Abstract
Background
Kawasaki disease (KD) is an acute febrile vasculitis. Patients with previous KD have increased risk of coronary arterial aneurysms (CAA) and early-onset arteriosclerosis. Endothelial dysfunction is the earliest manifestation of arteriosclerosis. We aimed to explore the endothelial function and clinical characteristics of patients with previous KD.
Methods
In this case–control study, we investigated childhood KD patients, with and without CAA, and a group of healthy controls. We obtained the anthropometric measurements, metabolic markers, vascular ultrasonography evaluating arterial stiffness and flow-mediated dilatation (FMD), and clinical information obtained by reviewing the patients' charts. Continuous variables were compared using non-parametric analyses and categorical variables, using the chi-square or Fisher's exact tests.
Results
Seventy KD patients (median current age, 12.95 years; median follow-up duration, 10.88 years) and 14 healthy controls were recruited. FMD was significantly lower in the CAA group (n = 15) than the control group (FMDs: 5.59% [interquartile range, 3.99–6.86%] vs. 7.49% [5.96–9.42%], p = 0.049; diastolic FMD: 6.48% [4.14–7.32%] vs. 7.87% [6.19–9.98%], p = 0.042). The CAA group had a higher percentage of impaired FMD and the significantly largest coronary segments of the three groups. Other parameters including metabolic markers, carotid intima-media thickness, and arterial stiffness were not statistically different.
Conclusion
KD patients, especially those with CAAs, may have impaired endothelial function. FMD may be a good indicator of endothelial dysfunction for use in long-term follow-up of KD patients.
Keywords: Kawasaki disease, Coronary arterial aneurysm, Endothelial function, Flow-mediated dilatation
At a glance commentary
Scientific background on the subject
Patients with a history of KD may have an increased risk of early-onset atherosclerosis. Endothelial dysfunction is one of the earliest manifestations of atherosclerosis. Carotid intima-media thickness (cIMT) and flow-mediated dilatation (FMD) have recently been established in the evaluation of endothelial function in pediatric populations.
What this study adds to the field
This study assessed endothelial function by vascular ultrasound in patients with childhood KD. Flow-mediated dilatation may be served as a surrogate index of coronary artery status during long-term follow-up for KD, especially in those with coronary arterial aneurysm, to lower the risk of progression to cardiovascular morbidity or mortality.
Kawasaki disease (KD) is an acute, self-limited febrile vasculitis mainly affecting children under the age of 5 years. Three vasculo-pathological processes, including acute necrotizing arteritis, subacute or chronic vasculitis, and luminal myofibroblastic proliferation, are found in patients with KD [1]. Coronary arterial aneurysms (CAA), may develop in 20–25% of untreated patients. Long-term coronary artery sequelae are the most significant complications of KD and can result in myocardial infarction or sudden death. Patients with a history of KD may have an increased risk of early-onset atherosclerosis [2]. Accelerated atherosclerosis can develop in children with KD, even if no obvious CAAs were identified in echocardiography during the acute phase [3,4].
Endothelial dysfunction is one of the earliest manifestations of atherosclerosis [5]. In the early disease stage, the development of atherosclerotic intimal-medial structural change, which precedes atherosclerosis, is a strong predictor of cardiovascular disease (CVD), including coronary vasoconstriction, hypertension, and myocardial ischemia [6]. In addition to type 1 diabetes mellitus, obesity, and familial hypercholesterolemia, it has been suggested that KD may also cause endothelial dysfunction for years after its onset [7]. However, there are conflicting reports regarding systemic endothelial function in KD patients with or without CAA [4]. Several noninvasive measurements, including carotid intima-media thickness (cIMT) and flow-mediated dilatation (FMD), have recently been established in the evaluation of endothelial function in pediatric populations [8]. Increased cIMT is a well-known structural index of subclinical atherosclerosis, which has been described in high-risk children, such as those with hypercholesterolemia and type 1 diabetes mellitus, and patients with a family history of myocardial infarction. Based on the arterial response during reactive hyperemia, reduced FMD can be used as a noninvasive index of endothelial dysfunction [9].
This study aimed to assess endothelial function via vascular ultrasound in patients with a history of KD during childhood. A better understanding and the early detection of endothelial dysfunction and arteriosclerosis in KD patients might lower the risk of progression to cardiovascular morbidity or mortality.
Methods
Ethics approval
Study approval was obtained from the Institutional Review Board of Chang Gung Medical Foundation, Taiwan (IRB:201305870A3). Written informed consents were obtained from all individuals and their guardians.
Participants
In this case–control study, we enrolled patients with previous childhood KD, with and without CAA, and healthy children and adolescents younger than 20 years old with similar sex distribution as the KD group between June 2014 and August 2017 from the outpatient clinic. All patients with KD met the criteria of presence fever for ≥5 days and the presence of ≥4 of the five principal clinical features including bilateral bulbar nonexudative conjunctival injection, changes of the lips and oral cavity, cervical lymphadenopathy, skin erythematous rash, and changes in the extremities. The control subjects had no documented systemic disease and their development and growth were within normal limit. In this study, KD patients with CAA were defined as any z-score of the coronary artery segment ≥5, internal lumen diameter >4 mm, or an internal diameter of a segment measuring more than 1.5 times that of an adjacent segment [1,10]. The exclusion criteria included patients with underlying chronic medical illness, metabolic disease, structural or functional cardiovascular abnormalities, inability to complete the major data collection procedures, and pregnancy.
Anthropometric measurements
Body mass index was calculated as weight in kilograms divided by the height in meters squared. Resting blood pressure was recorded from each participant's left arm using an automatic oscillometric cuff device (Philips MP5, Boeblingen, Germany), after the subject had been seated for 30 min. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg for patients aged ≥18 years [11], SBP ≥130 mmHg for children aged ≥13 to < 18 years, and SBP ≥95th percentile for children aged <13 years [12].
Measurement of metabolic markers and endothelial dysfunction parameters
Traditional metabolic parameters (i.e., glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol [HDL], and low-density lipoprotein cholesterol [LDL]) and asymmetric dimethylarginine (ADMA) were taken after 12 h of fasting. The ADMA levels were quantified using a high-performance liquid chromatography method, while the traditional metabolic parameters were measured by standard laboratory assays.
Measurements of cardiovascular function, including echocardiography, cIMT, and FMD were performed at the same visit. Echocardiography was performed using a Philips IE33 system (Philips, Bothell, WA, USA). In addition to standard anatomic and physiological images, we focused on imaging the left main coronary artery, left anterior descending artery, and right coronary artery. The coronary artery dimensions were normalized for body surface area as z-scores [13].
Carotid ultrasound studies and FMD at both systolic and diastolic phases (FMDs and FMDd) were performed under the optimal condition using an Aloka Prosound A7 (Hitachi Aloka, Tokyo, Japan) and repeated at least twice by two cardiologists to confirm the result. The data collected in the study was the single measurement under the most optimal condition. The patient was placed on the examination table in a comfortable supine position with the face turned away from the examiner. After resting for approximately 10 min, cIMT and arterial stiffness of each carotid artery were measured using a high-frequency vascular linear transducer [14]. FMD was performed using a high-frequency vascular transducer which was fixed with a stereotactic probe-holding device [7,8,15]. The baseline diameter of the right brachial artery was recorded for 1 min, and then the blood pressure cuff placed on the wrist was rapidly inflated to 220 mmHg for 5 min to create reactive hyperemia. Then, we deflated the cuff rapidly and the pressure of the brachial artery was recorded for another 5 min. FMD was calculated as [(post-deflation diameter – resting diameter)/resting diameter] x 100%. Comparisons between KD patients (including with and without CAA) and the control group were made with respect to sex, age, blood pressure, traditional metabolic parameters, and endothelial dysfunction parameters. Fair FMD was defined as the percent FMDs ≥6 and endothelial dysfunction was defined as the percent FMDs <6 [16].
Statistical analysis
The statistical analysis was performed using SPSS. Data that were not normally distributed were expressed as medians and interquartile ranges (IQR). Intergroup comparisons of the clinical parameters were performed using the Mann–Whitney U test and Kruskal–Wallis test with post-hoc Bonferroni correction for pair-comparisons for continuous variables [17]. Non-continuous variables were analyzed using the chi-square test or Fisher's exact test. p values < 0.05 were considered statistically significant.
Results
Baseline characteristics
Eighty-four participants were enrolled in our study. The ages of the participants ranged from 7.20 to 28.90 years, with a median age of 13.43 years. Fifty-eight (69.05%) of them were male. Seventy patients were included in the KD group, 15 of whom had CAA. Demographic characteristics and clinical presentations of the study participants are shown in Table 1.
Table 1.
Demographic characteristics and clinical presentations.
| KD with CAA (n = 15) | KD without CAA (n = 55) | Healthy Control (n = 14) | p value | |
|---|---|---|---|---|
| Male, n (%) | 12 (80.00) | 38 (69.09) | 8 (57.14) | 0.444 |
| Age (years) | 15.70 (9.72–21.73) | 11.98 (9.77–16.13) | 14.40 (11.73–15.13) | 0.152 |
| Disease duration (years) | 12.00 (6.67–19.56) | 9.88 (8.40–14.88) | n.a. | 0.261 |
| Body weight (kg) | 61.00 (39.20–74.50) | 49.00 (33.50–58.50) | 50.70 (44.13–57.25) | 0.142 |
| Body height (cm) | 169.00 (146.00–178.00) | 152.00 (138.00–168.00) | 159.00 (150.50–172.25) | 0.213 |
| Body mass index (kg/m2) | 20.13 (18.39–25.04) | 19.23 (16.56–22.53) | 19.54 (17.37–21.52) | 0.356 |
| SBP (mmHg) | 111.00 (100.00–122.00) | 115.00 (104.00–123.00) | 112.00 (103.50–120.00) | 0.749 |
| Diastolic blood pressure (mmHg) | 74.00 (64.00–80.00) | 73.00 (68.00–77.00) | 74.00 (63.75–80.00) | 0.988 |
| Mean blood pressure (mmHg) | 87.33 (78.00–96.00) | 86.67 (81.33–93.33) | 87.33 (78.17–92.58) | 0.957 |
| Hypertension, n (%) | 3 (20.00) | 10 (18.18) | 2 (14.29) | 0.999 |
| Heart rate (BPM) | 76.00 (62.00–84.00) | 79.00 (68.00–87.00) | 75.50 (66.00–91.25) | 0.496 |
Abbreviations: BPM: beats per minute; SBP: systolic blood pressure.
Data are presented as medians (interquartile range), or the number with the proportion of the number, n (%), compared among three groups by using either Kruskal Wallis test or Chi-square test or Fisher's exact test.
The follow-up duration, from the onset of KD to the date of evaluation of FMD, was not significantly different between KD patients with CAA (CAA group) and those without CAA (non-CAA group). There were no significant differences in sex, age, body weight, body height, blood pressure, and heart rate between the KD groups, with and without CAA, and the healthy control group. Glucose, triglycerides, total cholesterol, LDL, HDL, and asymmetric dimethylarginine (ADMA) levels were all within normal limits and were not significantly different between the KD groups and the healthy control group (Table 2).
Table 2.
Comparison of ADMA and traditional metabolic parameters among KD patients with and without CAA, and healthy children.
| KD with CAA | KD without CAA | Healthy control | p value | |
|---|---|---|---|---|
| ADMA (μmol/L) | 0.71 (0.61–0.81) | 0.80 (0.70–0.89) | 0.72 (0.63–0.98) | 0.191 |
| Glucose (mg/dL) | 89.00 (87.00–94.00) | 89.00 (85.00–92.25) | 93.50 (79.50–96.25) | 0.534 |
| HDL (mg/dL) | 57.00 (44.00–71.00) | 54.00 (45.00–68.00) | 55.00 (50.50–63.00) | 0.915 |
| LDL (mg/dL) | 82.00 (68.00–100.00) | 82.00 (69.00–103.00) | 105.00 (71.50–118.50) | 0.591 |
| Cholesterol/HDL | 3.10 (2.14–3.39) | 2.82 (2.45–3.61) | 2.75 (2.62–3.55) | 0.913 |
| LDL/HDL | 1.54 (1.00–1.93) | 1.53 (1.18–2.08) | 1.52 (1.39–2.16) | 0.598 |
| Cholesterol (mg/dL) | 162.00 (149.00–178.00) | 158.00 (147.00–179.00) | 174.00 (140.50–195.00) | 0.747 |
| Triglycerides (mg/dL) | 69.00 (45.00–98.00) | 66.00 (48.00–95.00) | 45.00 (39.50–76.00) | 0.321 |
| Non-HDL (mg/dL) | 100.00 (79.00–121.00) | 101.00 (90.00–116.00) | 105.00 (89.00–140.00) | 0.699 |
Abbreviations: ADMA: asymmetric dimethylarginine; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol.
Data are presented as medians (interquartile range).
Analysis of endothelial function parameters
Upon analysis of the noninvasive endothelial function measurement parameters, 33 (47.14%) of the 70 KD patients (9 [60.00%] out of 15 in the CAA group and 24 [43.63%] out of 55 in the non-CAA group) had a systolic FMD (sFMD) of less than 6%, which indicated endothelial dysfunction. The percentage of patients with endothelial dysfunction was significantly higher in the CAA group than that in the controls (3 [21.43%] out of 14) (p = 0.035). The FMDs and diastolic FMD (FMDd) were significantly lower in the CAA group than those in the control group (Table 3). The CAA group significantly had the largest coronary segments of the three groups, including the absolute size and standard deviations from the mean (z score). However, the analysis of other parameters, including cIMT and arterial stiffness, revealed no statistical significance.
Table 3.
Comparison of FMD, cIMT and arterial stiffness among KD patients with and without CAA, and healthy children.
| KD with CAA | KD without CAA | Healthy control | p value | ||
|---|---|---|---|---|---|
| FMDs (%) | 5.59 (3.99–6.86)∗ | 7.03 (5.04–9.50) | 7.49 (5.96–9.42)∗ | 0.036 | |
| FMDd (%) | 6.48 (4.14–7.32)∗ | 7.87 (5.52–10.02) | 7.87 (6.19–9.98)∗ | 0.035 | |
| cIMT-left (mm) | 0.40 (0.30–0.50) | 0.40 (0.30–0.40) | 0.30 (0.30–0.40) | 0.454 | |
| β-value-left | 3.60 (3.10–3.80) | 3.00 (2.50–3.70) | 3.40 (3.00–4.40) | 0.066 | |
| AI-left (%) | −7.70 (−10.20–1.00) | −5.50 (−11.00–2.3) | −4.3 (−6.98–8.05) | 0.316 | |
| cIMT-right (mm) | 0.40 (0.30–0.40) | 0.40 (0.30–0.40) | 0.30 (0.30–0.40) | 0.373 | |
| β-value-right | 3.50 (3.00–4.10) | 3.32 (2.80–3.90) | 3.50 (3.00–4.38) | 0.420 | |
| AI-right (%) | −7.60 (−9.60–6.80) | −5.60 (−10.80–2.0) | −4.60 (−8.33–9.33) | 0.238 | |
| LCA (mm) | 4.50 (4.13–5.82)∗† | 3.43 (3.04–3.65)† | 3.23 (2.90–3.76)∗ | <0.001 | |
| LAD (mm) | 4.08 (3.18–4.84)∗ | 2.82 (2.34–3.15)∗ | 3.01 (2.86–3.32) | <0.001 | |
| RCA (mm) | 5.36 (3.82–6.31)∗† | 2.68 (2.42–3.33)† | 2.61 (1.94–3.11)∗ | <0.001 | |
| LCA z score | 2.83 (1.98–3.80)∗† | 1.04 (0.56–1.59)† | 0.86 (0.13–1.69)∗ | <0.001 | |
| LAD z score | 2.01 (1.56–2.36)∗ | 1.03 (0.63–1.31)∗ | 1.13 (0.88–1.55) | <0.001 | |
| RCA z score | 3.49 (2.14–4.27)∗† | 1.07 (0.59–1.65)† | 0.88 (0.1–1.43)∗ | <0.001 | |
Abbreviations: AI: augmentation index; cIMT: carotid intima media thickness; FMDd: diastolic flow-mediated dilation; FMDs: systolic flow-mediated dilation; LCA: left main coronary artery; LAD: left anterior descending branch of coronary artery; RCA: right coronary artery. Data are presented as medians (interquartile range), or the number with the proportion of the number, n (%), compared among three groups by using either Kruskal Wallis test or Chi-square test or Fisher's exact test. (∗ and †, p < 0.05 individually indicative of pair-comparisons with post-hoc Bonferroni correction between two groups).
Analysis of previous intravenous immunoglobulin therapy
We also analyzed the history of previous intravenous immunoglobulin (IVIG) therapy in KD patients (Table 4). Sixty-six (94.29%) out of seventy patients received single high-dose IVIG treatment at the acute phase. Patients in the CAA group had a significantly higher rate of IVIG-resistance than the non-CAA group. Analysis of the day-interval from fever onset to initiation of IVIG treatment, the number of times IVIG treatment was received, and the disease duration did not differ significantly between the CAA and non-CAA groups. Among the 15 CAA patients, one-third each received long-term aspirin monotherapy, received dual anti-platelet therapy, and were nonadherent to the prescribed medication prior to FMD evaluation (Table 5). The FMDs and FMDd were not significantly different between the three treatment groups of CAA patients. The non-CAA group did not receive long-term medication.
Table 4.
History of previous IVIG therapy at acute phase in the studied KD patients.
| KD with CAA | KD without CAA | p value | |
|---|---|---|---|
| High-dose of IVIG, n (%) | 13 (86.67) | 53 (96.36) | 0.199 |
| IVIG Resistance, n (%) | 5 (33.33) | 4 (7.27) | 0.018 |
| Day-interval to initiate IVIG, days | 6.50 (3.25–8.00) | 6.00 (5.00–7.00) | 0.518 |
| Times of IVIG therapy | 1 (1–2) | 1 (1–1) | 0.631 |
Table 5.
Endothelial functions in KD CAA patients based on their current medication.
| Aspirin monotherapy (n = 5) |
Dual anti-platelet therapy (n = 5) | No anti-platelet or anticoagulation (n = 5) | p value | |
|---|---|---|---|---|
| FMDs | 4.04 (3.04–7.03) | 6.76 (4.04–7.16) | 5.57 (4.42–6.08) | 0.468 |
| FMDd | 4.29 (3.17–7.14) | 7.32 (4.30–8.04) | 6.48 (4.89–7.30) | 0.403 |
KD patients were categorized by current coronary status, based on their FMD results (Table 6), to evaluate the percentage of patients who received IVIG therapy at the acute phase, the proportion of IVIG-resistance, the day-interval from fever onset to initiation of IVIG treatment, and disease duration. There was no significant difference between the fair and impaired endothelial function groups. Additionally, there was no significant difference between the diameter of the coronary arteries and the presence of stenosis between the two groups.
Table 6.
Characteristics of previous IVIG treatment and current coronary status in KD patients based on their endothelial functions.
| Fair FMDs (FMDs ≥6%, n = 37) | Impaired FMDs (FMDs <6%, n = 33) | p value | |
|---|---|---|---|
| No IVIG, n (%) | 3 (8.11) | 1 (3.03) | 0.361 |
| IVIG Resistance, n (%) | 5 (13.51) | 4 (12.12) | 0.999 |
| Day-interval to initiate IVIG, days | 6.00 (5.00–7.00) | 6.00 (4.00–7.00) | 0.430 |
| Disease duration, years | 11.15 (8.52–15.12) | 10.61 (7.15–16.00) | 0.491 |
| LCA z score | 1.21 (0.70–1.71) | 1.39 (0.88–1.94) | 0.261 |
| LAD z score | 1.13 (0.71–1.56) | 1.17 (0.55–1.51) | 0.693 |
| RCA z score | 1.41 (0.67–2.12) | 1.44 (0.78–2.44) | 0.768 |
| Coronary stenosis, n (%) | 5 (13.51) | 5 (15.15) | 0.999 |
Results of cardiac catheterization
During the two years after initial FMD examination, seven patients in the CAA group underwent cardiac catheterization, and vascular stents were implanted in two patients. Two other patients developed multiple aneurysms and coronary artery stenosis. Coronary bypass surgery was suggested if significant stenosis progresses in the future. The remaining three patients exhibited focal aneurysm formation and were administered antiplatelet and anticoagulation therapy to prevent thrombus formation.
Of the eight patients who did not receive cardiac catheterization, two underwent computed tomographic angiography, and medical follow-up was suggested. The remaining six patients were followed-up with echocardiography.
Discussion
In this study, we observed that KD patients with CAA had significantly inferior endothelial function than that of healthy controls, despite the fact that their BMI; blood pressure; and cardiovascular risk markers, including cholesterol, fasting glucose, and ADMA levels, were not statistically different from those in patients without CAA and in healthy controls. Additionally, the coronary artery diameters of CAA patients were the largest among the three groups. Mild CAAs in KD patients tend to resolve within one to two years after acute onset of illness; whereas, severe CAA contributes to chronic vascular remodeling, including persistent aneurysms, stenosis, thrombosis, and neovascularization [1]. Thus, the presence of CAAs in KD patients highlights the ongoing process of vascular remodeling and the importance of preventing coronary events.
KD is an acute vasculitis that may lead to CAA in approximately 25% of untreated children [1]. According to the American heart association [18], KD patients with and without current CAAs are categorized as being at high and moderate risk for CVD, respectively. Endothelial dysfunction is the first clinical stage of arteriosclerosis and can be the earliest indicator of CVD [5,13]. Assessing the endothelial function of KD patients, and the early identification of those at high risk of CVD, will greatly improve the global cardiovascular health burden. Conflicting results have been reported in previous studies concerning endothelial function in children with KD. Several studies demonstrate that systemic endothelial dysfunction exists in KD patients, with or without CAA, due to systemic vasculitis, which may persist many years after the resolution of the acute KD. The longer the duration of fever in KD patients, the greater the risk of endothelial dysfunction [19]. Dhillon et al. reported that 20 KD patients with resolved coronary lesions exhibited markedly lower FMD compared to control subjects [3]. However, Silva et al. found no difference in FMD between KD patients and normal subjects [4]. Ikemoto et al. and Niboshi et al. concluded that FMD correlates with the severity of coronary artery lesions in KD patients [[20], [21], [22]]. FMD in KD patients, without or with mild coronary involvement, does not significantly differ from that in controls [21]. The CAA group in our study had a higher percentage of endothelial dysfunction than did the non-CAA group, although the difference was not statistically significant. Some non-CAA patients had impaired FMD without any current identifiable cause.
Few studies have discussed the relationship between endothelial function and previous treatment of KD. Deng et al. studied whether the use of high-dose gamma globulin therapy in the acute stage of KD would later affect endothelial function [23]. They found that endothelial dysfunction occurs in KD, irrespective of coronary artery involvement, and was not influenced by early treatment with high-dose gamma globulin during the acute stage. Our results suggested that mid-term endothelial dysfunction after acute KD was not related to previous IVIG treatment. However, the drug's effect on endothelial function could not be ignored, despite no significant difference of FMD being observed between the three treatment groups. Aspirin and clopidogrel can improve endothelial function and restore FMD in coronary artery disease [[24], [25], [26]], which may explain why patients on dual anti-platelet therapy did not have the worst FMDs. Most of these KD patients were enrolled in a different prospective KD cohort study, where their FMD was followed-up. One of the originally recruited CAA patients exhibited a restored FMD after percutaneous coronary intervention and stent implantation, concomitant with dual anti-platelet therapy. One patient exhibited improvement in endothelial function after receiving oral anti-coagulation in conjunction with prior dual anti-platelet therapy. Another patient exhibited improved FMD after changing to dual anti-platelet therapy from a preceding aspirin monotherapy. Unfortunately, one CAA patient who received aspirin monotherapy for years after percutaneous coronary intervention exhibited deteriorating FMD during follow-up. He had an episode of angina 5 years thereafter. Inadequate therapy to prevent myocardial ischemia is seemingly associated with endothelial dysfunction in KD patients with CAA. For these patients who are at high risk of premature cardiovascular events, CVD risk stratification should be mandatory in clinical practice [27]. Therefore, it is important to further investigate whether FMD could be used as a non-invasive assessment of endothelial function in KD patients and, furthermore, for coronary artery disease [28].
Endothelial dysfunction has lifelong consequences in KD children, even in the absence of obvious coronary artery involvements [23,29]. Although we did not observe a correlation between FMD and disease duration in the mid-term follow-up, we suspect that the endothelial dysfunction in KD patients may progress, depending on the presence of CAA and disease duration. In the previously-mentioned KD cohort study, ten (66.67%) of the originally-recruited CAA patients and 39 (78%) of the non-CAA individuals were followed-up every 1–2 years for FMD evaluation. The follow-up duration, up to the final FMD evaluation, of CAA and non-CAA subjects was a median of 2.13 (IQR 1.35–4.49) years and 2.12 (IQR 1.23–3.0) years, respectively (p = 0.45). The preliminary results showed that, during this period, a minor alteration of cIMT was observed in each patient, none of whom exhibited a significant increase in cIMT, in either group. However, FMD varied individually. Three (30%) patients in the CAA group and seven (17.95%) in the non-CAA group exhibited an improvement in FMD (greater than 1.5% increase in FMD) from a previous abnormality to the normal range (p = 0.41, compared between the two groups). Four non-CAA patients and two CAA patients experienced worsening FMD (greater than 1.5% decline in FMD) (p = 0.59, compared between the two groups). Interestingly, the non-CAA group significantly had the higher percentage of patients (18 out of 39 and 0 out of 10 in the non-CAA and CAA group, respectively; p = 0.008) who had stationary fair FMD (FMD value ≥ 6% and with less than 1.5% decline) during follow-up. The CAA group had a higher percentage of impaired FMD than the non-CAA group (5 out of 10 vs. 10 out of 39); however, this was not statistically significant (p = 0.25). Long-term follow-up and integration of FMD results in conjunction with other imaging modalities, such as coronary angiography, is necessary to further understand the role of FMD.
Increased cIMT is a well-known structural marker of atherosclerosis and is widely utilized in the evaluation of early structural changes in the arterial wall [30,31]. In adults, elevated cIMT is associated with coronary artery disease and stroke [32]. Previous studies concerning cIMT in patients with a history of KD have reported varying results. Some authors found increased cIMT in patients with KD compared with control participants [29,33,34]. Wu et al. investigated cIMT in children aged 3–60 months with acute KD [35]. They found that children with KD had a significantly greater cIMT compared with controls (0.550 ± 0.081 vs. 0.483 ± 0.046 mm, respectively; p = 0.01) and concluded that cIMT could be a useful tool in the early diagnosis of acute KD. Dietz et al. and Noto et al. found that cIMT initially increases in KD patients without CAAs and subsides over time in most patients. In patients with giant- or medium-sized CAAs, cIMT continually increased and had a more marked impact on the arterial wall [[34], [35], [36], [37]]. However, other studies found that cIMT was not significantly different between children with KD and controls [19,21,38,39]. We also failed to identify any significant difference in cIMT between patients with KD and healthy children. The influence of cIMT and arterial stiffness in KD patients was not obvious in this study, and earlier functional change to the endothelium, rather than anatomic change, was a possible reason.
ADMA is a major and potent endogenous nitric oxide synthase inhibitor, associated with endothelial dysfunction, hypertension, atherosclerosis, cardiovascular mortality, and renal diseases. However, the levels of traditional metabolic markers and ADMA were within normal limits and were not significantly different among KD patients and healthy individuals. In a previous study, we also found that obese children had impaired FMD [7]. However, the ADMA-related biomarkers did not differ these obese children from healthy ones. We hypothesized that traditional metabolic markers and ADMA are not influenced during childhood and adolescents. Perhaps there is a need for further studies to corroborate the relationship between KD patients’ ADMA biomarkers and arterial stiffness.
In our study, univariate linear regression analyses were performed to analyze the potential factors contributing to FMD. Neither blood pressure nor the other studied variables, such as arterial stiffness (β-value) or ADMA levels, were capable of significantly predicting the value of FMD (data not shown).
Limitations
FMD could be affected by numerous factors including obesity, autonomic dysfunction, and anxiety. Thus, data interpretation should take this into consideration.
The limitation of this study was the relatively small number of healthy controls. Most control children refused blood collection and were difficult to enroll into the study. A larger sample size would be required for study series and a long-term cohort study to monitor the subsequent change of endothelial function, arterial stiffness, blood pressures, and the occurrence of cardiovascular events.
Conclusions
In this study, we illustrated that KD in children adversely affects subsequent endothelial function, especially in the patients with CAA. It may imply that ongoing low-grade inflammation after the convalescent phase of KD occurs in patients with coronary artery involvement. FMD, a noninvasive examination, may be a good modality to evaluate endothelial function to early prevent patients with previous KD from cardiovascular events during later years of life.
Funding
This work was supported by grants from Chang Gung Memorial Hospital, Taiwan (CMRPG8L0151, and CMRPG8F0203) and Ministry of Science and Technology (108-2314-B-182A-092). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation process.
Conflicts of interest
All authors have no conflicts of interest to disclose.
Acknowledgements
We appreciate the help of the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital.
Footnotes
Peer review under responsibility of Chang Gung University.
Contributor Information
Ho-Chang Kuo, Email: erickuo48@yahoo.com.tw.
I-Chun Lin, Email: uc22@cgmh.org.tw.
References
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