Inflammatory reaction in the acute phase of Kawasaki disease may better predict chronic cardiac dysfunction than coronary artery lesions

Introduction

Kawasaki disease (KD) is a pediatric acute vasculitis primarily affecting the coronary arteries and the heart, including the myocardium, pericardium, and valves (1,2). Anomalies in vascular structure and function caused by KD, such as the formation of coronary artery aneurysms (CAAs), endothelial dysfunction, and microcirculatory disturbances, can result in prolonged myocardial ischemia and impaired cardiac function (1-4). Further, the persistent effect of ongoing myocardial inflammation may contribute to chronic subclinical cardiac dysfunction (5,6). Therefore, the cardiac function of children with KD has become a focal point of clinical research (4,7-22). However, to date, most studies have focused on the acute assessment of cardiac function in patients with KD, the predictive value of methods for predicting intravenous immunoglobulin (IVIG) resistance in children with KD undergoing treatment, and the occurrence of coronary artery lesions (CALs). Only a few studies have evaluated chronic cardiac function (3-6,23-26). The timely detection of chronic cardiac function decline could help to identify patients at particularly high risk of cardiovascular morbidity and mortality (27). Unfortunately, a major limitation of current research relates to the global assessment of cardiac function in all KD patients and the lack of subgroup analyses based on different CAL grades. CAL severity may lead to diverse outcomes. Moreover, most studies have been retrospective in nature.

Surprisingly, there is increasing evidence of the presence of subclinical cardiac dysfunction in the long term, even in KD patients without CALs (20,28,29). Additionally, there is currently a lack of research on whether KD patients with medium- to large-sized CAAs universally exhibit chronic cardiac dysfunction or whether there is a subset of patients with normalized cardiac function. Research has shown that myocarditis occurs in all KD patients during the acute phase, regardless of coronary artery status (30,31). Myocarditis, which can be caused by various factors, may lead to the development of long-term myocardial fibrosis, resulting in subclinical cardiac functional abnormalities, and even the onset of cardiomyopathy (32-34). Thus, we hypothesized that CALs may not be the sole risk factor for chronic cardiac dysfunction in children with KD, and the extent of acute-phase inflammatory response may also be associated with the subsequent development of subclinical cardiac functional impairment.

We conducted a prospective study to investigate the effect of CAL grading on the chronic cardiac function of KD patients. The objectives of this study were to: (I) explore the effect of CAL grading on chronic-phase cardiac function in KD patients; and (II) test whether acute-phase inflammatory markers before IVIG infusion are associated with chronic cardiac dysfunction in KD patients. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2352/rc).

Methods

Subjects

We reviewed the data of KD patients at West China Second University Hospital, Sichuan University from 2005 to 2020. In this study, the recruitment of subgroups of patients with giant coronary aneurysms (GCAs) was based on various considerations. Despite the relatively low incidence rate of GCA, its potential effect (e.g., the formation of blood clots and myocardial ischemia) is the most severe. Given that GCA may lead to long-term cardiovascular functional damage, we chose to focus on GCA as one of the main areas of study to ensure that our research results accurately reflected the effect of GCAs on the cardiovascular system, which in turn could provide more targeted clinical management and treatment strategies for improving patient prognosis.

A total of 25 children with GCA were included in the study. Children were included in this study if they met the following criteria: (I) had been diagnosed with KD as per the 2004 American Heart Association (AHA) guidelines (35); (II) had received standard KD treatment (IVIG and aspirin); (III) had a disease course that exceeded 2 months from the onset of fever to the start of this study; (IV) had a GCA, which was defined as a coronary artery internal diameter Z score ≥10 or an absolute size ≥8 mm (36,37); and (V) had previously undergone echocardiography, cardiac catheterization, or coronary computed tomography to exclude coronary artery stenosis.

As Figure 1 shows, the 25 GCA patients were gender-, height-, and weight-matched with patients in the medium coronary aneurysm (MCA) group, the small coronary aneurysm (SCA) group, and the no coronary artery dilatation group at a 1:1 ratio, and the subgroups were defined as follows: MCA group (5≤ Z score <10, absolute size <8 mm); SCA group (2.5≤ Z score <5), and the no coronary artery dilatation group (Z score <2). Additionally, 89 healthy control subjects, who had normal growth and development, were afebrile, and had no history of KD, congenital heart disease, obesity, diabetes, rheumatologic, or respiratory diseases, were included in the study.

Figure 1 Study’s research flowchart. AHA, American Heart Association; CT, computed tomography; GCAs, giant coronary aneurysms; GLS, global longitudinal strain; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; MCAs, medium coronary aneurysms; SCA, small coronary aneurysm.

The exclusion criteria for each subgroup in this study (Figure 1) included obesity (N=3), heart failure (N=1), current treatment with medication affecting cardiac function (captopril, metoprolol, or betaxolol), or the discontinuation of such treatment less than one month prior (N=4), congenital heart disease (N=1), contrast agent allergy (N=1), and/or poor-quality imaging windows (N=12). The specific exclusion criteria for acoustic window quality were as follows: (I) ≥2 myocardial segments in the apical four-chamber (4C)/three-chamber (3C)/two-chamber (2C) views that could not be tracked; and/or (II) an overall tracking success rate <85%).

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the University Ethics Committee on Human Subjects at Sichuan University (No. K2019105), and all patients’ legal guardians provided written informed consent.

We retrospectively reviewed the acute-phase data of the study subjects before the study began, including age at onset, incidence of incomplete KD, IVIG resistance rate, and pre-IVIG laboratory indices [i.e., white blood cell (WBC) count, neutrophils (Ns), lymphocytes (Ls), platelets (PLTs), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), albumin (ALB), phosphate (P³⁺), potassium (K⁺), sodium (Na⁺), calcium (Ca²⁺), and magnesium (Mg²⁺) levels]. After the study commenced, data on current cardiac function indicators were collected, as well as data on patient age, gender, height, weight, blood pressure (BP), heart rate (HR), total disease duration (Figure S1), coronary artery classification (Z scores, Figure S2) (1,2,37), and the location and number of affected coronary arteries.

A stricter criterion than the diagnostic standards for cardiac oncology strain imaging was adopted. Left ventricular (LV) systolic dysfunction was defined as LV-global longitudinal strain (GLS) absolute values <18% (38,39). The KD patients were categorized into different subgroups based on LV-GLS values and coronary aneurysm classification. Among the patients, 68 had LV-GLS values ≥18%, of whom 11 had GCAs, 16 had MCAs, 21 had SCAs, and 20 had no coronary dilation. Additionally, 21 patients had LV-GLS values <18%, of whom 7 had GCAs, 7 had MCAs, 4 had SCAs, and 3 had no coronary dilation.

Further, to explore the risk factors for reduced cardiac function in the chronic phase, the patients who underwent laboratory tests during the acute phase (N=64) were divided into the following two groups based on whether their GLS values were abnormal: the GLS ≥18% group (N=54), and the GLS <18% group (N=10).

Cardiac ultrasound equipment and image acquisition

In this study, the cardiac function of the KD patients was assessed by echocardiography using a GE Vivid E95 ultrasound machine (Horten, Norway). The M5S cardiac probe was used, and the frame rate was controlled at 60–70 frames per second. The image acquisition and examination planes included the parasternal long-axis view, the parasternal short-axis view at the mitral valve (MV) plane, the parasternal short-axis view at the papillary muscle (PM) plane, and the parasternal short-axis view at the apical plane (AP), apical 4C plane, apical 3C plane, and apical 2C plane. The ultrasound techniques used in the study were M-mode echocardiography, two-dimensional (2D) echocardiography, tissue Doppler imaging (TDI), pulse-wave (PW) Doppler imaging, and speckle tracking echocardiography (STE).

Analysis of cardiac ultrasound image data

The images were acquired by professional cardiac ultrasound technicians with extensive experience in myocardial function and coronary artery assessment, who were blinded to the grouping. The analysis was conducted by researchers familiar with cardiac function analysis, who were also blinded to the grouping. After image acquisition, all data processing was carried out offline using the GE EchoPAC 201 workstation (Horten, Norway). Measurements were obtained from the relevant sections, and data from three stable cardiac cycles with the same view were selected. The average values of these measurements were used for the subsequent statistical analysis. All the strain analyses were independently performed by two experienced cardiac sonographers, with inter-observer consistency assessed using intraclass correlation coefficients (ICCs). A random selection of 10% of cases was re-measured after a three-month interval to assess intra-observer consistency.

LV and LA functional measurements

Conventional echocardiography

From the apical 4C view, 2D echocardiographic images were used to determine the LV end-systolic and end-diastolic diameters/areas/volumes, and the biplane-plane Simpson method was used to calculate the left ventricular ejection fraction (LVEF).

Transmitral PW echocardiography was performed to determine the peak mitral inflow velocities at early (E) and late (A) diastole, and thus calculate the E/A ratio. PW tissue Doppler echocardiography was performed with the sample volume positioned at the basal LV free wall/ventricular septum-mitral annular junctions to measure the lateral and septal peak systolic (s), early (e) diastolic, and late (a) diastolic myocardial tissue velocities and e/a ratio. An average from the lateral and septal E/e ratio (E/e average) was derived and expressed as the mean E/e ratio.

STE

Systolic and diastolic myocardial deformation in left atrium (LA) and LV were determined by 2D STE with frame rates between 60 and 70 frames per second. Briefly, based on tracking of the entire LV contour from the 4C/3C/2C, the 4C/3C/2C/LV-GLS, and systolic strain rates (4C/3C/2C/LV-GLSRs), and global longitudinal early (4C/3C/2C/LV-GLSRe) and late (4C/3C/2C/LV-GLSRa) diastolic strain rates (SRs) were obtained (Figure S3). From the parasternal short-axis view at the MV/PM/AP plane, the global circumferential strain (MV/PM/AP/LV-GCS), MV/PM/AP/LV-GCSRs, MV/PM/AP/LV-GCSRe, and MV/PM/AP/LV-GCSRa were measured. In relation to the LA deformation measurement, the onset of the R wave was taken as the reference point for the determination of the following parameters of global atrial deformation: LA reservoir strain, LA conduit strain, LA contractile strain and atrial strain rate at systole (LA-SRs), early diastole (LA-SRe), and late diastole (LA-SRa).

Coronary artery diameter measurements

The study used a 5S probe for the coronary artery measurements. Measurements of the diameters of the right coronary artery (RCA), left coronary artery (LCA), left anterior descending (LAD) artery, and left circumflex (LCX) artery were taken from the inner to inner edges of the parasternal short-axis images obtained from echocardiography. The measurements were performed from the opening of the LAD artery and LCX artery to the junction with the LCA (40). Measurements were also taken 0.2–0.5 cm from the origin of the RCA, LAD artery, and LCX artery. If CAAs were present in different branches, the maximum diameter of the largest aneurysm was measured, and the Z scores were calculated (37).

Statistical analysis

The statistical analysis was performed using IBM SPSS software (version 21.0). The qualitative data are reported as the frequency (%), and the Chi-squared test was used to compare proportions. The quantitative data with a normal distribution are represented as the mean ± standard deviation, and were analyzed using independent sample t-tests for two-group comparisons and a one-way analysis of variance for multiple group comparisons. Post-hoc tests (Bonferroni or Tamhane’s T2) were used for pairwise comparisons as appropriate. The non-normally distributed data are represented as the median and range, and the Mann-Whitney U test and Kruskal-Wallis H test were used for comparisons. Pearson’s correlation was used to test the continuous variable correlations. Significant variables from the single-factor analysis (P<0.05) were included in the binary logistic regression model for the multivariate analysis. Receiver operating characteristic (ROC) curves were used to determine the cut-off values of the variables, area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). All the P values were two-tailed, and a P value <0.05 was considered statistically significant. In this study, intra- and inter-group variability analyses of echocardiographic indices demonstrated that all ICCs were >0.75, indicating good reproducibility.

Results

Comparison of cardiac function between the children with chronic KD and the healthy controls

Table 1 sets out the clinical baseline data of the 89 children with KD in the study group (of whom, 18 had GCAs, 23 had MCAs, 25 had SCAs, and 23 had no dilation) and 89 children in the healthy control group. There were no statistically significant differences between the two groups in terms of age, gender, height, weight, body surface area (BSA), and HR (P>0.05).

The ICC values for all LV and LA myocardial strain and SR measurements exceeded 0.75 in both the intra- and inter-observer analyses (Table S1). In terms of LV function, the 4C-SRs, 3C-GLS, 3C-SRs, 2C-GLS, 2C-SRs, MV-GCS, MV-SRs, PM-GCS, PM-SRs, and LV-GLS, LV-GLSRs, and LV-GCS exhibited decreased systolic function in the KD group compared to the healthy control group (P<0.05). Additionally, in terms of diastolic function, the transmitral E peak velocity, septal E/e, 4C-SRe, 3C-SRe, 2C-SRe, MV-SRe, MV-SRa, PM-SRe, PM-SRa, LV-GLSRe, and LV-GCS-SRe were decreased in the KD group compared to the healthy control group (P<0.05). The LA-SR values were significantly higher in the KD group than the healthy control group (P<0.05), but no statistically significant differences were observed in the other LA functions between the two groups (P>0.05).

Comparison of different CAL grades between KD and healthy control groups

Table 2 and Figure S4 compare the cardiac function between different CAL grades in the KD and healthy control groups. The study included 18 patients with GCAs, 23 with MCAs, 25 with SCAs, 23 with no dilation, and 89 healthy controls. There were no statistically significant differences among the subgroups in terms of baseline characteristics, such as age, gender, height, weight, BSA, SBP, DBP, HR, and disease duration (P>0.05).

The study also examined the association between CAL risk stratification and cardiac function. Overall, no significant inter-group differences (P>0.05) were found in the 2D echocardiography, M-mode, PW, TDI, and STE measurements among the four subgroups of the patient group. In the MCA and LCA subgroups, a certain proportion of patients (GCAs 61.11%, MCAs 69.57%) had LV-GLS ≥18%, while in the SCA (16.00%) and no dilation (13.04%) subgroups a certain proportion of patients had LV-GLS <18%. In terms of LV function, compared to the healthy control group, the patient group (comprising the four subgroups) showed reduced systolic function in terms of 3C-GLS, 2C-GLS, MV-GCS, MV-SRs, PM-GCS, PM-SRs (P<0.05). Early diastolic function, as indicated by E, E/A, 4C-SRe, 3C-SRe, 2C-SRe, MV-SRe, and PM-SRe, was also reduced (P<0.05). No statistically significant differences were observed in terms of LA function (different CAL grades in the KD and healthy control groups, P>0.05).

Risk factors associated with reduced cardiac function (GLS <18%)

The inter-observer ICC for LV-GLS was 0.778, and the intra-observer ICC was 0.790. In terms of the acute-phase hematological indicators (Table 3), the GLS <18% group had lower PLTs (P=0.041) and elevated CRP levels (P=0.021) compared to the GLS ≥18% group. Additionally, the GLS <18% group had lower Na⁺ (P=0.008) and reduced Ca²⁺ (P=0.042) than the GLS ≥18% group. Significant differences were observed between the two groups in terms of the sites affected by CAL (P<0.05).

Table 4 sets out the results of a binary logistic regression analysis aimed at identifying the independent risk factors associated with decreased cardiac function. Notably, after excluding three patients with incomplete segment tracking data, the association trend between CRP and GLS <18% remained consistent [adjusted odds ratio (OR) =1.021, 95% confidence interval (CI): 1.001–1.043, P<0.05]. The ROC curve in Figure 2 shows the predictive capability of CRP for GLS <18%. The analysis determined a cut-off value of 127.79 mg/L for CRP, which had an AUC of 0.702 (95% CI: 0.51–0.89), indicating moderate predictive performance. CRP had a sensitivity of 0.600, a specificity of 0.849, a PPV of 79.89%, and a NPV of 67.97%, which confirmed the utility of CRP in predicting GLS <18%.

Figure 2 ROC curve illustrating the capacity of CRP to predict GLS <18%. This analysis yielded a cut-off value of 127.79 mg/L. The AUC reached 0.702 (95% confidence interval: 0.51–0.89), indicating moderate predictive performance. It had a sensitivity of 0.60 and a specificity of 0.849. AUC, area under the curve; CI, confidence interval; CRP, C-reactive protein; GLS, global longitudinal strain; ROC, receiver operating characteristic.

Correlation analysis between acute-phase indicators and chronic-phase cardiac function in children with KD

This study selected several hematological indicators (i.e., WBC, N, L, PLT, NLR, PLR, SII, CRP, ALT, AST, TB, ALB, CAR, K⁺, Na⁺, and Ca²⁺) that reflect the degree of inflammation or predict IVIG resistance, and explored their correlations with chronic myocardial strain and SR in 64 children with KD (Tables 5,6, and Figure 3). Several noteworthy correlations were found. First, no significant correlation was observed between the chronic-phase Z score of the coronary arteries and chronic myocardial strain and SR. Second, the NLR was negatively correlated with MV-GCS (r=–0.319, P=0.023) and MV-SRe (r=–0.363, P=0.009). The SII was negatively correlated with MV-SRe (r=–0.317, P=0.025). Na⁺ was positively correlated with MV-GCS (r=0.296, P=0.026) and MV-SRe (r=0.339, P=0.011).

Figure 3 Correlation between acute-phase indicators and chronic-phase cardiac function in children with KD. KD, Kawasaki disease; MV-GCS, mitral valve plane global circumferential strain; MV-SRe, mitral valve plane systolic strain rate; NLR, neutrophil-to-lymphocyte ratio; SII, systemic immune-inflammation index.

Discussion

In this study, we conducted the first investigation into the cardiac function of KD patients in the chronic phase stratified by different CAL risks, and systematically analyzed the factors influencing chronic-phase cardiac function. This study had two main findings. First, even if they have LVEF values within the normal range, KD patients may still experience impaired global myocardial contraction and relaxation (strain and SR) in the chronic phase. Notably, no significant correlation between the decline in cardiac function in the chronic-phase KD patients and CAL risk stratification was found; thus, it appears that there was no gradient change in cardiac function decline with increasing CAL severity. KD patients without CALs and those with SCAs still carry a risk of subclinical cardiac dysfunction in the chronic phase. Surprisingly, most KD patients with moderate- to large-sized CALs exhibited completely normal cardiac function. Second, the extent of inflammatory response in the acute-phase KD patients appears to be a potential risk factor for the decline in chronic-phase cardiac function. Most importantly, a CRP level >127.79 mg/L in the acute phase was found to be an important predictor of decline in chronic-phase GLS in KD patients.

In exploring cardiac function in KD patients, previous studies have shown that even in the absence of CALs, children with KD may experience subclinical cardiac dysfunction during both the acute and chronic phases of the disease. Wang et al. (18) found that in the acute phase, IVIG-resistant patients (N=50) had significantly lower GLS values than healthy children (15.82%±3.32% vs. 20.01%±2.98%, P=0.001), and a considerable portion of IVIG-resistant patients (76%) had no CALs. Similarly, Lin et al. (4) employed three-dimensional (3D)-STE, and found that in the chronic phase, both KD patients with CALs (−16.09%±3.00% vs. –19.84%±2.73%) and those without CALs (−17.91%±4.50% vs. −19.84%±2.73%) had reduced GLS compared to the control group (P<0.05). Similarly, this study found that during the chronic phase of the disease, the KD patients had impaired LV systolic and diastolic function compared to the healthy controls (in terms of 4C-SRs, 3C-GLS, 3C-SRs, 2C-GLS, 2C-SRs, MV-GCS, MV-SRs, PM-GCS, PM-SRs, LV-GLS, LV-GLSRs, LV-GCS, transmitral E peak velocity, septal E/e, 4C-SRe, 3C-SRe, 2C-SRe, MV-SRe, MV-SRa, PM-SRe, PM-SRa, LV-GLSRe, and LV-GCS-SRe; Table 1). Further, in the subgroup analysis, we observed that the subgroups of KD patients displayed varying degrees of cardiac dysfunction compared to the healthy controls (in terms of 3C-GLS, 2C-GLS, MV-GCS, MV-SRs, PM-GCS, PM-SRs, E, E/A, 4C-SRe, 3C-SRe, 2C-SRe, MV-SRe, and PM-SRe). However, there was no gradient change in the decline of cardiac function among the subgroups with worsening CAL severity (Table 2). Additionally, our study observed that the KD patients without CALs and those with small SCAs still had a risk of subclinical cardiac dysfunction during the chronic phase (LV-GLS <18%, 16% and 13.04%, respectively). Conversely, a significant proportion of the KD patients with GCAs (61.11%) and MCAs (69.57%) had normalized cardiac function (LV-GLS >18%). Given these findings, appropriate choices should be made in determining follow-up strategies and assessments in the future.

It is important to note that KD patients without CALs and those with SCAs may still face a risk of subclinical cardiac dysfunction during the chronic phase. For KD patients with significant subclinical cardiac dysfunction, medical intervention measures may help reduce the occurrence of long-term adverse outcomes. Extending the follow-up period, rather than terminating it, may be more appropriate in such cases. Conversely, a considerable portion of the KD patients with moderate- to large-sized CALs showed normalized cardiac function during the chronic phase. For such patients, further research and multidisciplinary discussion is required in relation to whether preventive treatment is necessary, whether physical activity should be strictly limited, and how to conduct rational follow up require to reduce the burden placed on individuals, families, and society. Moreover, the high proportion of GLS abnormalities in the GCA patients (38.89%) may reflect the sensitivity of STE to changes in focal cardiac function being higher than that of anatomical assessments of CAL. However, due to the limited sample size of our study, future validation in larger cohorts is necessary.

Dedeoglu et al. (5) found that in 35 KD patients, chronic-phase LV mechanical damage predominantly occurred in the LAD artery branch region. However, no significant correlation was observed between coronary artery involvement and reduced myocardial segmental strain. This suggests that, apart from myocardial ischemia caused by CALs, there are likely other contributing factors. Similarly, in our analyses of both the entire KD patient cohort and the subgroups based on CAL risk stratification, we observed no notable correlation between the extent of subclinical cardiac dysfunction and CAL severity. Thus, alternative risk factors that could potentially contribute to subclinical cardiac dysfunction during the chronic phase need to be investigated.

Previous research has established that myocarditis occurs in all KD patients during the acute phase, irrespective of coronary artery status (30,31). Myocarditis, stemming from various causes, can lead to the development of chronic-phase myocardial fibrosis, giving rise to subclinical cardiac functional abnormalities and even cardiomyopathy (32-34). Myocarditis is correlated with inflammatory markers, myocardial troponin levels, and natriuretic peptides (41). Changes in blood cell counts (e.g., Ns, Ls, and PLTs) and circulating proteins (e.g., CRP) and blood calcium levels are related to the inflammatory response (41,42). We defined GLS absolute values of <18.0% as abnormal, and included both KD patients with normal and decreased cardiac function. We compared their acute-phase blood parameters to investigate potential risk factors for mid- to long-term cardiac function decline. The results showed that factors such as age of onset, proportion of incomplete KD, time from fever onset to treatment initiation, and IVIG resistance had no significant effect on mid- to chronic-phase cardiac function (P>0.05). However, acute-phase blood indices before IVIG administration, including decreased PLT, Na⁺, and Ca²⁺ levels, and elevated CRP, were identified as potential risk factors for abnormal cardiac function in the chronic phase (P<0.05). These indices reflect the severity of acute-phase inflammatory response to some extent, and appear to predict whether mid- to chronic-phase cardiac function will decline. Additionally, we found that a CRP level >127.79 mg/L before IVIG administration in the acute phase was an independent risk factor for predicting GLS <18% in the chronic phase (P<0.05). The higher the CRP level, the higher the likelihood of GLS <18% (AUC: 0.702, P=0.044; sensitivity: 0.60, and specificity: 0.849). Although the absolute value of the OR of CRP (OR =1.021) was modest, its synergistic effects with the NLR (r=−0.319, P=0.023) and SII (r=−0.317, P=0.025) suggest that combining inflammatory markers may improve predictive performance of GLS <18%. A CRP level >127.79 mg/L had a NPV of 92.0%, supporting its utility as a practical risk stratification tool for high-risk patients. However, due to the limited sample size of our study, future validation in larger cohorts is necessary.

Moreover, in previous research, elevated WBC (2), NLR (43), PLR (43), CAR (44), SII (45), and ALT (2) levels were associated with predicting IVIG resistance, myocarditis, and valve regurgitation. Our study found weak negative correlations between the NLR, SII, and circumferential strain, and the SR of the LV (P<0.05), and a weak positive correlation between blood Na⁺ levels and these strain indices (P<0.05). However, no significant correlation was found between these blood parameters and the longitudinal strain and SR of the LV. This could be due to the gradual recovery of myocardial function as the disease progresses, as well as the restoration of coronary artery damage and alleviation of inflammatory injury (3,25).

Hu et al. (25) found that despite the gradual recovery of myocardial function with disease progression, the subendocardial myocardium remains damaged. Conversely, our study found sustained impairment in the circumferential motion of the mid-myocardium and subepicardium. This inconsistency may be due to the limited sample size of our study. Conversely, given the relatively poor tolerance of the subendocardial layer to hypoxia, as inflammation and coronary structure gradually recover, the myocardial function of the subendocardium [which is responsible for the longitudinal strain of the LV (25,46)] is restored first, while the mid-myocardium and subepicardium [which responsible for the circumferential and twisting motion of the LV (25,46)] and microvascular function require more time for recovery. In summary, CRP serves not only as a key indicator of acute-phase inflammatory responses but also as a predictor of chronic-phase cardiac function changes and adverse cardiovascular events (47). For KD patients with a CRP elevation >127.79 mg/L in the acute phase, extending the monitoring window for chronic cardiac function allows for the timely intervention and treatment of early cardiac dysfunction. Further, while the correlations between the NLR, SII, Na⁺, and cardiac function were relatively low, combining these indices for assessment may enhance predictive efficacy of early cardiac dysfunction.

The current 2017 AHA guidelines and 2020 Japanese Circulation Society (JCS) guidelines for the management of sequelae in KD are based on CAL risk stratification. However, our research findings revealed certain potentially overlooked aspects. Our results suggest that incorporating acute-phase inflammatory indicators into CAL stratification and subcategorizing individual management in children with KD may have important clinical implications.

Conclusions

This was the first study to explore chronic-phase cardiac function in KD patients. Using CAL grading, a systematic analysis of the risk factors associated with chronic-phase cardiac dysfunction was conducted. Our findings indicate the potential occurrence of subclinical cardiac dysfunction in the LV myocardium during the chronic-phase of KD. Crucially, this dysfunction was not found to be significantly correlated with CAL severity. Additionally, the extent of the acute-phase inflammatory response was found to be a predictor of change in chronic-phase cardiac function. However, given the limitations of this study, further research with a larger sample size needs to be conducted to validate these findings. Subsequent investigations should adopt a comprehensive and longitudinal approach to monitor changes in cardiac functional status and trends over time in the same cohort of KD patients. Despite strict quality control, the incomplete tracking of basal segments (especially the lateral/posterior walls) by STE may still affect GLS accuracy. The use of 3D-STE or cardiac MRI could address this issue.

Acknowledgments

We are grateful to the patients and families for their contributions to this work.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2352/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2352/dss

Funding: This work was supported by Science-Technology Support Plan Projects in Sichuan Province (Nos. 2024YFFK0272, 2024NSFSC1711, and 2024YFFK0078), the National Natural Science Foundation of China (Nos. 82370236 and 82070324), and the National Key Research and Development Program of China (Nos. 2023YFC2706402 and 2022YFC2703902).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2352/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the University Ethics Committee on Human Subjects at Sichuan University (No. K2019105), and all patients’ legal guardians provided written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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