Original ResearchFree Access

Subendocardial Involvement as an Underrecognized Cardiac MRI Phenotype in Myocarditis

Published Online:https://doi.org/10.1148/radiol.2021211276

Abstract

Background

Subendocardial late gadolinium enhancement (LGE) detected with cardiac MRI in myocarditis represents a diagnostic dilemma, since it may resemble myocardial ischemia.

Purpose

To explore and compare the histopathologic characteristics and clinical features and outcomes in patients with myocarditis with and without subendocardial involvement at cardiac MRI.

Materials and Methods

This retrospective study evaluated 39 patients with myocarditis pathologically proven by means of either endomyocardial biopsy or explant pathologic findings between 2015 and 2020. Patients were divided into two groups according to cardiac MRI phenotype: 18 with subendocardial involvement (mean age ± standard deviation, 40 years ± 17; 10 women) and 21 with no subendocardial involvement (mean age, 35 years ± 11; six women). The median follow-up period was 784 days (interquartile range [IQR], 90–1123 days). The Student t test, Mann-Whitney U test, and univariable Cox regression were used for statistical analyses.

Results

In the 18 patients with subendocardial involvement, 12 (67%) had lymphocytic myocarditis and six (33%) had giant cell myocarditis. Patients with subendocardial involvement compared with those without subendocardial involvement had lower left ventricular ejection fraction (mean ± standard deviation, 27% ± 11 vs 41% ± 19; P = .004), larger LGE extent (median, 13% [IQR, 10%–22%] vs 5% [IQR, 2%–17%]; P < .001), higher rates of cardiac death or transplant (eight of 18 patients [44%] vs one of 21 patients [4.8%]; P = .006), higher probability of giant cell myocarditis (six of 18 [33%] vs one of 21 [4.8%]; P = .02), and more major adverse cardiovascular events (MACE) (15 of 18 [83%] vs seven of 21 [33%]; P = .002). In a subgroup of patients with comparable LGE extent (median, 15% vs 16%; P = .40) and left ventricular ejection fraction (median, 27% vs 31%; P = .26), the prognostic difference in terms of MACE remained (15 of 17 patients [88%] vs five of 10 [50%]; P = .02).

Conclusion

Subendocardial involvement detected with cardiac MRI in myocarditis indicated more severe clinical features, including a higher frequency of severe lymphocytic myocarditis or giant cell myocarditis and worse prognosis.

© RSNA, 2021

See also the editorial by de Roos in this issue.

Summary

The cardiac MRI phenotype of subendocardial involvement in myocarditis indicated more severe clinical features, including a higher frequency of severe lymphocytic myocarditis or giant cell myocarditis and worse prognosis.

Key Results

  • ■ In a retrospective study of 39 patients with pathologically proven myocarditis, 18 had subendocardial involvement and 21 had no subendocardial involvement at cardiac MRI, while 12 of 18 (67%) with subendocardial involvement had lymphocytic myocarditis.

  • ■ The 18 patients with subendocardial involvement had higher rates of cardiac death or transplant (eight of 18 [44%] vs one of 21 [4.8%]; P = .006) and more patients with giant cell myocarditis (six of 18 [33%] vs one of 21 [4.8%]; P = .02) than those with no subendocardial involvement.

Introduction

The diagnosis of myocarditis is challenging, especially for chronic scenarios (>3 months) with a highly variable trajectory and nonspecific clinical presentations, in addition to varied histologic classifications. The diagnostic reference standard is endomyocardial biopsy (EMB) (1), and cardiac MRI is considered the most accurate noninvasive approach. According to the Lake Louise criteria for diagnosing myocarditis with cardiac MRI, there are three important diagnostic criteria detected with use of T2 weighting, early gadolinium enhancement, and late gadolinium enhancement (LGE): edema, hyperemia, and necrosis and/or fibrosis, respectively (2). Among these criteria, LGE has the most reliable diagnostic efficacy (3). The sensitivity and specificity of LGE in the diagnosis of myocarditis range from 49%–85% and 43%–100%, respectively (36). The description of the signature pattern of LGE is nonischemic inflammatory injury, which tends to be patchy, epicardial, and located midwall at basal to midinferolateral walls (7). However, there are some atypical patterns of LGE at cardiac MRI. One of the most confusing patterns is subendocardial LGE (810) because it most commonly appears in myocardial ischemia. Although subendocardial LGE in myocardial ischemia usually has coronary distribution not observed in myocarditis, the differential diagnosis relies heavily on expertise. The infarct-like clinical manifestation in some patients with myocarditis adds to the diagnostic difficulty (6). Therefore, many studies have tended to exclude patients with subendocardial LGE from myocarditis cohorts (8,9,11) due to diagnostic ambiguity. Thus, the aim of this study is to explore and compare the histopathologic characteristics and clinical features and outcomes in patients with pathologically proven myocarditis with and without subendocardial involvement at cardiac MRI.

Materials and Methods

Study Sample

The study screened consecutive patients with a primary diagnosis of myocarditis on the discharge form and who underwent cardiac MRI between November 2015 and May 2020 at Fuwai Hospital and Peking Union Medical College Hospital, China. The inclusion criteria consisted of (a) fulfilled diagnostic criteria of both clinically suspected and pathologically proven myocarditis according to the 2013 European Society of Cardiology position statement (1,12) and (b) absence of severe (>50%) epicardial coronary stenosis at coronary angiography for patients over 35 years old and at coronary CT for patients 35 years old or younger. Exclusion criteria consisted of patients with known preexisting cardiovascular disease or extracardiac causes, such as sarcoidosis. Patients undergoing heart transplant were fully evaluated by the ethics committee of heart transplantation. The investigation conforms with the principles outlined in the Declaration of Helsinki. The hospital research ethics committee approved this study, and informed consent was obtained from the patients. Patients were not involved in design, conduct, reporting, or dissemination plans of this research.

Cardiac MRI Protocol

Scanning was performed with a clinical 3.0-T MRI scanner (Ingenia, Philips Healthcare). Cine steady-state free precession imaging (repetition time, 2.8 msec; echo time, 1.39 msec; views per segment, 15; time resolution, 42 msec; flip angle, 45°) was used to obtain left ventricular volumes and function. T2-weighted short-tau inversion-recovery imaging (repetition time, two to three heartbeats; echo time, 80 msec; inversion time, 230 msec; voxel size, 2 × 2.12 × 8 mm) was used for edema evaluation. Two-dimensional segmented phase-sensitive inversion-recovery sequence (repetition time, 6.1 msec; echo time, 3.0 msec; inversion time, 300 msec; field of view, 360 × 346 mm; voxel size, 1.61 × 1.93 × 8 mm; flip angle, 5°) was used for LGE scanning, starting 10–15 minutes after the second injection of weight-based (cumulative dose, 0.15 mmol per kilogram) gadopentetate dimeglumine (Bayer) (13).

Image Analysis

All images were transported to an Advantage Windows 4.3 workstation (GE Healthcare). Subendocardial and epicardial contours were manually traced, excluding papillary muscles and trabeculae. End-systolic and end-diastolic volume were calculated with use of the Simpson rule. To group the patients, all cardiac MRI scans were independently read by two specialized radiologists, M.J.L. (with 15 years of experience in cardiac MRI) and another radiologist (with 11 years of experience in cardiac MRI and independent from the research team of this study), and both were blinded to clinical information. Scans with different grouping results by the two radiologists were grouped by the adjudicator (S.H.Z., with 20 years of experience in cardiac MRI), who was blinded to clinical information, by selecting the results he most agreed with.

Myocardial edema was evaluated by assessing the ratio of the signal intensity in different myocardial segments compared with the skeletal muscle (2,9). The extent of LGE was quantified by using commercially available software (Circle Cardiovascular Imaging, version 5.13.5). Epicardial and endocardial contours were drawn on left ventricular short-axis sections of LGE images. Areas of signal intensity greater than 5 standard deviations from normal myocardium were defined as LGE, while areas confirmed as artifactual at visual analysis were manually excluded. The LGE extent was calculated by dividing LGE mass by the total left ventricular mass. All images were analyzed by one radiologist (J.H.L., with 6 years of experience in cardiac MRI) blinded to clinical information. Scans from a subgroup of 20 randomly selected patients were measured by a second observer (with 5 years of experience in cardiac MRI) blinded to both clinical information and the first observer’s measurement results as an interobserver reproducibility test. The measurements for the same patients were repeated by the first observer (J.H.L.) 2 weeks later as an intraobserver reproducibility test.

EMB and Immunohistochemistry

The indications for EMB were considered according to the scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology (14). It was mainly restricted to patients with life-threatening presentations and no cardiovascular comorbidities. EMBs were performed in the septal region of the right ventricular chamber, which was approached by using 7F Jawz endomyocardial biopsy forceps (Argon Medical Devices). Four samples (2–4 mm3) per patient were drawn and processed for histologic and immunohistochemical information. Multiple slices were stained with hematoxylin-eosin and Masson trichrome and examined by using light microscopy. Immunohistochemical analysis for the characterization of inflammatory infiltrates was performed using the following antibodies: CD3, CD4, CD8, CD19, CD20, CD68, and leukocyte common antigen. The pathologist H.Y.W. and another pathologist (with 33 and 8 years of experience, respectively, in cardiac pathology) analyzed the slices independently, and both were blinded to clinical and cardiac MRI results. There was no disagreement between the two pathologists for patients included in this study. The classifications and histologic and immunohistochemical diagnostic criteria for myocarditis were followed in accordance with published studies (1,12,15).

Patient Follow-up

All patients were assessed with electronic medical records of their regular follow-ups, with a median follow-up period of 784 days (interquartile range [IQR], 90–1123 days). When electronic medical records were insufficient, patients were evaluated by means of telephone interview based on a standardized questionnaire. The major adverse cardiovascular events (MACE) included cardiac death, heart transplant, and recurrent myocarditis or heart failure decompensation requiring hospital readmission.

Statistical Analysis

Data for continuous variables are shown as means ± standard deviations for normally distributed values and medians with IQRs for nonnormally distributed variables. Categorical variables are reported as numbers with percentages. Comparisons between groups were analyzed by using the Mann-Whitney U test for nonnormally distributed continuous variables and Student t test for normally distributed variables. The χ2 test and Fisher exact test were used as appropriate. Univariable Cox regression models were used to assess associations of subendocardial involvement to time-to-event outcomes, and hazard ratios (HRs) were adjusted for covariates one by one. To further exclude the impact of left ventricular ejection fraction (LVEF) and LGE extent differences on outcomes, subanalyses for patients with LVEF less than 50% and LGE over 5% were conducted. In this way, we were actually comparing patients with subendocardial involvement versus patients with classic epicardial LGE. Analyses were performed with SPSS version 23 (IBM). Two-tailed P < .05 was considered indicative of statistically significant difference.

Results

Characteristics of the Study Sample

There were 174 inpatients who fulfilled the diagnostic criteria of clinically suspected myocarditis and having undergone cardiac MRI at admission. Cardiac MRI findings showed 143 of 174 patients (82%) with no subendocardial involvement and 31 (18%) with noncoronary subendocardial involvement (Figs 12). The group of patients with no subendocardial involvement included 55 patients with no LGE and 88 patients with classic epicardial and/or midwall LGE. The group of patients with subendocardial involvement included 21 patients with pure subendocardial LGE and 10 patients with major subendocardial LGE plus patchy transmural LGE (Fig 3).

Flow diagram. EMB = endomyocardial biopsy, LGE = late gadolinium                         enhancement, Nov = November, TnI = troponin I.

Figure 1: Flow diagram. EMB = endomyocardial biopsy, LGE = late gadolinium enhancement, Nov = November, TnI = troponin I.

Myocardial inflammation with subendocardial involvement in a                         56-year-old man with dyspnea and palpitations for more than 1 year. His                         cardiac troponin I level was 0.644 ng/mL. His echocardiogram showed                         atrioventricular block and pathologic Q waves, and his coronary artery                         angiograph was normal. (A, B) Cardiac MRI scans obtained with                         phase-sensitive inversion-recovery sequence in two-chamber and short-axis                         views show left ventricular subendocardial late gadolinium enhancement. (C)                         Photograph of explant pathologic specimen shows diffuse subendocardial                         fibrosis, with 1:1 mm ruler for scale. (D) Cross-section from left                         ventricular lateral wall shows diffuse lymphocytic infiltration and myocyte                         necrosis (hematoxylin-eosin stain, ×40 magnification). (E)                         Hematoxylin-eosin stain, ×200 magnification; magnified from                         D.

Figure 2: Myocardial inflammation with subendocardial involvement in a 56-year-old man with dyspnea and palpitations for more than 1 year. His cardiac troponin I level was 0.644 ng/mL. His echocardiogram showed atrioventricular block and pathologic Q waves, and his coronary artery angiograph was normal. (A, B) Cardiac MRI scans obtained with phase-sensitive inversion-recovery sequence in two-chamber and short-axis views show left ventricular subendocardial late gadolinium enhancement. (C) Photograph of explant pathologic specimen shows diffuse subendocardial fibrosis, with 1:1 mm ruler for scale. (D) Cross-section from left ventricular lateral wall shows diffuse lymphocytic infiltration and myocyte necrosis (hematoxylin-eosin stain, ×40 magnification). (E) Hematoxylin-eosin stain, ×200 magnification; magnified from D.

Cardiac phase-sensitive inversion-recovery MRI scans show examples of                         late gadolinium enhancement (LGE) patterns.

Figure 3: Cardiac phase-sensitive inversion-recovery MRI scans show examples of late gadolinium enhancement (LGE) patterns.

In total, 54 patients underwent pathologic examination: 46 patients underwent EMB and eight underwent pathologic examination of heart explant. There were 29 patients with lymphocytic myocarditis, seven with giant cell myocarditis, three with eosinophilic myocarditis, and 15 with nonspecific pathologic findings. The group of patients with subendocardial involvement had higher positive pathologic findings for myocarditis (18 of 20 patients [90%] vs 21 of 34 patients [62%]; P = .01).

Thirty-nine patients with pathologically proven myocarditis were enrolled in this study: 18 with noncoronary subendocardial involvement and 21 with no subendocardial involvement. Among the 18 patients with subendocardial involvement, 12 (67%) had lymphocytic myocarditis and six (33%) had giant cell myocarditis. Ages were similar between patients with and patients without subendocardial involvement (mean age ± standard deviation, 40 years ± 17 vs 35 years ± 11; P = .22) (Table 1). We found no evidence of a gender difference between the two groups (10 of 18 patients [56%] vs six of 21 [29%] were women; P = .16).

Table 1: Characteristics of the 39 Included Patients with Pathologically Proven Myocarditis

Table 1:

Clinical and Cardiac MRI Features

The main symptoms in both groups were dyspnea (13 of 18 patients with subendocardial involvement [72%] vs 15 of 21 without subendocardial involvement [71%]; P = .96), followed by palpitations (eight of 18 [44%] vs eight of 21 [38%]; P = .69). We found no evidence of a difference in terms of pathologic Q waves and ventricular arrhythmia in patients with and without subendocardial involvement (both were observed in seven of 18 patients [39%] vs three of 21 [14%]; P = .14).

Patients with subendocardial involvement had less history of infection (five of 18 patients [28%] vs 14 of 21 [67%]; P = .02), longer disease duration (median, 102 days [IQR, 60–346 days] vs 22 days [IQR, 14–58 days]; P = .04), lower LVEF (mean ± standard deviation, 27% ± 11 vs 41% ± 19; P = .004), and larger LGE extent (median, 13% [IQR, 10%–22%] vs 5% [IQR, 2%–17%]; P < .001) compared with patients without subendocardial involvement.

Patient Prognosis

In a median follow-up period of 784 days (IQR, 90–1123 days), patients with subendocardial involvement had higher cardiac death or transplant rate (eight of 18 patients [44%] vs one of 21 [4.8%]; P = .006) and more MACE (15 of 18 [83%] vs seven of 21 [33%]; P = .002) than patients without subendocardial involvement (Table 1). There were more patients with normal echocardiographic findings at last follow-up among those with no subendocardial involvement than with subendocardial involvement (15 of 21 patients [71%] vs four of 18 [22%]; P = .004).

With use of Cox regression analysis, subendocardial involvement was confirmed as a significant univariable predictor for cardiac death or transplant (HR, 13; 95% CI: 2, 106; P = .02) and MACE (HR, 5; 95% CI: 2, 12; P = .001). After separate adjustment for disease duration (HR for cardiac death or transplant, 10; 95% CI: 1, 88; P = .03; HR for MACE, 4; 95% CI: 1, 9; P = .01), LVEF (HR for cardiac death or transplant, 8; 95% CI: 1, 68; P = .047; HR for MACE, 4; 95% CI: 1, 10; P = .001), LGE extent (HR for cardiac death or transplant, 11; 95% CI: 1, 88; P = .03; HR for MACE, 4; 95% CI: 1, 10; P = .006), and giant cell myocarditis (HR for cardiac death or transplant, 10; 95% CI: 1, 84; P = .04; HR for MACE, 5; 95% CI: 2, 12; P = .002), the risk of subendocardial involvement remained significant (Table 2).

Table 2: Cox Model Analyses Assessing the Relationship between Subendocardial Involvement and Outcomes in the 39 Patients with Pathologically Proven Myocarditis

Table 2:

Subanalyses in patients with comparable LVEF (LVEF <50%: mean ± standard deviation, 26% ± 10 vs 25% ± 11; P = .89) and LGE extent (LGE extent >5%: median, 15% [IQR, 12%–24%] vs 16% [IQR, 9%–25%]; P = .40) showed that patients with subendocardial involvement still had a higher MACE rate (15 of 17 patients with subendocardial involvement [88%] vs four of 10 without [40%] [P = .005] in patients with LVEF <50%; 15 of 17 [88%] vs five of 10 [50%] [P = .02] in patients with LGE extent >5%). However, we found no significant difference in terms of cardiac death or heart transplant rate (eight of 17 patients [47%] vs one of 10 patients [10%]; P = .09) between the two groups in the subanalyses (Table 3).

Table 3: Subanalysis for Patients with Pathologically Proven Myocarditis with LVEF Less than 50% and LGE Extent Greater than 5%

Table 3:

Giant Cell Myocarditis

Patients with subendocardial involvement had a higher rate of giant cell myocarditis (six of 18 patients [33%] vs one of 21 [4.8%]; P = .02). Compared with other classifications of myocarditis, giant cell myocarditis showed more subendocardial involvement pattern (six of seven [86%] vs 12 of 32 [38%]; P = .04) and a higher cardiac death or heart transplant rate (four of seven [57%] vs five of 32 [16%]; P = .04). However, there was no difference in terms of MACE between patients with giant cell myocarditis and other myocarditis classifications (six of seven patients [86%] vs 16 of 32 patients [50%], respectively; P = .11) (Table 4). After controlling the difference of LGE extent in the subanalysis (median, 17% [IQR, 13%–31%] in giant cell myocarditis vs 15% [IQR, 10%–23%] in other forms of myocarditis; P = .64), the difference in cardiac death or heart transplant rate (four of six patients [67%] vs 14 of 21 patients [24%]; P = .14) was not significant.

Table 4: Characteristics of Patients with Giant Cell Myocarditis Compared with Other Myocarditis

Table 4:

Intra- and Interobserver Variability

The intraclass correlation coefficients for inter- and intraobserver variability in the extent of LGE were 0.94 and 0.96, respectively.

Discussion

Subendocardial late gadolinium enhancement (LGE) detected with cardiac MRI in clinically suspected myocarditis represents a diagnostic dilemma because it may resemble myocardial ischemia. In our study, we identified the cardiac MRI phenotype of subendocardial involvement in patients with myocarditis who had longer disease duration (median period, 102 days [interquartile range {IQR}, 60–346 days] vs 22 days [IQR, 14–58 days]; P = .04), worse left ventricular ejection fraction (mean ± standard deviation, 27% ± 11 vs 41% ± 19; P = .004), larger LGE extent (median, 13% [IQR, 10%–22%] vs 5% [IQR, 2%–17%]; P < .001), higher rates of cardiac death or transplant (eight of 18 patients [44%] vs one of 21 patients [4.8%]; P = .006), and higher rate of a more severe pathologic type (giant cell myocarditis, six of 18 patients [33%] vs one of 21 [4.8%]; P = .02). Our results could be helpful for physicians to be aware of the more severe status and the possibility of giant cell myocarditis in patients with suspected myocarditis.

The real-world incidence of subendocardial LGE in myocarditis may not be rare. However, in the absence of pathologic evidence, most studies have tended to exclude patients with this phenotype from myocarditis cohorts, assuming that such a phenotype may reflect myocardial infarction. Gutberlet et al (16) reported three transmural and two subendocardial findings of LGE out of 83 patients with clinically suspected myocarditis. Lurz et al (4) reported eight transmural and six subendocardial findings of LGE among 132 patients with clinically suspected myocarditis. In a retrospective study including 150 patients with clinically suspected myocarditis, 24 with subendocardial or transmural LGE (15.9%) were excluded from the myocarditis cohort (8). In another study on 744 patients with clinically suspected myocarditis, 35 similar patients (4.7%) were excluded (9). However, the proportion of noncoronary distributive subendocardial LGE and pathologically proven myocarditis in these studies remained unknown.

The mechanism behind the noncoronary subendocardial LGE phenotype in myocarditis is unclear. The most common explanation for this cardiac MRI phenotype is myocardial infarction with nonobstructed coronary arteries, and the most common cause of myocardial infarction with nonobstructed coronary arteries is myocarditis (17). Many studies have followed up on the ischemic theory in myocarditis. Klein et al (18) found a diminished coronary reserve due to reduced coronary vasodilator capacity in 29 patients with biopsy-proven inflammatory infiltrates. Yilmaz et al (19) showed that in patients with pathologically proven myocarditis without epicardial coronary artery stenosis, vasospasm could be induced through intracoronary acetylcholine testing. On the other hand, the coronary spasm could also be directly provoked by some viruses (eg, parvovirus B19) or indirectly by the activated immune response and inflammatory mediators (20). Additionally, the prevalence of coronary artery spasm was higher among the Asian population, with a reported frequency of 81% in Japanese patients and 61% in Korean patients presenting with myocardial infarction with nonobstructed coronary arteries (21,22). A case report of COVID-19–related myocarditis in a Korean patient also showed noncoronary subendocardial to transmural LGE (23). Other explanations, such as viral infection–related arterial thrombotic and coagulopathic abnormalities (eg, from influenza and coronaviruses) (24) and nonischemic mechanisms, may also exist.

In our study, most patients with giant cell myocarditis presented with multiple patchy areas of transmural LGE in addition to diffusive subendocardial LGE. This appearance at cardiac MRI was consistent with published case reports (10,2527) and the nature of giant cell myocarditis as a frequently fatal condition (28,29). Giant cell myocarditis showed worse outcomes compared with other kinds of myocarditis. However, the difference of outcomes was not significant after controlling the difference in LGE extent. On the other hand, subendocardial involvement still remained a risk factor when univariable Cox analysis was adjusted for giant cell myocarditis as a potential confounder. Therefore, giant cell myocarditis and subendocardial involvement may interactively contribute to worse outcomes.

Three patients with eosinophilic myocarditis had no subendocardial involvement. Although eosinophilic myocarditis may be more severe than lymphocytic myocarditis (30), they would not increase the statistical difference of the outcomes between the two groups in this study.

Our study had limitations. First, the number of patients enrolled in this study was small because of the invasive nature of EMB. However, data on this topic were limited, especially in the Asian population. Second, it would be ideal to perform multivariable regression analysis to see the pure effect of subendocardial involvement on outcomes, but the sample size was not suitable. Therefore, we used univariable Cox analysis, adjusting for each covariate one by one, and conducted subanalyses controlling the differences in LVEF and LGE extent.

In conclusion, the aim of this study was to provide a description of the clinical and pathologic nature of patients with myocarditis with subendocardial involvement. Subendocardial involvement detected with cardiac MRI in myocarditis was associated with greater severity and may imply a higher frequency of severe lymphocytic myocarditis or giant cell myocarditis and worse outcomes. Studies with larger sample sizes are warranted.

Disclosures of Conflicts of Interest: J.H.L. No relevant relationships. X.Q.X. No relevant relationships. Y.J.Z. No relevant relationships. C.Y.C. No relevant relationships. M.J.L. No relevant relationships. H.Y.W. No relevant relationships. Y.N.W. No relevant relationships. Z.C.J. No relevant relationships. S.H.Z. No relevant relationships.

Author Contributions

Author contributions: Guarantors of integrity of entire study, J.H.L., S.H.Z.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, J.H.L., X.Q.X., M.J.L., Z.C.J., S.H.Z.; clinical studies, J.H.L., X.Q.X., M.J.L., H.Y.W., Y.N.W., Z.C.J., S.H.Z.; statistical analysis, J.H.L., X.Q.X., Y.J.Z., C.Y.C.; and manuscript editing, all authors

* J.H.L. and X.Q.X contributed equally to this work.

Supported by the National Key Research and Development Program of China (grant 2016YFC0901502), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant 2016-I2M-1-002), the Major International (Regional) Joint Research Project (grant 81620108015), and the Key Research Project of the National Natural Science Foundation of China (grant 81930044).

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Article History

Received: May 20 2021
Revision requested: June 25 2021
Revision received: July 20 2021
Accepted: Aug 2 2021
Published online: Oct 12 2021
Published in print: Jan 2022