Clinical characteristics and risk factors of coronary artery lesions in chinese pediatric Takayasu arteritis patients: a retrospective study

TAK is a chronic, nonspecific, large- and medium-sized vascular inflammatory disease that mainly affects the aorta and its branches. The coronary artery is an important medium-sized vessel in the heart that may also be involved. Once the lesion is aggravated, thrombosis can develop, leading to MI and even death [23,24,25]. Even if immediate ischemia does not occur because of coronary artery occlusion, vessels that have been inflamed in systemic vasculitides, such as TAK, show premature atherosclerosis, placing patients at risk for MI [27]. TAK combined with CALs directly affects prognosis [28.29]. Therefore, it is of great significance to screen the risk factors for CAL in TAK patients, and to take appropriate prevention and control measures to improve their prognosis.

Previous studies [30.31] reported that the incidence of adult TAK combined with CAL varies greatly (3–30%), and the incidence in pediatric TAK patients (55.6%) was significantly higher than in adults [32]. This study shows that pediatric TAK combined with CAL was 39.4%. More attention should be paid to CAL in pediatric patients with TAK. In our cohort, children in the CAL group were all subclinical, the common coronary arteries involved were LMCA and RCA, and some patients may have had four coronary arteries involved. CAL is mostly a small or middle coronary artery aneurysm; some children may have giant coronary aneurysmal dilations, thrombosis, and heart failure. Therefore, once a patient is diagnosed with pediatric TAK, the coronary arteries should be evaluated. Adult TAK usually uses coronary CT or angiography, which is better than coronary ultrasound to identify problems of the distal coronary artery, especially stenosis [4.33.34]. However, we found that the CALs of pediatric TAK were different from those of adult patients, the most common of which was coronary artery stenosis. Coronary ultrasound, which is a noninvasive examination that can detect coronary artery dilation, is more suitable for pediatric TAK coronary artery evaluation. Our results also suggest that pediatric TAK treated with regular glucocorticoids, immunosuppressants, or biological agents was well controlled. Most CALs regressed or returned to normal, and no patient suffered from MI. Two deaths in the CAL group were recorded and considered to be related to irregular treatment. After treatment, there was no difference in the survival rates between the CAL and non-CAL groups. Early detection of CAL and prompt corresponding intervention effectively improved the prognosis of pediatric TAK.

The main mechanism of adult TAK involvement in coronary artery stenosis is inflammation of the aorta extending to the opening and near the segment of the coronary artery, leading to intimal hyperplasia, and fibrosis contracture of the middle and outer membranes causes stenosis of the lumen. Previous studies [10] reported that homocysteine, TG, and the TG/HDL-C ratio were independent risk factors for adult TAK complicated with CAL. Ohigashi et al. [35] reported that the incidence of CAD in adult patients with TAK increased with age. In contrast, Shi-Min et al. [36] reported that the age of patients with TAK combined with CAL was mostly < 40 years. After multivariate analysis, Wang et al. [11] proposed that age at onset, disease course, height, and body mass index (BMI) were risk factors for adult TAK involving the coronary arteries. In summary, inflammation is not the only mechanism in adult TAK patients with CAD related to atherosclerosis. The latter is associated with age, glucocorticoid use, and traditional cardiovascular risk factors. However, in our cohort, these children did not have traditional cardiovascular risk factors and did not receive glucocorticoids. The result suggest that pediatric TAK with CAL is associated with inflammation (higher CRP, WBC, PLT, TNF-α and IL-2R levels, lower HGB ), which differs from that in adults. In addition, our study showed that the course of disease in the CAL group was shorter than that in the non-CAL group. This observation suggests that CAL tended to have a relatively more rapid clinical course and stronger inflammatory state on admission, including destroyed elastic lamina or muscle media and arterial vasodilation. This may partly explain why CALs quickly resolved in children who received biological agents in combination with traditional immunosuppressive therapy.

In our cohort, age at onset was an independent risk factor for pediatric TAK combined with CAL. This indicates that early disease onset in these patients is more likely to cause CAL, especially at less than 36 months. These findings are similar to those reported by Lu, who presented an unusual case of sudden death in an 8-month infant with TAK [37]. An autopsy revealed that the proximal segment of the left and right coronary arteries showed approximately 60% and over 90% occlusion, respectively. It is suggested that we be alert in recognizing and screening CALs on time and pay close attention to the comprehensive control of inflammation, which is very important in improving the prognosis of TAK in children. In addition, this suggests that TAK and KD should be identified in infants with fever and CALs, which was also Reported by Lee et al. [38]. However, Zhao et al. and Filiz Ekici et al. reported some cases of infant KD complicated by systematic artery aneurysms (SAAs) and CAL [39,40,41]. This makes it more difficult to distinguish between the two types of systemic vasculitis. Taking our patients into consideration, we believe that the following three points will help distinguish between the two diseases. First, no or weak pulse, hypertension, or blood pressure difference between the upper extremities may exist in pediatric patients with TAK. Second, KD has no reports of diffuse aortitis or arterial stenosis, making it distinguishable from TAK. Third, the responses to treatment were different. Patients with IVIG, ASP, and a short course of glucocorticoids that failed to completely control the inflammation were more likely to be pediatric TAK patients.

Lei et al. [12] reported that TAK children with coronary aneurysmal dilation had more aneurysms or dilation of the aorta and its main branches than those with stenotic lesions only. However, no significant differences were observed in the present cohort. We found that pediatric TAK patients with RAS were less likely to develop CAL. It is well known that RAS, which can cause renal vascular hypertension and decrease renal perfusion, is more common in patients with TAK. In severe cases, heart failure and/or renal failure may occur [42]. Renal dysfunction can activate the renin-angiotensin-aldosterone system, cause oxidative stress, and increase the synthesis of endothelin and inflammatory factors,often combined with a variety of risk factors such as old age, obesity, smoking history, hypertension, diabetes, dyslipidemia, and hyperuricemia, which leads to endothelial dysfunction and promotes atherosclerosis [11]. In accordance with this notion, we speculate that adult TAK patients with RAS are more likely to have CALs. However, this is contrary to our results on pediatric TAK. The following points are worth considering: 1.There is little correlation between CAL and atherosclerosis in pediatric TAK. 2. The characteristics of blood vessels in children are related. The arteries in pediatric TAK are in the developmental stage, which are thin wall, low elasticity and shorter diameter than adults. It is more prone to dilation than adults. 3. Is the order of blood vessels affected by vasculitis related to age? Currently, no literature on RAS and CAL has been retrieved. Therefore, further study is needed to investigate the mechanism by which pediatric TAK with RAS are less likely to develop CALs.

This study was limited by its retrospective design, associated biases, and missing data. The relatively small number of samples collected in our single center might have introduced some bias into the results of the comparisons. Nevertheless, our pediatric cohort represents the largest reported worldwide, and we still conclude with significant findings that can guide our clinical work.

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