Left atrial and ventricular impairment of asymptomatic pediatric myocarditis survivors: analysis by speckle tracking and exercise stress echocardiography

Introduction

Pediatric myocarditis is a non-specific inflammatory reaction of myocardial cells induced by infection, toxic drugs, ischemia or mechanical injury, or autoimmune diseases. Viral myocarditis is the most common clinical cause (1). With the improvement of medical science and technology, the survival rate in pediatric myocarditis during the acute phase has increased significantly. Although routine monitoring is usually discontinued after 6 months of uneventful recovery when patients resume physical activity, it is important to note that low-grade autoimmune activity may persist. This subclinical process is not detectable through conventional testing but can cause ongoing cardiomyocyte injury, ultimately progressing to dilated cardiomyopathy (2,3). Therefore, it is quite essential to detect sub-clinical myocardial impairment for pediatric myocarditis survivors, particularly for asymptomatic ones.

Speckle tracking echocardiography (STE) has recently emerged as a noninvasive and useful tool to detect pre-clinical myocardial dysfunction in different pediatric populations (4-6). Its prognostic role in the acute phase of myocarditis has been extensively studied and verified (7,8). However, the myocardial function in pediatric myocarditis survivors assessed by STE at follow-up of five years has not been investigated. Furthermore, subclinical myocardial injury is challenging to identify at rest, as the heart employs various compensatory mechanisms to preserve its pumping function (9). Additionally, stress echocardiography can unmask initial subclinical dysfunction, which often manifests as an impaired systolic or diastolic response (10,11). Closer follow-up should be considered for patients with signs of subclinical impairment compared to those with preserved stress response. Unfortunately, data regarding myocardial function reserve in pediatric myocarditis survivors are also lacking. Therefore, this study aims to prospectively evaluate the left atrial (LA) and ventricular (LV) function of asymptomatic pediatric myocarditis survivors by STE combined with stress echocardiography and to uncover its potential risk factors regarding myocardial impairment during follow-up. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1310/rc).

Methods

Subjects

This study prospectively enrolled a total of 90 patients between January 2010 and June 2022. All these children were diagnosed with acute myocarditis at West China Second University Hospital of Sichuan University or Women’s and Children’s Central Hospital of Chengdu. Included criteria were based on the Lake Louise cardiac magnetic resonance (CMR) criteria and its updated version of 2018 (12). Excluded criteria were patients with cardiovascular diseases, cardiovascular drug usage during the last 6 months, respiratory system disease, and severe arrhythmia that affect cardiac function and patients with poor echo images. As a result, 15 cases of asymptomatic myocarditis survivors with New York Heart Association (NYHA) Class I were enrolled as the final group, and fifteen age- and sex-matched healthy children were recruited as the controls (seen in Figure 1). The clinical demographic data of pediatric myocarditis survivors in the acute phase were collected. Written informed consent was obtained from the parents or guardians of the children. The study was both approved by the Ethics Committee of Human Subjects at Sichuan University (No. 2020121) and Women’s and Children’s Central Hospital of Chengdu (No. 2019131). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Figure 1 Flow chart detailing the identification of the study cohort. CMR, cardiac magnetic resonance.

Exercise echocardiography protocol

All examinations were performed according to our standardized institutional laboratory protocol. Without contraindication, a symptom-limited bicycle exercise stress test was performed in a computer-controlled sitting bicycle ergometer (ERG 911 Plus, Ergosana GmbH Schiller, Bitz, Germany) using a continuous incremental bicycle protocol with a work rate increment between 5 and 20 W/min according to gender, height and weight. The test was interrupted either for symptoms (fatigue, chest pain, electrocardiographic changes) or when the target HR (80% of the maximal heart rate for age) was reached. All patients were allowed to familiarize themselves with the cycle ergometer, and the procedure was discussed with the patient and parent/guardian before the test started. A Vivid E95 Echocardiography System with the M5Sc transducer (GE Medical System, Horten, Norway) was used for all imaging. Echocardiographic imaging was obtained at rest and peak stress test. Only images acquired within 90 seconds of exercise cessation were selected and used for ischemia assessment. At last, all children in the control group completed the exercise stress test while two cases failed to perform the test since the height was under 120 cm.

Conventional and Doppler echocardiographic assessments

All data were analyzed offline using the Echopac software (GE Medical System, Horten, Norway). The echocardiographic parameters from three cardiac cycles were averaged for statistical analysis (Figure 2). From the apical four-chamber view, two-dimensional echocardiographic images were used for the determination of LV end-systolic and end-diastolic areas/volumes, and the left ventricular ejection fraction (LVEF) was calculated based on the single-plane Simpson method.

Figure 2 Speckle tracking echocardiography assessment of left atrioventricular function. GS, global strain.

Transmitral pulsed-wave Doppler echocardiography was performed for the determination of peak mitral inflow velocities at early (E) and late (A) diastole, E/A ratio. Pulsed-wave tissue Doppler echocardiography was performed with the sample volume positioned at the basal LV free wall/ventricular septum-mitral annular junctions for measurement of lateral and septal peak-systolic (s), early-diastolic (e), and late-diastolic (a) myocardial tissue velocities and e/a ratio. An average from the lateral and septal E/e ratio (E/e AVG) was derived and expressed as the mean E/e ratio.

STE

Systolic and diastolic myocardial deformation in 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 apical four-chamber view, the LV global longitudinal strain (GLS) and systolic strain rate (SRs), and global longitudinal early (SRe) and late (SRa) diastolic strain rates were obtained. From the parasternal short-axis view at the mid-ventricular level, the global circumferential strain (GCS), SRs, SRe, and SRa were measured. As for 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 (εR), LA conduit strain (εCD), LA contractile strain (εCT) and atrial strain rate at systole (SRs), early diastole (SRe) and late diastole (SRa). In addition, the GLS reserve (∆GLS%) = (peak GLS − rest GLS)/rest GLS; the LA εR reserve (∆εR%) = (peak LA εR − rest LA εR)/rest LA εR; the LA εCD reserve (∆εCD%) = (peak LA εCD − rest LA εCD)/rest LA εCD; the septal s’ reserve (∆septal s’%) = (peak septal s’ − rest septal s’)/rest septal s’; the mitral s’ reserve (∆mitral s’%) = (peak mitral s’ − rest mitral s’)/rest mitral s’.

Statistical analysis

All statistical analyses were performed by SPSS, version 22.0 (SPSS Inc., Chicago, IL, USA). Quantitative data were presented as mean ± standard deviation or median with the 25^th and 75^th percentiles, while qualitative data were expressed as numbers or percentages as appropriate. Shapiro-Wilk test and homogeneity test of variance were used to confirm that quantitative data from different groups come from a normal distribution and meet the homogeneity of variance. The Chi-squared test, independent-sample t-test, or Mann-Whitney U test were applied to compare the differences between the two groups. Spearman’s correlation analysis was used to explore the relationships between resting LA deformation indices and post-exercise LV deformation indices for the total group and to investigate relationships between laboratory parameters during the acute phase of myocarditis and positive echocardiographic follow-up indices for pediatric myocarditis survivors. Statistical significance was defined as P<0.05.

Intra- and inter-observer agreement was analyzed by intraclass correlation coefficient (ICC). Intra-observer variability was assessed in two different blind evaluations 30 days apart, whereas inter-observer variability was assessed by two different observers. ICC values indicated poor (<0.5), moderate (0.5–0.75), good (0.76–0.9), or excellent (>0.9) reliability. As shown in Table S1 in detail, the intra- and inter-group variability analysis of echocardiographic indices showed that all ICC were >0.75, indicating good reproducibility.

Results

Basic clinical data

As shown in Table 1, the basic clinical data including age, sex proportions, body height, body weight, heart rate, and blood pressure were comparable between the two groups (all P>0.05). All the pediatric myocarditis survivors were followed up with a median duration of 5.5 years.

Echocardiographic indices at rest

As shown in Table 2 and Figure 3, the echocardiographic parameters of LV deformations at rest were not significantly different between the two groups except for the global circumferential SRe (1.45±0.23 vs. 1.72±0.22, P=0.003). Additionally, it was found that LA εR (34.33±5.93 vs. 40.72±6.71, P=0.01) and εCD (25.42±4.88 vs. 30.41±5.52 P=0.014) were significantly lower in the pediatric myocarditis survivors compared to that of controls.

Figure 3 Comparisons of left atrial function at rest between two groups. *, P<0.05. LA, left atrial.

Echocardiographic indices at the peak for the exercise stress test

As illustrated in Table 3 and Figure 4, after the exercise stress test, pediatric myocarditis survivors displayed worse systolic and diastolic function in comparison with controls as evidenced by lower peak s’ of mitral (10.23±1.75 vs. 12.08±1.84, P=0.012), septal s’ (8.35±0.48 vs. 9.07±0.94, P=0.021), GLS (19.39±1.08 vs. 21.18±1.44, P=0.001), GCS (18.88±1.34 vs. 20.89±1.59, P=0.001) as well as global circumferential SRe (1.54±0.30 vs. 1.93±0.39, P=0.008). In addition, the LA εR (38.81±6.69 vs. 45.62±7.04, P=0.015) and εCD (28.78±5.06 vs. 34.53±5.62, P=0.009) remained lower in the pediatric myocarditis survivors after the exercise stress test.

Figure 4 Comparisons of left cardiac function after exercise test between two groups. *, P<0.05; **, P<0.01. GCS, global circumferential strain; GLS, global longitudinal strain.

LV function reserve

As demonstrated in Table 4 and Figure 5, the cardiac function reserve was reflected as the differences in systolic/diastolic indices between at rest and peak-exercise. It was found that the systolic function reserve of pediatric myocardial survivors was significantly reduced as evidenced by smaller changes of post-exercise peak s’ of mitral (1.20±1.03 vs. 2.69±0.78, P<0.001), septal s’ (0.76±0.42 vs. 1.30±1.10, P<0.001), GLS (0.53±0.32 vs. 2.13±1.90, P<0.001) and GCS [0.97 (0.49, 2.25) vs. 2.03 (1.63, 2.77), P=0.041].

Figure 5 The change of left ventricular function reserve in the myocarditis and controls. GCS, global circumferential strain; GLS, global longitudinal strain; s', systolic myocardial velocity.

Correlations between LA deformations at rest and peak LV systolic function as well as systolic function reserve for the total group

The correlations between LA deformations (εR and εCD) at rest and peak LV systolic function (lateral s’, septal s’ and GLS), as well as LV systolic function reserve (Δpeak s’ of mitral, Δseptal s’ and ΔGLS) for the total group, were explored and the results are shown in Table 5 and Figure 6. It was found that LA εR at rest displayed moderate correlations with peak lateral s’ (r=0.409, P=0.031), septal s’ (r=0.424, P=0.025), GLS (r=0.422, P=0.025), as well as Δlateral s’ (r=0.606, P=0.001), Δseptal s’ (r=0.490, P=0.008) and ΔGLS (r=0.475, P=0.011). Similarly, moderate correlations were also observed between LA εCD at rest and peak GLS (r=0.397, P=0.037) as well as Δpeak s’ of mitral (r=0.495, P=0.007), Δseptal s’ (r=0.506, P=0.006) and ΔGLS (r=0.428, P=0.023).

Figure 6 The correlation between LA and LV function. Δ, changes before and after exercise; GLS, global longitudinal strain; LA, left atrial; LV, left ventricular; s’, systolic myocardial velocity; εR, reservoir strain.

Discussion

This study presents several novel findings regarding long-term cardiac function in asymptomatic pediatric myocarditis survivors (median follow-up: 5.5 years) using speckle-tracking and stress echocardiography. First, resting LA strain was significantly impaired despite preserved LV systolic and diastolic function. Second, LV systolic reserve, which was assessed by changes in LV-GLS and peak s’ velocity at the septal and mitral annulus, was significantly reduced in survivors without overt cardiac dysfunction. Finally, we observed a moderate correlation between impaired resting LA strain and reduced LV systolic reserve, identifying LA strain as a promising non-invasive tool for prospectively evaluating subclinical impairment in this population.

LA function is a recognized barometer of elevated LV filling pressure (13,14), and a reduction in LA strain can indicate diastolic impairment earlier than conventional Doppler parameters (15-17). Although LA εR has established diagnostic and prognostic value in conditions like atrial fibrillation (AF) (18), heart failure (HF) (19), its role in myocarditis survivors remains unexplored. Our study addresses this critical knowledge gap. Singh et al. enrolled 76 patients with varying LV function who underwent both echocardiography and cardiac catheterization. Their study compared LA εR with invasive hemodynamics to detect elevated LV filling pressures. Notably, a peak LA strain <20% showed better agreement with invasive measurements than the guideline algorithm (81% vs. 72%), particularly in patients with normal LV function (20). This finding was validated by Begieneman et al., who demonstrated that myocardial inflammation in myocarditis affects both the LV and LA. This phenomenon may be explained by the close functional interplay between the two chambers throughout the cardiac cycle (21). In our pediatric myocarditis cohort, we observed significantly reduced LA εR and εCD at rest, alongside a diminished stress reserve. These novel findings suggest the presence of persistent myocardial inflammation or fibrosis. Consequently, long-term LA function monitoring may offer earlier prognostic information than conventional parameters.

Although LV dysfunction in pediatric myocarditis typically recovers, the required observation period before stopping medication is unknown (22). The myocardium remains vulnerable to slow remodeling and future cardiomyopathy, making this subclinical, underdiagnosed process a significant long-term risk (23). In pediatric practice, stress echocardiography is employed for early detection of myocardial dysfunction. Integrating it with tissue Doppler and speckle-tracking echocardiography facilitates a more quantitative assessment (9). Currently, few studies have used transthoracic echocardiography (TTE) to assess LV deformation in pediatric myocarditis survivors, and none have explored its prognostic value combined with exercise testing. In our study, we observed no significant differences in resting LV systolic function or in post-stress LVEF and left ventricular fractional shortening (LVFS) between groups. This indicates that resting deformation imaging may be insufficiently sensitive to detect subtle impairment, and that conventional post-exercise parameters lack prognostic power in this population. Similarly, Sieswerda et al. also demonstrated that post-exercise LVEF, LVFS, and resting echocardiography offered no incremental predictive value for late cardiotoxicity in childhood cancer survivors (24). The significantly lower post-exercise myocardial velocities (s’ and Δpeak s’) observed in our cohort align with previous work by Ha et al. (25) and Akcakoyun et al. (11), indicating potential myocardial functional disturbance after recovery from acute myocarditis. The consistent abnormalities in post-exercise strain parameters and their reserve (LV-GLS, LV-GCS, ΔLV-GLS, ΔLV-GCS) point to an impaired LV systolic reserve in asymptomatic survivors, underscoring the need for regular follow-up—an observation consistent with reports in other cardiac conditions (10,26).

More interestingly, we found that reduced LA strain at rest and during stress correlated with impaired LV systolic reserve in asymptomatic pediatric survivors, suggesting its utility as an early marker of compromised contractile reserve. Assessing LA deformation via STE thus provides secondary, early evidence of these subclinical LV changes. This implies that resting LA assessment can identify subtle LV impairment even when conventional parameters like LV-GLS and LV-GCS remain within the normal range. Actually, the LA is an active chamber whose impairment often precedes LV structural remodeling. Our finding that LA dysfunction correlates with contractile reserve in myocarditis aligns with the established view from various cardiovascular diseases, including AF (27,28), HF (29), valvular heart disease (30), and hypertension (31). Therefore, integrating LA functional assessment into clinical practice may refine risk prediction and therapeutic decision-making for the long-term management of asymptomatic pediatric myocarditis survivors.

Although most pediatric acute myocarditis survivors recover well and resume normal activities after 6 months of monitoring, emerging evidence suggests that subclinical cardiac impairment may persist. This is supported by a high prevalence of persistent magnetic resonance imaging (MRI) abnormalities, such as ongoing inflammation or residual scarring (32). Furthermore, Leitman et al. reported that when cardiac MRI is not readily available, speckle-tracking echocardiography can aid in the diagnosis of acute myocarditis (33). Additionally, Schauer et al. demonstrated that even when conventional echocardiographic measures of systolic function were largely normal, abnormal GLS by STE persisted over time in pediatric myocarditis (34). Our integrated speckle-tracking and stress echocardiography data identified a subgroup of acute myocarditis patients with persistent, subclinical functional impairment despite normal LVEF. This mandates a risk-stratified follow-up strategy, especially for those with severe initial inflammation. We therefore recommend that subsequent evaluations focus on LA strain and stress echocardiography to guide timely, personalized interventions.

Limitations

This is a bi-center and small-sample prospective study. Even though the diagnostic gold standard in acute myocarditis relies on endomyocardial biopsy, none of the children in this study had the biopsy, since it is unnecessary or even contraindicated in patients without wall motion abnormalities and preserved ejection fraction. Meanwhile, owing to ensuring qualities by acquiring images immediately after the exercise stress test, only images on four-chamber and short-axis papillary muscle planes are collected and it was difficult to discover all changes on other planes. Besides, the global left ventricle strain cannot directly reflect the regional segmental strain abnormality. Therefore, image acquisition with a larger sample size based on the 17-segment model can be carried out in future prospective studies.

Conclusions

Although patients with acute myocarditis may recover well and display clinical asymptomatic status at follow-up, LA functional assessment using with STE should be monitored regularly for asymptomatic pediatric myocarditis survivors to detect early myocardial impairment and probably refine risk prediction.

Acknowledgments

A version of the abstract for this article has been previously presented at the 31st Annual Scientific Congress of the Hong Kong College of Cardiology Abstracts.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1310/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1310/dss

Funding: This work was supported by grants from the Natural Science Foundation of Sichuan province (Nos. 2024YFFK0272; 2024NSFSC1711; 2025ZNSFSC0705); the Key Research and Development Project of Chengdu Science and Technology Bureau (Nos. 2024-YF05-00237-SN; 2024-YF05-00300-SN); the National Natural Science Foundation of China (No. 82370236); and the National Key Research and Development Program of China (No. 2022YFC2703902).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1310/coif). H.D. reports the funding from the Natural Science Foundation of Sichuan province (No. 2025ZNSFSC0705) and the Key Research and Development Support Program of Chengdu Science and Technology Bureau (No. 2024-YF05-00300-SN). C.W. reports the funding from the Natural Science Foundation of Sichuan Province (No. 2024YFFK0272). K.Z. reports the funding from the National Natural Science Foundation of China (No. 82370236) and the National Key Research and Development Program of China (No. 2022YFC2703902). F.M. reports the funding from the Natural Science Foundation of Sichuan Province (No. 2024NSFSC1711). S.S. reports the funding from the Key Research and Development Project of Chengdu Science and Technology Bureau (No. 2024-YF05-00237-SN). The other 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was both approved by the Ethics Committee of Human Subjects at Sichuan University (No. 2020121) and Women’s and Children’s Central Hospital of Chengdu (No. 2019131). Written informed consent was obtained from the parents or guardians of the children.

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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