Thrombotic risk stratification using computational modeling in patients with coronary artery aneurysms following Kawasaki disease

Kawasaki disease (KD) is the leading cause of acquired heart disease in children and can result in life-threatening coronary artery aneurysms in up to 25 % of patients. These aneurysms put patients at risk of thrombus formation, myocardial infarction, and sudden death. Clinicians must therefore decide which patients should be treated with anticoagulant medication, and/or surgical or percutaneous intervention. Current recommendations regarding initiation of anticoagulant therapy are based on anatomy alone with historical data suggesting that patients with aneurysms \(\ge \) 8 mm are at greatest risk of thrombosis. Given the multitude of variables that influence thrombus formation, we postulated that hemodynamic data derived from patient-specific simulations would more accurately predict risk of thrombosis than maximum diameter alone. Patient-specific blood flow simulations were performed on five KD patients with aneurysms and one KD patient with normal coronary arteries. Key hemodynamic and geometric parameters, including wall shear stress, particle residence time, and shape indices, were extracted from the models and simulations and compared with clinical outcomes. Preliminary fluid structure interaction simulations with radial expansion were performed, revealing modest differences in wall shear stress compared to the rigid wall case. Simulations provide compelling evidence that hemodynamic parameters may be a more accurate predictor of thrombotic risk than aneurysm diameter alone and motivate the need for follow-up studies with a larger cohort. These results suggest that a clinical index incorporating hemodynamic information be used in the future to select patients for anticoagulant therapy.     

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.     

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.     

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.     

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.     

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.     

Stent implantation for a totally occluded right coronary artery in a six-year-old boy after Kawasaki disease: a case report

Introduction

Coronary stenting has previously been considered to be less feasible in children under 12 years old due to the limitation of vascular access. We report the case of a six-year-old boy who successfully underwent stent implantation for his totally occluded right coronary artery.

Case presentation

A Taiwanese boy aged six years and nine months old was found to have giant aneurysms after an acute episode of Kawasaki disease. An angiography revealed that his middle right coronary artery was totally occluded. A 0.014-inch guidewire was advanced to cross the totally occluded site. After pre-dilating the middle portion of his right coronary artery with a 1.5 mm balloon, stenting of his right coronary artery was accomplished using a 2.5 × 28 mm and a 2.5 × 18 mm bare metal stent. A final angiography demonstrated no residual stenosis or dissection.

Conclusion

Coronary stenting could be a therapeutic option for children as young as six years old. Close follow-up is mandatory because the long-term outcome is still unclear, especially in a small child.     

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).     

Treatment of coronary artery aneurysms by percutaneous sealing with bovine-pericardium-covered stents

The clinical significance of coronary artery aneurysms is briefly discussed. Until recently, surgical excision was the only treatment available. Single-case reports have documented aneurysm exclusion with vein-covered stents using 10 or 11 F. guiding catheters. This paper reports four patients with coronary artery aneurysms which were successfully excluded with the use of a novel pericardium-covered stent which is less invasive and shortens procedure time compared with the use of an autologous vein-grated stent and can be deployed using 8 F. or 9 F. guiding catheters. Short-term (five- to eight-month) clinical follow-up has been event-free in all patients, and in three patients six-month follow-up angiography has shown insignificant luminal loss.     

Image-based modeling of hemodynamics in coronary artery aneurysms caused by Kawasaki disease

Kawasaki Disease (KD) is the leading cause of acquired pediatric heart disease. A subset of KD patients develops aneurysms in the coronary arteries, leading to increased risk of thrombosis and myocardial infarction. Currently, there are limited clinical data to guide the management of these patients, and the hemodynamic effects of these aneurysms are unknown. We applied patient-specific modeling to systematically quantify hemodynamics and wall shear stress in coronary arteries with aneurysms caused by KD. We modeled the hemodynamics in the aneurysms using anatomic data obtained by multi-detector computed tomography (CT) in a 10-year-old male subject who suffered KD at age 3?years. The altered hemodynamics were compared to that of a reconstructed normal coronary anatomy using our subject as the model. Computer simulations using a robust finite element framework were used to quantify time-varying shear stresses and particle trajectories in the coronary arteries. We accounted for the cardiac contractility and the microcirculation using physiologic downstream boundary conditions. The presence of aneurysms in the proximal coronary artery leads to flow recirculation, reduced wall shear stress within the aneurysm, and high wall shear stress gradients at the neck of the aneurysm. The wall shear stress in the KD subject (2.95-3.81 dynes/sq cm) was an order of magnitude lower than the normal control model (17.10-27.15 dynes/sq cm). Particle residence times were significantly higher, taking 5 cardiac cycles to fully clear from the aneurysmal regions in the KD subject compared to only 1.3 cardiac cycles from the corresponding regions of the normal model. In this novel quantitative study of hemodynamics in coronary aneurysms caused by KD, we documented markedly abnormal flow patterns that are associated with increased risk of thrombosis. This methodology has the potential to provide further insights into the effects of aneurysms in KD and to help risk stratify patients for appropriate medical and surgical interventions.     

介入栓塞治疗内脏动脉瘤的临床研究

目的:探讨介入血管腔内栓塞治疗内脏动脉瘤的方法、疗效及安全性。方法:选择内脏动脉瘤患者23例,包括脾动脉瘤13例,肝动脉瘤2例,胃十二指肠动脉瘤3例,肠系膜上动脉瘤4例,肾动脉瘤1例。其中,9例行远近端动脉栓塞术,4例采用支架辅助弹簧圈瘤体内填塞,3例采用弹簧圈瘤体内填塞加瘤体内注胶栓塞术,4例行弹簧圈瘤体内栓塞术,2例行分支动脉颗粒栓塞术,1例行单纯注胶栓塞术。术后1月、3月、6月行超声、CTA或血管造影复查,以后每年复查一次。结果:本组均成功行介入血管腔内栓塞治疗内脏动脉瘤,栓塞治疗后造影示动脉瘤体和/或载瘤动脉闭塞,动脉瘤体内无明显对比剂显影,脾动脉瘤栓塞患者有3例出现发热,脾区疼痛等脾梗塞症状,未见栓塞术相关严重并发症发生。4例消化道出血患者出血均停止。术后随访3~48个月,未见动脉瘤破裂出血、动脉瘤复发或增大,支架置入者,支架内及分支动脉血流均保持通畅。结论:介入血管腔内栓塞是一种治疗内脏动脉瘤的简便、微创、安全有效的方法。     

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.     

Pathogenetic determinants in Kawasaki disease: the haematological point of view

Kawasaki disease is a multisystemic vasculitis that can result in coronary artery lesions. It predominantly affects young children and is characterized by prolonged fever, diffuse mucosal inflammation, indurative oedema of the hands and feet, a polymorphous skin rash and non‐suppurative lymphadenopathy. Coronary artery involvement is the most important complication of Kawasaki disease and may cause significant coronary stenosis resulting in ischemic heart disease. The introduction of intravenous immunoglobulin decreases the incidence of coronary artery lesions to less than 5%. The etiopathogenesis of this disease remains unclear. Several lines of evidence suggest that an interplay between a microbial infection and a genetic predisposition could take place in the development of the disease. In this review, we summarize the state of the art of pathogenetic mechanisms of Kawasaki disease underscoring the relevance of haematological features as a novel field of investigation.     

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。     

Ultrasound screening for clinically occult abdominal aortic aneurysm.

In a review of the records of 74 patients who had undergone repair of an abdominal aortic aneurysm at a community hospital between 1977 and 1983 we found that the aneurysm had been undiagnosed before rupture in 35%; these patients had an operative death rate of 50%, whereas elective repair carried a death rate of 4%. The characteristic patient was an obese man over the age of 55 years with hypertension, coronary artery disease, cerebrovascular disease or peripheral vascular disease. Ultrasound examination was performed in 45 patients with these characteristics, and six aneurysms were diagnosed. Either surgery or computed tomography confirmed the diagnosis. The rate of false-negative results was estimated by review of the charts of 100 men over the age of 55 years who had undergone abdominal ultrasonography for other indications: no undetected aneurysms were discovered over 3 years of follow-up. Routine screening in this high-risk group would improve the rate of diagnosis of this potentially fatal condition before rupture and offer the patient the lower mortality rate associated with elective surgery.     

Computational modeling of blood component transport related to coronary artery thrombosis in Kawasaki disease

Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case—mechanical or biochemical—could help define improved strategies for thrombosis prevention tailored for each patient.     

Prognosis after graft replacement operation for abdominal aortic aneurysm.

We analyze findings on the long-term survival of patients undergoing elective graft replacement operations for abdominal aortic aneurysm. We review the principal surgical case series published in peer-reviewed, English-language journals over the past 15 years. Preoperative mortality was 4.0%, and 5-year survival was 69% in 16 reviewed studies encompassing 4,288 patients. Articles on late survival have largely focused on the preoperative assessment of coronary artery disease in patients who are candidates for aortic resection. The influence of other recognized risk factors, such as advanced age, hypertension, cerebrovascular disease, congestive heart failure, diabetes mellitus, and multiple aneurysms, is often not well specified in these studies. As a greater number of older patients with abdominal aortic aneurysm are seen with serious associated disease, knowledge about the expected survival of patients with surgically treated aneurysms is becoming more important to both primary care physicians and vascular surgeons when eliciting patient preferences for surgical treatment.     

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。     

血管内介入治疗颅内动脉瘤合并缺血性脑血管疾病的临床研究

摘要 目的：探讨血管内介入治疗颅内动脉瘤（IA）合并缺血性脑血管疾病的安全性和有效性。方法：回顾性分析了2018年1月至2020年12月使用血管内介入治疗IA合并缺血性脑血管疾病的32例临床资料。结果：32例中共发现了35枚IA,37处狭窄。IA平均大小为（5.17±3.12）mm,其中位于颈内动脉有26枚（74%）,位于椎基底动脉有9枚（26%）,7例（22%）患者术前检查发现存在两枚IA。37处狭窄中,位于椎基底动脉有9处（24%）,位于颅外段有8处（22%）,其余20处狭窄（54%）均位于颈内动脉,术前平均狭窄率为75.7%。所有病例手术过程顺利,术后IA中达到完全栓塞有31枚（89%）,4枚残留颈部（11%）。37处狭窄中,术后平均狭窄率为8.8%,所有患者术后造影脑血管远端均通畅。治疗期间1例支架内再狭窄,1例脑血管痉挛,出院时所有病例改良Rankin评分量表（mRS）均小于2分。32位患者均得到术后全脑血管造影（DSA）随访,随访时间为6到18个月（平均为8.8个月）,随访期间1例出现支架内再狭窄。结论：血管内介入治疗IA合并缺血性脑血管疾病是安全有效的,值得临床借鉴应用。