KD is an idiopathic type of acute vasculitis mainly occurring in infants and children younger than 5 years old. Some potential etiologies like certain genetic markers, viral pathogens or immune responses have been reported to be related with KD [13, 14]. It is most common in the Asian race compared to the non-Asian population. In Japan, Korea, and China, the incidence varies from 39 to 250 in 100,000 children < 5 years old, which appears to be on the rise [15, 16]. The prevalence is much lower in non-Asian countries: 17-20 per 100 000 children < 5 years old in the USA, 26.2 in Canada, and 8.4-31 in Europe, with boys having a higher incidence than girls [16].
Coronary artery lesions are the main complications of KD, occurring in up to 40% of patients. CAA has a highest incidence of less than 5% following the administration of IVIG [17, 18]. Other complications associated with KD include coronary artery dilation, thrombosis, stenosis and occlusion, leading to myocardial infarction, heart failure and sudden death. CAA usually forms 2 weeks after onset and thrombosis may be caused by injury to the endothelium and platelet activation. In the chronic phase, there is reconstruction of the vessel wall leading to progressive stenosis, thrombosis and occlusion [5, 19]. Compared with atherosclerosis in adults, thrombus formation in KD is much severe. As instructed by the 2017 AHA and 2014 JCS guidelines, KD necessitates long term management till adulthood.
The size of CAA has always been used as a parameter to distinguish CAAs with higher risks for cardiovascular events. JCS and AHA guidelines of triple-therapy (anticoagulation and dual-antiplatelet therapy) are basically based on the CAA’s diameter: Diameter ≥8 mm or z-score ≥10 [4, 20]. Cardiac complications have been proven to be more common in giant aneurysms. In a review by Tsuda consisting of 245 patients with giant CAA, death, myocardial infarction, and surgery occurred in 15 (6%), 57 (23%), and 90 patients (37%), respectively [21]. In another study composed of 1006 patients covering 44 participating institutions, the cardiac events free rate was 100%, 96%, and 79% for small, medium, and large CAAs [22]. Over 50% of CAA regress to normal size within 5 years and the likelihood of regression seems to highly correlate with the original size of the lesion [23, 24]. In agreement with previous studies, we also confirmed the value of the CAA’s size. Dmax ≥ 6.850mm and Z-score ≥ 18.753 may be used as predictors of thrombotic risk.
Some specific locations were prone to form large CAAs and thrombosis, including the LCA/LAD branching site and the RCA’s proximal segment. Risk was increased when extensive dilation or multiple aneurysms were found in one coronary artery (Fig. 1A, 1B). Distal aneurysms may be more prone to thrombosis than proximal ones, even those with same sizes and similar hemodynamic dates (Fig. 1D).
Hemodynamic variables could also be useful in risk stratification schemes for CAA. In precedent experimental studies, sites exposed to low WSS and high OSI have been demonstrated to be more susceptible to develop intimal thickening and thrombosis [25–27]. Local low WSS induced platelets aggregation close to the vascular wall and promoted clot formation [28]. Endothelial cells would respond to the hemodynamic changes of low WSS and high OSI to modulate intracellular signaling, stimulating structural remodeling, thrombogenesis, inflammation, and atherosclerosis [5, 25]. Dibyendu discovered that aneurysms with thrombosis presented longer RRT (mean 7.8±2.8 vs. 4.0 ± 2.0) and 108% lower WSS compared to aneurysms without thrombosis [29]. Grande studied 10 KD patients with CAAs and depicted that hemodynamic parameters were sensitive to thrombosis [7].
In Fig. 2, we also noticed a large variation in TAWSS, OSI and RRT in CAAs with similar sizes. The correlation was medium between geometric and hemodynamic variables, in accordance with other papers’ reports [7].
Regarding those CAAs with more obvious hemodynamic abnormalities, the risk of thrombosis was higher. For example, compared with larger CAA in LCA/LAD, the dilated RCA exhibited longer RRT along the entire artery, inducing extensive thrombosis (Fig. 1A). Another patient had two CAAs of similar dimensions located in the RCA and LCA/LAD junction, however the hemodynamic abnormalities were more severe in the RCA’s CAA (lower TAWSS, higher OSI and RRT), coupled with thrombosis (Fig. 1C). In Fig. 1B and Fig. 1D, RCA had 2 CAAs and had more severe decreased TAWSS. Apart from the decreased TAWSS, the larger CAA demonstrated higher OSI and RRT which prompted the formation of thrombi (Fig. 1B). In Fig. 1D, the thrombosed CAA was in the distal segment of RCA, which had lower blood flow velocity and higher RRT. Our results suggested that hemodynamic parameters can be reliable supplements to the aneurysm size for better predicting thrombotic risk.
Nowadays, CFD studies have been coupled with coronary artery disease, including atherosclerosis, coronary artery bypass grafting surgery, and myocardial bridging [30–32]. Vortices, WSS, OSI, and RRT have been identified as key hemodynamic quantities having the potential to be conventionally used in clinical work. Other new parameters like aneurysm shape index, aneurysm spherality, and aneurysm surface area have also demonstrated the potential to describe the complexity of aneurysm geometry, but only used in single centers and still require further research to support their accuracy [7, 29, 33]. Based on these facts, we adopted the classical parameters for analysis in our research instead of other new indices.
The results of our study differed somewhat from the smaller study by Grande Gutierrez et al [7]. They applied fluid-structure interactions (FSI) in the modeling which was not adapted in our study. FSI is a technique to combine the change of flow field with the mechanical change of blood vascular wall. However, in order to make the results more reliable, it is necessary to know the accurate parameter of blood vascular wall when calculating fluid-solid coupling. At present, these parameters are difficult to obtain in the pediatric population. There are some papers showing that the WSS varies between FSI and rigid-wall models but the difference sometimes is small to affect the result and clinical use [34, 35]. Moreover, FSI takes a long time and considerable computational power to run, so we chose to set the vessels as rigid walls in this study. In the future, with the progress of technology, FSI can be further used for the study of hemodynamics in our institution.
In our research, we employed a 3D SSFP sequence for patient-specific modeling. Compared to CT angiography, CMRI does not involve any dose of radiologic exposure, which is particularly essential for children in development and in need of serial scanning for future follow-up. Furthermore, CMRI can also be used to observe thrombi and intimal hyperplasia of the coronary artery. The AHA and JCS both uphold the use of CMRI for myocardial injury evaluation and observation of the complete coronary tree during the follow-up of KD patients [36].