TNF-alpha is necessary for induction of coronary artery inflammation and aneurysm formation in an animal model of Kawasaki disease

Kawasaki disease is the most common cause of multisystem vasculitis in childhood. The resultant coronary artery lesions make Kawasaki disease the leading cause of acquired heart disease in children in the developed world. TNF-alpha is a pleiotropic inflammatory cytokine elevated during the acute phase of Kawasaki disease. In this study, we report rapid production of TNF-alpha in the peripheral immune system after disease induction in a murine model of Kawasaki disease. This immune response becomes site directed, with migration to the coronary arteries dependent on TNF-alpha-mediated events. Production of TNF-alpha in the heart is coincident with the presence of inflammatory infiltrate at the coronary arteries, which persists during development of aneurysms. More importantly, inflammation and elastin breakdown in the coronary vessels are completely eliminated in the absence of TNF-alpha effector functions. Mice treated with the TNF-alpha-blocking agent etanercept, as well as TNFRI knockout mice, are resistant to development of both coronary arteritis and coronary aneurysm formation. Taken together, TNF-alpha is necessary for the development of coronary artery lesions in an animal model of Kawasaki disease. These findings have important implications for potential new therapeutic interventions in children with Kawasaki disease.     

川崎病患儿肠道菌群构成及分布与其冠状动脉病变的相关性分析

摘要 目的：分析川崎病患儿肠道菌群构成及分布与其冠状动脉病变的相关性。方法：选择我院自2020年1月至2023年2月接诊的86例川崎病患儿作为研究对象,根据是否出现冠状动脉病变,分为冠状动脉病变组（35例）和非冠状动脉病变组（51例）。检测所有患儿的肠道菌群多样性[肠道菌群丰度（Ace指数）、肠道菌群多样性（Shannon指数）]、肠道菌群构成比例[门水平（变形菌门、厚壁菌门、拟杆菌门）、属水平（乳杆菌属、拟杆菌属、韦荣球菌属）],使用多因素Logistic回归分析肠道菌群构成及分布与冠状动脉病变的关系。结果：冠状动脉病变组Ace指数大于非冠状动脉病变组（P＜0.05）;冠状动脉病变组与非冠状动脉病变组的Shannon指数比较无差异（P＞0.05）;冠状动脉病变组肠道厚壁菌门占比低于非冠状动脉病变组,拟杆菌门占比高于非冠状动脉病变组（P＜0.05）;冠状动脉病变组与非冠状动脉病变组的肠道变形菌门占比比较无差异（P＞0.05）;冠状动脉病变组肠道乳杆菌属占比、韦荣球菌属占比均低于非冠状动脉病变组（P＜0.05）;冠状动脉病变组与非冠状动脉病变组的肠道拟杆菌属占比比较无差异（P＞0.05）;经多因素Logistic回归分析,肠道Ace指数、厚壁菌门、拟杆菌门、乳杆菌属、韦荣球菌属均是川崎病患儿发生冠状动脉病变的独立影响因素（P＜0.05）。结论：川崎病患儿肠道菌群构成及分布与其冠状动脉病变密切相关,为改善肠道菌群失调、增加患儿的临床获益提供依据,应引起临床重视。     

Presence of IFN-gamma does not indicate its necessity for induction of coronary arteritis in an animal model of Kawasaki disease

Kawasaki disease is the most common cause of vasculitis affecting children, and the leading cause of acquired heart disease in the developed world. To date, studies on the role of IFN-gamma in the pathogenesis of Kawasaki disease have focused on peripheral production of IFN-gamma, and have yielded conflicting results. Affected heart tissue is not available from children with Kawasaki disease. In this study, we use an animal model of Kawasaki disease, Lactobacillus casei cell wall extract (LCWE)-induced coronary arteritis, to examine the role of IFN-gamma in the development of coronary artery lesions. We report the presence of IFN-gamma, both at the mRNA and protein levels, in the affected vessels. Its biphasic expression, first at days 3-7 and again at days 28-42 post-LCWE injection, corresponds to the first appearance of inflammatory infiltrate in coronary arteries, and later to vascular wall disruption and aneurysm formation, respectively. Interestingly, ablation of IFN-gamma expression did not dampen the inflammatory response, and IFN-gamma-deficient lymphocytes proliferated more vigorously in response to LCWE than those of wild-type animals. Of more importance, the incidence of coronary arteritis was the same in IFN-gamma-deficient and wild-type mice. Taken together, our findings demonstrate that IFN-gamma regulates the immune response during development of coronary arteritis, but is not required for the induction of coronary artery disease.     

超声在完全与不完全川崎病患儿冠状动脉病变评估中的应用价值

摘要 目的：探讨超声在完全与不完全川崎病（Kawasaki Disease,KD）患儿冠状动脉病变（Coronary artery lesions,CAL）评估中的应用价值。方法：2019年6月到2021年5月选择在西安医学院第二附属医院住院诊治的83例川崎病患儿,其中完全川崎病患儿43例（完全组）,不完全川崎病患儿40例（不完全组）。所有患儿都给予超声检查,评估两组的临床表现、血液学指标、冠状动脉病变情况以及超声的诊断价值。结果：完全组的球结膜充血、皮疹、口唇破裂、手足硬肿、颈部淋巴结肿大等发生率高于不完全组（P>0.05）。两组的白细胞计数、血红蛋白对比差异有统计学意义（P<0.05）,C反应蛋白、血小板、白蛋白对比差异无统计学意义（P>0.05）。完全组的冠状动脉病变发生率为60.5 %,高于不完全组的27.5 %（P<0.05）。在83例患儿中,超声诊断为完全川崎病42例,不完全川崎病41例,超声对完全与不完全川崎病患儿的鉴别诊断敏感性与特异性为97.7 %（42/43）和100.0 %（40/40）。结论：完全与不完全川崎病患儿在临床表现、冠状动脉病变与实验室检测指标上都存在一定的差异,超声能鉴别诊断完全与不完全川崎病患儿的敏感性与特异性都比较好。     

Atypical and complicated Kawasaki disease in infants. Do we need criteria?

Case reports suggest that infants with Kawasaki disease have atypical presentations and a high complication rate, likely related to delayed diagnosis and treatment. To date, no study of consecutive cases has compared infants with older children who have both atypical and typical Kawasaki disease. We retrospectively reviewed 44 cases of Kawasaki disease treated at our hospital from March 1980 to 1990: 11 (25%) were infants; 9 (20%) had atypical Kawasaki disease, of which 5 (56%) were infants; the male to female ratio was 1.7:1. Infants had a higher incidence of atypical Kawasaki disease (5 [45%] versus 4 [12%]; P = .007) and of coronary artery complications (7 [64%] versus 3 [9%]; P = .002), and coronary artery complications developed in all of the infants with atypical Kawasaki disease (5 [100%] versus 0 [0%]; P < .01). Yet, the other manifestations and laboratory changes were at least as common as in the older children. Coronary artery complications did not develop in any patient who received early intravenous immune globulin therapy. We suggest that in infants with Kawasaki disease, accepted criteria are too restrictive to allow early diagnosis and effective treatment. Until a definitive test is available, clinical judgment is required in the diagnosis of atypical Kawasaki disease. Intravenous immune globulin is known to be safe, and its early use in patients with suspected atypical Kawasaki disease is appropriate.     

Kawasaki disease: Canadian update.

Kawasaki disease, or mucocutaneous lymph node syndrome, is a multisystem disorder that affects young children. Between 1979 and 1982, 357 patients from 15 university pediatric centres in Canada were reported to have the disease. The diagnosis of Kawasaki disease is based on six clinical features, including fever, conjunctivitis, cracked lips, reddening and swelling of the hands and feet, rash and cervical lymphadenopathy. A scoring system is described that may help predict the development of cardiovascular complications. Coronary artery involvement can be recognized early by two-dimensional echocardiography. Anti-inflammatory therapy, principally with acetylsalicylic acid, is indicated in the acute phase and antithrombotic treatment in the subacute and chronic phases of the disease if coronary artery aneurysms have developed. Prolonged follow-up for patients with aneurysms is necessary. The length of follow-up for patients without aneurysms will depend on the results of studies on patients with Kawasaki disease after they reach adulthood.     

Recognition and management of Kawasaki disease

Kawasaki disease is the leading cause of acquired heart disease in children in the developed world, with coronary artery aneurysms occurring in up to 25% of untreated cases. The mean annual incidence of Kawasaki disease across Canada is about 13 per 100,000 children less than 5 years of age, based on hospital discharge data from 1990 to 1995. The cause remains unknown, and the diagnosis is based on the same clinical criteria used to describe the disease over 30 years ago. However, nonspecific clinical features, evolving presentations and atypical or incomplete presentations make early diagnosis and timely treatment difficult. Delays in diagnosis and treatment, which occur more frequently in older children, are associated with an increased risk of coronary artery aneurysms. Hence, high diagnostic suspicion and prompt referral are required to reduce the rate of cardiac complications.     

A critical appraisal of the role of intracellular Ca2+-signaling pathways in Kawasaki disease

Kawasaki disease is a multi-systemic vasculitis that generally occurs in children and that can lead to coronary artery lesions. Recent studies showed that Kawasaki disease has an important genetic component. In this review, we discuss the single-nucleotide polymorphisms in the genes encoding proteins with a role in intracellular Ca²⁺ signaling: inositol 1,4,5-trisphosphate 3-kinase C, caspase-3, the store-operated Ca²⁺-entry channel ORAI1, the type-3 inositol 1,4,5-trisphosphate receptor, the Na⁺/Ca²⁺ exchanger 1, and phospholipase Cß4 and Cß1. An increase of the free cytosolic Ca²⁺ concentration is proposed to be a major factor in susceptibility to Kawasaki disease and disease outcome, but only for polymorphisms in the genes encoding the inositol 1,4,5-trisphosphate 3-kinase C and the Na⁺/Ca²⁺ exchanger 1, the free cytosolic Ca²⁺ concentration was actually measured and shown to be increased. Excessive cytosolic Ca²⁺ signaling can result in hyperactive calcineurin in T cells with an overstimulated nuclear factor of activated T cells pathway, in hypersecretion of interleukin-1ß and tumor necrosis factor-α by monocytes/macrophages, in increased urotensin-2 signaling, and in an overactivation of vascular endothelial cells.     

冠状动脉弥漫性长病变治疗的研究进展

冠心病目前已经成为全球性关注的健康问题,为当今人类一大灾难性疾病。既往研究表明,冠状动脉弥漫性长病变占冠心病总患者约20%,冠状动脉弥漫性长病变患者其动脉粥样硬化的病变范围更加广泛,病变呈弥漫性,而且更多累及左主干,常常伴有血管直径小,血管成角、钙化、扭曲等特点,而且多发生于高龄、糖尿病患者中,以上特点又决定了冠状动脉弥漫性长病变成为冠心病治疗的又一难题。因此,有效的预防与治疗冠状动脉弥漫性长病变,已成为目前的关注重点与热点,本文概述了冠状动脉弥漫性长病变临床治疗中的常用方法以及各方法的疗效与优劣之势,多年临床实践经验表明PCI治疗仍占有主导位置,虽然目前冠状动脉弥漫性长病变的介入治疗应用药物洗脱支架的已经取得良好的临床效果,在很大程度降低了心血管事件发生率和再次血管重建率,但药物洗脱支架支架治疗冠状动脉弥漫性长病变的远期疗效仍在评估中。     

淀粉样蛋白A、D-二聚体、肌酸激酶同工酶联合检测对川崎病患儿冠状动脉损伤的诊断价值分析

摘要 目的：探讨血清淀粉样蛋白A(SAA)、D-二聚体(D-D)、肌酸激酶同工酶(CK-MB)联合检测对川崎病患儿冠状动脉损伤(CAL)的诊断价值。方法：选取2018年9月～2021年5月我院收治的80例川崎病患儿,根据是否合并CAL分为CAL组(n=34)和NCAL组(n=46)。收集患儿基础资料,并检测SAA、D-D、CK-MB水平。多因素Logistic回归分析川崎病患儿CAL影响因素,受试者工作特征（ROC）曲线分析血清SAA、D-D、CK-MB水平对川崎病患儿CAL的诊断价值。结果：与NCAL组比较,CAL组C反应蛋白(CRP)、红细胞沉降率(ESR)、SAA、D-D、CK-MB水平升高(P＜0.05)。多因素Logistic回归分析显示,CRP、ESR、SAA、D-D、CK-MB为川崎病患儿CAL独立影响因素(P＜0.05)。SAA、D-D、CK-MB、三项联合诊断川崎病患儿CAL的曲线下面积（AUC）分别为0.661、0.687、0.746、0.799,联合应用的诊断效能最高。结论：血清SAA、D-D、CK-MB是川崎病患儿CAL独立影响因素,且联合检测以上指标可辅助诊断川崎病患儿CAL。     

不同糖代谢冠心病患者的糖化血红蛋白水平与冠状动脉病变的关系

目的：研究不同糖代谢冠心病患者的糖化血红蛋白（HbA1c）水平与和冠状动脉病变的关系。方法：选取2013 年5 月到2014 年5 月我院收治的冠心病患者100 例,分为糖代谢正常组、异常组和糖尿病组。分析三组患者的HbA1c 水平、冠状动脉狭窄程度 及冠状动脉病变指数之间的关系和冠状动脉病变的危险因素。结果：三组患者的冠状动脉狭窄程度、冠状动脉病变支数、空腹血 糖（FPG）、餐后2 小时血糖（2hPG）、HbA1c 和三酰甘油（TG）水平比较,差异具有统计学意义（P<0.05）;HbA1c 水平与冠状动脉狭 窄程度呈正相关（P<0.05）;Logistic 结果显示年龄、性别、高血压、HbA1c、FPG、总胆固醇（TG）和高密度脂蛋白胆固醇（HDL-C）是 冠状动脉病变的危险因素（P<0.05）。结论：HbA1c 水平和冠状动脉病变具有相关性,是影响冠状动脉病变的重要危险因素。     

川崎病患儿的心率变异性指标与血清NT-proBNP及cTnI水平的相关性

目的:研究川崎病患儿的心率变异性指标与血清氨基末端脑钠肽前体(NT-pro BNP)及肌钙蛋白I(cTnI)水平的相关性,为临床诊疗提供依据。方法:选取2013年7月到2015年7月我院收治的川崎病患儿120例为研究组,根据患者是否存在冠状动脉损害分为A组(有冠状动脉损害)60例和B组(无冠状动脉损害)60例,同时选取同期健康体检儿童60例为对照组,比较各组窦性N-N间期标准差(SDNN)、5min N-N间期平均值标准差(SDANN)、极低频功率(VLF)、低频功率(LF)、高频功率(HF)、NT-proBNP水平以及cTnI水平。结果:研究组SDNN、SDANN、VLF、LF以及HF显著低于对照组,且A组显著低于B组,差异具有统计学意义(P0.05);研究组NT-proBNP水平和cTnI水平显著高于对照组,且A组显著高于B组,差异具有统计学意义(P0.05);研究组NT-proBNP与SDNN和HF呈负相关关系(P0.05),cTnI与SDNN和HF呈负相关关系(P0.05)。结论:心率变异性指标与川崎病患儿冠状动脉损害有关,与NT-proBNP、cTnI呈负相关关系。     

Platelet immune complex interaction in pathogenesis of Kawasaki disease and childhood polyarteritis.

The role of platelets in the pathogenesis of vasculitis and the formation of coronary artery aneurysms was studied in 19 children with Kawasaki disease and five with polyarteritis. All patients with Kawasaki disease developed thrombocytosis in the third week of illness. The peak platelet count was significantly correlated (p less than 0.005) with the subsequent development of coronary artery aneurysms. The rise in platelet count was associated with the appearance in the circulation of a factor that induced aggregation and serotonin release in normal platelets. This factor was shown to be of high molecular weight, and its activity was lost at low pH--features suggestive of an immune complex. Immune complexes, detected by precipitation with polyethylene glycol, also appeared in the circulation as the platelet count increased. These complexes induced platelet aggregation, and there was a significant correlation (p less than 0.001) between the concentrations of IgG and IgA in the polyethylene glycol precipitated material and the platelet aggregating activity. Similar platelet aggregating activity was also detected in patients with polyarteritis but followed a different time course, persisting in the circulation for several months in association with continued disease activity. These findings imply that different mechanisms have a role in distinct phases of Kawasaki disease. The initial feverish phase (probably infective) is probably followed by an immune complex vasculitis that occurs when antibodies to the initiating agent appear in the circulation. The immune complexes aggregate platelets and induce release of serotonin. Platelet derived vasoactive mediators may increase vascular permeability and facilitate further deposition of complexes in the tissues.     

Kawasaki disease causing saccular aneurysms of the coronary arteries

A 22-year-old man was referred for treatment of a 45 mm saccular aneurysm of the right coronary artery (RCA) and a 15 mm saccular aneurysm of the left anterior descending artery (LAD). The patient developed Kawasaki disease in 1998. The aneurysms were diagnosed in 2002. The RCA showed thrombus formation. Until now the patient had remained asymptomatic. He now presented with effort angina. On coronary angiography and magnetic resonance imaging, an occluded aneurysm of the proximal RCA (45 mm) was seen with a second aneurysm more distally (22 mm).     

Gene-expression patterns reveal underlying biological processes in Kawasaki disease

Background  

Kawasaki disease (KD) is an acute self-limited vasculitis and the leading cause of acquired heart disease in children in developed countries. No etiologic agent(s) has been identified, and the processes that mediate formation of coronary artery aneurysms and abatement of fever following treatment with intravenous immunoglobulin (IVIG) remain poorly understood.     

Hypertension exacerbates coronary artery disease in transgenic hyperlipidemic Dahl salt-sensitive hypertensive rats

BACKGROUND: The mechanisms underlying the known interaction of two complex polygenic traits, hypertension and hyperlipidemia, resulting in exacerbation of coronary artery disease have not been elucidated. Identification of critical pathways underlying said exacerbation could identify mechanism-based targets for intervention and prevention. MATERIALS AND METHODS: To investigate hypertension- atherosclerosis interaction, we studied the inbred transgenic atherosclerosis-polygenic hypertension Dahl salt-sensitive (S) rat model (Tg53), which over-expresses human cholesteryl ester transfer protein (hCETP) in the liver, and exhibits coronary artery disease and decreased survival compared with control non-transgenic Dahl S rats. Using serial-section histopathological and immunohistochemical analyses, we analyzed the coronary artery disease phenotype of Tg53 rats at end-stage marked by cardio-respiratory compromise as the experimental equivalent of acute coronary syndromes, and determined the effects of reduction of blood pressure through low salt diet (0.008% NaCl) on the coronary artery disease phenotype and survival. RESULTS: End-stage Tg53 rats exhibit coronary artery lesions in the proximal right coronary artery system which exhibit "culprit plaque" features such as plaque inflammation, matrix degradation, apoptosis, neovascularization, thrombosis and hemorrhage recapitulating said features and heterogeneity of human coronary "culprit plaques". Comparative analysis of 6 month vs end-stage lesions reveals distinct lesion development profiles of proximal coronary lesions which quickly progress from eccentric non-occlusive foam-cell rich lesions at 6 months to occlusive "culprit plaques", compared with more distal coronary lesions which exhibit occlusive thick-cap atheroma that remain relatively unchanged from 6 months to end stage. Reduction of hypertension through a low-salt (0.008% NaCl) diet increased survival (P < 0.0001) of Tg53 rats and significantly attenuated the coronary artery disease phenotype detected at 10 months of age marked by diminished apoptosis, neovascularization, matrix degradation compared with end-stage lesions detected at <8 months of age. CONCLUSIONS: End stage coronary lesions in the Tg53 rats recapitulate many, albeit not all, features of "culprit plaques" in humans supporting proposed paradigms of plaque vulnerability implicating lesion macrophage enrichment, apoptosis, matrix degradation and pathological neovascularization. Comparative time course analysis of coronary lesions reveals that plaques which develop into end-stage "culprit plaques" are distinct from "stable plaques" by location and early lesion morphology, suggesting distinct lesion development and progression pathways. The significant effects of low-salt diet-induced decrease in hypertension on right coronary disease phenotype provides compelling evidence that polygenic hypertension accelerates coronary plaque progression and complication independent of cardiac hypertrophy, and more importantly provides paradigmatic support for public health policy.     

The specific features of coronary artery lesion in patients with signs of high cardiac risk in non-ST segment elevation acute coronary syndrome

The paper covers risk stratification for cardiac events in patients with non-ST segment elevation acute coronary syndrome. It defines an association between risk factors, the specific features of coronary artery lesions, and the outcomes of the disease in relation to the used treatment policy. Particular emphasis is laid on the factors that are a handicap to the detection of a symptom-associated coronary artery in this category of patients.     

Vasculitis induced by immunization with Bacillus Calmette-Guérin followed by atypical mycobacterium antigen: a new mouse model for Kawasaki disease

Kawasaki disease causes systemic vasculitis. The development of skin lesions at the vaccination site with Bacillus Calmette-Guérin (BCG) is an important diagnostic symptom. We hypothesized that infection with ubiquitous microorganisms immunogenically related to BCG might induce an immunopathologic reaction leading to the development of Kawasaki disease. Mice were first inoculated with BCG, and then secondarily inoculated 4 weeks later with crude extract from Mycobacterium intracellulare (cMI), an abundant atypical mycobacterium. Animals inoculated with BCG followed by cMI developed coronary arteritis with infiltration of inflammatory cells, whereas control animals inoculated with only cMI or BCG did not, suggesting that the immune response to the mycobacteria induced autoimmunity to the vascular wall. Intravenous injection with antibodies to peroxiredoxin II, a modulator of vascular remodeling and a suggested target for autoimmune vasculitis, also resulted in coronary arteritis, but only after prior inoculation with BCG. Tumor necrosis factor-alpha, MCP1 and interferon-gamma production were significantly higher in the animals inoculated with BCG than in the control groups (P<0.05). BCG immunization was required for the development of coronary arteritis, suggesting that these cytokines might play important roles. The results indicate that BCG induces primary autoimmunity and stimulates cytokine induction, and that atypical mycobacterial infection boosts the autoimmunity resulting in coronary arteritis.     

Contrasting patterns of coronary atherosclerosis in normocholesterolaemic smokers and patients with familial hypercholesterolaemia.

An angiographic comparison was made of the extent and severity of coronary artery disease in 25 patients with heterozygous familial hypercholesterolaemia and 25 normocholesterolaemic patients with coronary artery disease in whom heavy cigarette consumption was the chief risk factor. The patients with familial hypercholesterolaemia were younger and included a much higher proportion of women than the smokers. Significantly more patients with familial hypercholesterolaemia had disease of the main stem of the left coronary artery (eight v none, p less than 0.05) and triple-vessel disease (18 v four, p less than 0.05). Disease affecting only distal vessels occurred in five smokers, whereas all the patients with familial hypercholesterolaemia showed a combination of proximal and distal lesions. These findings suggest that cigarette smoking and familial hypercholesterolaemia predispose to different patterns of coronary atheroma. Early coronary angiography with a view to coronary artery bypass surgery seems desirable in symptomatic patients with familial hypercholesterolaemia because of the common association of this disorder with life-threatening left main-stem disease.     

不同病情冠心病患者血清心型脂肪酸结合蛋白与颈动脉内膜中层厚度的关系分析

目的:探讨不同病情冠心病患者血清心型脂肪酸结合蛋白(H-FABP)与颈动脉内膜中层厚度(IMT)的关系。方法:选择内蒙古科技大学包头医学院第一附属医院老年科收治的冠心病患者60例,其中稳定型心绞痛(SAP)和急性冠脉综合征(ACS)各30例,根据冠状动脉病变支数将患者分为单支病变组19例、双支病变组19例和多支病变组22例;根据患者冠状动脉血管狭窄程度分为轻度病变组22例、中度病变组17例和重度病变组21例,选择同期健康体检者30例作为对照组。比较各组颈动脉IMT及血清H-FABP水平,并分析其相关性。结果:ACS组颈动脉IMT及血清H-FABP水平显著高于SAP组和对照组,SAP组颈动脉IMT及血清H-FABP水平显著高于对照组(P<0.05)。不同冠状动脉病变支数、病变程度冠心病患者颈动脉IMT及血清H-FABP水平整体比较差异有统计学意义(P<0.05),多支病变组和双支病变组血清H-FABP水平比较无统计学意义(P>0.05)。Spearman相关分析显示,冠心病患者血清H-FABP水平与颈动脉IMT呈正相关(r=0.754,P<0.05)。结论:冠心病患者血清H-FABP水平与颈动脉IMT异常升高,其水平随冠状动脉病变程度加重而升高,且两者呈正相关。