% and 33% in IFX group, whereas 77%, 51% and 48% in non-IFX group, respectively (P = 0.047). Multivariate logistic regression analysis indicated that the maximum z-score (hazard ratio 0.72, p < 0.001) and response to IFX (hazard ratio 4.56, p = 0.017) were independently related to regression.
IFX therapy was observed to be effective for the early improvement of CAAs in patients with intravenous immunoglobulin-resistant KD.
Difference Between Persistent Aneurysm, Regressed Aneurysm, and Coronary Dilation in Kawasaki Disease: An Optical Coherence Tomography Study
2018, Canadian Journal of CardiologyCoronary artery (CA) aneurysms are a serious complication of Kawasaki disease (KD). Conventional imaging techniques often described segments with regressed aneurysms as normal, whereas studies have shown significant endothelial dysfunction.
KD patients with aneurysms scheduled for routine coronary angiography underwent optical coherence tomography (OCT) imaging between 2013 and 2016. Microstructural coronary changes were compared between normal CA segments and those with dilation, regressed aneurysms, and persistent aneurysms.
OCT was performed on 33 patients aged 12.0 ± 5.4 years, 8.5 ± 5.4 years after KD diagnosis. Of the 79 segments analyzed, 25 had persistent aneurysms, 22 regressed aneurysms, 11 CA dilation, and 21 no CA involvement. Intimal thickness was 489 ± 173 μm, 304 ± 158 μm, 102 ± 68 μm, and 63 ± 29 μm, respectively (P < 0.001). There was a linear correlation between the maximum aneurysm size and the intimal thickness, as well as coronary dimension at the time of OCT. Fibrosis (54 segments, 68%) and cellular infiltration (22 segments, 28%) were found more often in segments with CA involvement, but also those without (P = 0.01; P = 0.02). Destruction of the media (34 segments, 43%), calcifications (6 segments, 8%), neovascularization (18 segments, 23%), and white thrombi (8 segments, 10%) were found almost exclusively in segments with a history of aneurysms.
Intimal hyperplasia, fibrosis, and cellular infiltration were found in all categories of CA involvement, whereas calcification, destruction of the media, neovascularization, and white thrombi were found essentially only in segments with saccular or fusiform aneurysms. Prospective studies with outcome correlations are needed to see if this is associated with an increased risk of late adverse events.
Les anévrysmes des artères coronaires (AC) sont une complication sérieuse de la maladie de Kawasaki (MK). Au moyen des techniques traditionnelles d’imagerie, les segments avec anévrysmes sont en ayant regressé apparaissent normaux, alors que les études ont montré une dysfonction endothéliale importante.
Les patients atteints de la MK qui ont subi un cathétérisme cardiaque entre 2013-2016 pour suivi des anévrysmes coronariens ont aussi subi une tomographie par cohérence optique (TCO). Nous avons comparé les modifications microstructurelles des AC entre les segments normaux des AC et ceux montrant une dilatation, une régression des anévrysmes et une persistance des anévrysmes.
Trente-trois patients âgés de 12,0 ± 5,4 ans ont subi une TCO 8,5 ± 5,4 ans après le diagnostic de MK. Parmi les 79 segments analysés, 25 montraient une persistance des anévrysmes, 22 montraient une régression des anévrysmes, 11 montraient une dilatation des AC et 21 ne montraient aucune atteinte des AC. L’épaisseur de l’intima était respectivement de 489 ± 173 μm, de 304 ± 158 μm, de 102 ± 68 μm et de 63 ± 29 μm (P < 0,001). Il y avait une corrélation linéaire entre la taille maximale de l’anévrysme et l’épaisseur de l’intima, ainsi que la dimension coronarienne au moment de la TCO. Nous avons plus souvent observé une fibrose (54 segments, 68 %) et une infiltration cellulaire (22 segments, 28 %) dans les segments montrant une atteinte des AC, mais également dans les segments n’en montrant pas (P = 0,01; P = 0,02). Nous avons observé une destruction de la média (34 segments, 43 %), des calcifications (6 segments, 8 %), une néovascularisation (18 segments, 23 %) et des thrombi blancs (8 segments, 10 %) presque exclusivement dans les segments avec anévrysmes coronariens.
Nous avons observé une hyperplasie de l’intima, une fibrose et une infiltration cellulaire dans toutes les catégories d’atteinte des AC, alors que nous observions une calcification, une destruction de la média, une néovascularisation et des thrombi blancs essentiellement dans les segments qui montraient des anévrysmes sacculaires ou fusiformes. Des études prospectives sont nécessaires pour determiner l'association des trouvailles à la TCO avec les effets cardiaques adverses tardifs.