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HomeJournal of the American Heart AssociationAhead of PrintLongitudinal
Assessment of Cardiac Outcomes of Multisystem Inflammatory Syndrome in Children
Associated With COVID‐19 Infections
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LONGITUDINAL ASSESSMENT OF CARDIAC OUTCOMES OF MULTISYSTEM INFLAMMATORY SYNDROME
IN CHILDREN ASSOCIATED WITH COVID‐19 INFECTIONS

 * Daisuke Matsubara
   , MD, PhD,
 * Joyce Chang
   , MD, MSCE,
 * Hunter L. Kauffman
   , BS,
 * Yan Wang
   , RDCS,
 * Sumekala Nadaraj
   , MD,
 * Chandni Patel
   , MD,
 * Stephen M. Paridon
   , MD,
 * Mark A. Fogel
   , MD,
 * Michael D. Quartermain
   , and MD, and
 * Anirban Banerjee
   MD

Daisuke Matsubara
Daisuke Matsubara





Division of Cardiology, , Department of Pediatrics, , The Children’s Hospital of
Philadelphia, , PA

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,
Joyce Chang
Joyce Chang





https://orcid.org/0000-0002-1691-4814

Division of Rheumatology, , Department of Pediatrics, , Children’s Hospital of
Philadelphia, , PA

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,
Hunter L. Kauffman
Hunter L. Kauffman





Division of Cardiology, , Department of Pediatrics, , The Children’s Hospital of
Philadelphia, , PA

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,
Yan Wang
Yan Wang





https://orcid.org/0000-0002-3144-1584

Division of Cardiology, , Department of Pediatrics, , The Children’s Hospital of
Philadelphia, , PA

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,
Sumekala Nadaraj
Sumekala Nadaraj





Division of Cardiology, , Department of Pediatrics, , The Children’s Hospital of
Philadelphia, , PA

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,
Chandni Patel
Chandni Patel





https://orcid.org/0000-0002-1172-961X

Division of Cardiology, , Department of Pediatrics, , The Children’s Hospital of
Philadelphia, , PA

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,
Stephen M. Paridon
Stephen M. Paridon





Division of Cardiology, , Department of Pediatrics, , The Children’s Hospital of
Philadelphia, , PA

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,
Mark A. Fogel
Mark A. Fogel





Division of Cardiology, , Department of Pediatrics, , The Children’s Hospital of
Philadelphia, , PA

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,
Michael D. Quartermain
Michael D. Quartermain





Division of Cardiology, , Department of Pediatrics, , The Children’s Hospital of
Philadelphia, , PA

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, and
Anirban Banerjee
Anirban Banerjee



* Correspondence to: Anirban Banerjee, MD, Division of Cardiology, Children’s
Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104.
E‐mail:

E-mail Address: banerjeea@email.chop.edu



https://orcid.org/0000-0003-1630-4802

Division of Cardiology, , Department of Pediatrics, , The Children’s Hospital of
Philadelphia, , PA

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Originally published19 Jan 2022https://doi.org/10.1161/JAHA.121.023251Journal of
the American Heart Association. 2022;0:e023251


ABSTRACT


BACKGROUND

In multisystem inflammatory syndrome in children, there is paucity of
longitudinal data on cardiac outcomes. We analyzed cardiac outcomes 3 to
4 months after initial presentation using echocardiography and cardiac magnetic
resonance imaging.


METHODS AND RESULTS

We included 60 controls and 60 cases of multisystem inflammatory syndrome in
children. Conventional echocardiograms and deformation parameters were analyzed
at 4 time points: (1) acute phase (n=60), (2) subacute phase (n=50; median,
3 days after initial echocardiography), (3) 1‐month follow‐up (n=39; median,
22 days), and (4) 3‐ to 4‐month follow‐up (n=25; median, 91 days). Fourteen
consecutive cardiac magnetic resonance imaging studies were reviewed for
myocardial edema or fibrosis during subacute (n=5) and follow‐up (n=9) stages.
In acute phase, myocardial injury was defined as troponin‐I level ≥0.09 ng/mL
(>3 times normal) or brain‐type natriuretic peptide >800 pg/mL. All deformation
parameters, including left ventricular global longitudinal strain, peak left
atrial strain, longitudinal early diastolic strain rate, and right ventricular
free wall strain, recovered quickly within the first week, followed by continued
improvement and complete normalization by 3 months. Median time to normalization
of both global longitudinal strain and left atrial strain was 6 days (95% CI,
3–9 days). Myocardial injury at presentation (70% of multisystem inflammatory
syndrome in children cases) did not affect short‐term outcomes. Four patients
(7%) had small coronary aneurysms at presentation, all of which resolved. Only 1
of 9 patients had residual edema but no fibrosis by cardiac magnetic resonance
imaging.


CONCLUSIONS

Our short‐term study suggests that functional recovery and coronary outcomes are
good in multisystem inflammatory syndrome in children. Use of sensitive
deformation parameters provides further reassurance that there is no persistent
subclinical dysfunction after 3 months.


NONSTANDARD ABBREVIATIONS AND ACRONYMS

CAA

coronary artery abnormality

EDSRL

longitudinal early diastolic strain rate

GCS

systolic circumferential strain

GLS

global longitudinal strain

LAS

left atrial strain

MIS‐C

multisystem inflammatory syndrome in children

RVFWS

right ventricular free wall strain



CLINICAL PERSPECTIVE

WHAT IS NEW?



 * We analyzed cardiac outcomes 3 to 4 months after initial presentation of
   multisystem inflammatory syndrome in children using conventional and
   speckle‐tracking echocardiography and cardiac magnetic resonance imaging.

 * All strain parameters, including left ventricular global longitudinal strain,
   peak left atrial strain, longitudinal early diastolic strain rate, and right
   ventricular free wall strain, improved quickly within the first week,
   followed by continued improvement and complete normalization by 3 months,
   suggesting absence of persistent subclinical dysfunction after 3 months.

 * Reassuringly, there was no fibrosis in cardiac chambers in the few children
   who underwent follow‐up cardiac magnetic resonance imaging; coronary outcomes
   were good during 3 to 4 months after initial presentation of multisystem
   inflammatory syndrome in children.



WHAT ARE THE CLINICAL IMPLICATIONS?



 * These findings may provide early guidelines for outpatient management
   strategies and recommendations for returning to competitive sports after
   3 months.

 * The echocardiographic parameters described in this study may form the basis
   of future long‐term follow‐up studies.





Multisystem inflammatory syndrome in children (MIS‐C) is a newly described
hyperinflammatory syndrome associated with antecedent COVID‐19 exposure.1
Cardiovascular involvement is frequent (80%–85% of cases), including shock, left
ventricular (LV) dysfunction, coronary artery abnormalities, and biochemical
evidence of myocardial injury.2, 3 Approximately 50% of children with MIS‐C have
decreased LV systolic function by conventional echocardiography during acute
illness. Although LV ejection fraction (LVEF) improves rapidly before discharge
from the hospital,2, 4 we have previously demonstrated that diastolic
dysfunction measured by deformation parameters (strain) persists during the
subacute phase.5 In addition, because of similarities between MIS‐C and Kawasaki
disease, coronary abnormalities have garnered significant attention. The
reported incidence of coronary abnormalities varies widely (4%–24%),2, 5 and
includes cases of progressive coronary artery aneurysms following discharge.6
Therefore, a detailed characterization of functional and coronary outcomes in
this population is needed to generate follow‐up guidelines and reduce ambiguity
about follow‐up.

The aim of this study is to describe cardiac outcomes during a 3‐month follow‐up
period, to determine the short‐term impact of acute myocardial injury caused by
MIS‐C. We hypothesize that children with MIS‐C will have good functional
recovery during this short‐term follow‐up period, regardless of biochemical
evidence of myocardial injury in the acute phase.


METHODS

The data that support the findings of this study are not publicly available
because of information that could compromise patient privacy. Requests to access
a limited data set from qualified researchers trained in human subject
confidentiality protocols may be sent to Dr Anirban Banerjee at the Children’s
Hospital of Philadelphia.

STUDY DESIGN

This is a retrospective, longitudinal cohort study of cardiac outcomes in
children with MIS‐C.

STUDY POPULATION

We included children aged ≤18 years admitted to the Children’s Hospital of
Philadelphia or its affiliate institution, St. Peter’s University Hospital,
meeting classification criteria for MIS‐C from April 2020 to January 2021. The
diagnosis of MIS‐C was made according to the Centers for Disease Control and
Prevention or World Health Organization definitions,7, 8 and secondarily
adjudicated by a pediatric rheumatologist (J.C.) before inclusion. All subjects
had confirmed SARS‐CoV‐2 exposure by nasopharyngeal reverse transcriptase
polymerase chain reaction test or serum IgG antibody positivity. Exclusion
criteria included a previous history of cardiac dysfunction, congenital heart
disease, exposure to cardiotoxic agents, and chronic lung disease, and patients
treated with extracorporeal membrane oxygenation. As controls, we included
age‐matched healthy children with structurally normal hearts, who underwent
echocardiography at the same centers to evaluate benign heart murmurs, chest
pain, syncope, or a family history of cardiac disease. Of the control subjects,
60% were chosen from the pre–COVID‐19 pandemic era before January 2020. The
remaining 40% of the control subjects were selected from patients who had
echocardiograms performed under the strict infection‐control regulations in our
institution during the COVID‐19 pandemic era after October 2020, which required
the absence of any COVID‐19–related symptoms. However, SARS‐CoV‐2 testing was
not required, and therefore previous exposure status was unknown.

STUDY PROCEDURES

This study was approved by the Institutional Review Boards of Children’s
Hospital of Philadelphia (20‐018085) and St. Peter’s University Hospital
(20:95).

We retrospectively analyzed 2‐dimensional transthoracic echocardiograms at the
following 4 time points in MIS‐C patients: (1) acute phase (initial
hospitalization), (2) subacute phase (within 1 week of the first
echocardiogram), (3) 1‐month follow‐up, and (4) 3‐ to 4‐month follow‐up. For
patients with multiple echocardiograms in the acute phase, the study
demonstrating the worst LV function was used for analysis. Subacute phase was
defined as the period after the complete withdrawal of all vasoactive‐inotropic
support during the hospitalization. Because of lack of standardization of
clinical protocols, the follow‐up period exceeded 3 months in some patients.

CONVENTIONAL ECHOCARDIOGRAPHY

Two‐dimensional echocardiography was performed by pediatric cardiac sonographers
using Affiniti 70C (Philips Medical Systems, Andover, MA) or EPIQ CVx ultrasound
system (Philips Medical Systems). Standard echocardiographic measurements of
cardiac systolic and diastolic function were obtained according to American
Society of Echocardiography guidelines.9 LVEF was confirmed by 2 reviewers (A.B.
and D.M.) in all studies.

Coronary artery abnormalities (CAAs) of right coronary or left main coronary
artery or left anterior descending artery were evaluated in accordance with
standard guidelines,10 and measurements were rechecked by 3 investigators (D.M.,
A.B., and M.Q.; the latter 2 were blinded to the diagnosis). Left main coronary
artery was measured with caution at the midpoint, away from the ostium and the
bifurcation points. Coronary artery z‐scores were derived from normative data
(Boston z‐score system) and classified as follows: normal, <2; dilatation, >2 to
<2.5; and aneurysm, ≥2.5.

SPECKLE‐TRACKING ECHOCARDIOGRAPHY

Two‐dimensional speckle‐tracking analysis was performed offline to assess
myocardial deformation using a vendor‐independent software (2D CPA 1.3.0.91;
TomTec Imaging Systems, Munich, Germany), as previously described.5 Briefly,
both systolic global longitudinal strain (GLS) and GLS rate from the endocardium
were averaged from measurements from 4‐, 3‐, and 2‐chamber views. LV segmental
longitudinal strain values were calculated using the 17‐segment model and
averaged for basal, mid, and apical segments generated by the software.
Longitudinal early diastolic strain rate (EDSRL), peak global left atrial strain
(LAS), and peak longitudinal strain of the right ventricular (RV) free wall were
measured from 4‐chamber images. Peak systolic circumferential strain (GCS), peak
systolic circumferential strain rate, and circumferential early diastolic strain
rate were obtained from midcavity short‐axis views. EDSRL, EDSRC, and LAS were
used as indexes of LV diastolic dysfunction.11, 12

CLINICAL DATA

We abstracted clinical data from medical records, including demographic factors
(age, sex, race, and ethnicity); hospital outcomes (length of stay, intensive
care, and respiratory support); treatment (inotropic and immunomodulatory
agents); and laboratory data (acute phase reactants, troponin‐I [Abbott
Laboratories, Abbott Park, IL], and brain‐type natriuretic peptide [BNP]).
Biochemical evidence of myocardial injury was defined as maximum troponin‐I
level ≥0.09 ng/mL (>3 times the upper limits of normal values) or BNP
>800 pg/mL.13, 14 All ECGs were reevaluated by the researchers from the acute to
follow‐up stages. New York Heart Association functional classification at the
last visit was used as a clinical outcome.

CARDIOVASCULAR MAGNETIC RESONANCE IMAGING

We retrospectively reviewed cardiac magnetic resonance imaging (CMR) studies
obtained for clinical purposes to confirm the diagnosis of myocarditis along
with assessment of ventricular function and coronary arteries during the acute
stage. Patients with severe LV systolic dysfunction with highly abnormal
baseline CMR during acute stage or with continued evidence of severe LV
dysfunction by echocardiography during the follow‐up stage were candidates for a
repeated CMR. The CMR was performed on a 1.5‐T Siemens Avanto FIT Whole Body MRI
system (Siemens Medical Solutions, Erlanghen, Germany) using CVI42 software
(Circle Cardiovascular, Calgary, Canada) and included (1) ventricular function
with ejection fraction, (2) T1 mapping using the modified Look‐Locker inversion
recovery sequence (MOLLI) and late gadolinium enhancement to document fibrosis,
(3) T2‐weighted imaging and T2 mapping to document edema, and (4)
gadolinium‐enhanced 3‐dimensional inversion recovery gradient echo coronary
imaging for coronary visualization. Fibrosis was defined as exceeding upper
limits of normal for native T1 relaxation time or increased extracellular volume
or the presence of nonischemic patterns of late gadolinium enhancement.
Myocardial edema was defined as an increased T2 relaxation time (>60 ms) or a
ratio of the myocardial signal intensity divided by the skeletal muscle signal
intensity >1.9 on T2‐weighted imaging. Myocarditis was defined using the
criteria based on expert recommendations.15

STUDY MEASURES

FUNCTIONAL OUTCOMES

Primary outcomes included strain parameters (GLS, EDSRL, RV free wall strain
[RVFWS], and LAS). Secondary outcomes included other conventional
echocardiographic parameters i.e. LVEF, left ventricular fractional shortening
(LVFS), ratio of peak early diastolic filling velocity (E) over early diastolic
mitral annular velocity (e′), expressed as an average of septal and lateral
annular velocities (E/e′), and tricuspid annular plane systolic excursion
(TAPSE), and additional strain measures of LV systolic function (GCS, GLS rate,
and GCS rate) and LV diastolic function (circumferential early diastolic strain
rate). We defined LV and RV systolic dysfunction by GLS < −17% and RVFWS <
−21%.16, 17 Because of the lack of normative pediatric reference data for EDSRL
and LAS, we used the distribution in our controls to define abnormal cutoff
values.

STRUCTURAL OUTCOMES

We included the presence of CAAs as a binary outcome.

MYOCARDIAL CHARACTERISTICS

The presence of myocardial edema or fibrosis by CMR.

STATISTICAL ANALYSIS

Baseline characteristics were summarized using standard descriptive statistics
and compared using Fisher exact tests for categorical variables and Student t
test or Wilcoxon rank‐sum test for continuous variables, as appropriate.
Normality was assessed using Shapiro‐Wilk test.

To estimate changes in strain over time among subjects with MIS‐C, we used
linear mixed effects models, an extension of simple linear models that allow for
both fixed and random effects, including within‐subject correlation attributable
to repeated measures. Mixed effects models use maximum likelihood methods for
estimation, and introduce less bias in the presence of missing data.
Subject‐specific random effects were modeled using an autoregressive covariance
structure to allow for unbalanced data and declining correlation between
measures with increasing time. We assumed a random intercept to allow for
variation in initial strain values. To determine whether rates of improvement
over time differed between those with or without acute phase myocardial injury,
we tested interactions between myocardial injury and time using Wald χ2 tests.
Patterns of missing follow‐up echocardiograms were evaluated using χ2 tests and
t tests, as appropriate, and a missing at random mechanism was assumed.

We used Kaplan‐Meier survival curves to estimate median time to recovery of
normal function for subjects with MIS‐C with abnormal strain at baseline.

To compare strains between MIS‐C cases at follow‐up and controls, we used linear
regression models adjusted for body mass index percentiles for age and sex. We
tested other potential confounders, including heart rate, age, race, and
ethnicity, and retained them in the models only if strain estimates changed by
>10%. To account for multiple comparisons, we used the Benjamini‐Hochberg
procedure to control the false discovery rate at 5%.

All statistical analyses were performed using STATA 15.0 (College Station, TX)
using a 2‐sided significance level of 0.05.

RELIABILITY

Intraclass correlation coefficients were used to assess intraobserver and
interobserver reliability for GLS, EDSRL, and LAS. We randomly selected 14
patients for de novo measurement for these parameters by 2 investigators (A.B.
and D.M.). For intraobserver reliability, one observer (D.M.) repeated each
measurement after 4 weeks. We have previously shown excellent intraobserver and
interobserver reliability of RVFWS in our laboratory, which were not repeated in
this study.18


RESULTS

SUBJECT CHARACTERISTICS

We identified 60 controls and 61 MIS‐C cases, of which 1 patient with MIS‐C was
excluded because of the incidental discovery of a congenital coronary artery
anomaly, by subsequent CMR (total MIS‐C=60). In the acute phase, all 60 subjects
with MIS‐C had evaluable echocardiograms. During the subacute phase (median,
3 days after initial echocardiography), 50 had repeated echocardiograms
attributable to clinical indications, 39 returned for 1‐month follow‐up (median,
22 days), and 25 had 3‐ to 4‐month follow‐up (median, 91 days). One patient had
3‐month follow‐up study without subacute and 1‐month follow‐up studies
(schematically depicted in Figure 1).

 * Download figure
 * Download PowerPoint

Figure 1. Schematic representation of our study population from the acute to the
follow‐up stages.

IQR indicates interquartile range; and MIS‐C, multisystem inflammatory syndrome
in children.

Most were treated with intravenous immunoglobulin (90%) and/or systemic steroids
(92%). Of the 60 subjects with MIS‐C, 42 had evidence of myocardial injury at
the time of presentation (isolated elevated BNP, n=6; isolated elevated
troponin, n=13; elevation of both, n=23). It is noteworthy that the BNP levels
in these 6 patients greatly exceeded the 97.5 percentile values in children by
many fold.14 Although 70% had biochemical evidence of myocardial injury at their
initial presentation, in most of them their cardiac markers returned to normal
levels in the subacute stage before discharge. There were no deaths or
unexpected cardiac events during follow‐up. All subjects were classified as New
York Heart Association class Ⅰ at their last clinical visit without cardiac
symptoms, fatigue, or other symptoms suggestive of the prolonged post–COVID‐19
syndromes described in adults (Table 1).

John Wiley & Sons, Ltd

TABLE 1. DEMOGRAPHICS IN MIS‐C AND CONTROL GROUPS

VariablesMIS‐C (n=60)Control (n=60)P valueAge, mean±SD,
y10.0±4.311.5±3.90.10Men, n (%)36 (60)33 (55)0.58BMI, median (IQR), percentile
for age and sex92 (75–98)79 (49–93)0.01Race, n (%)<0.01White16 (27)37
(62)Black29 (48)16 (27)Asian2 (4)2 (3)Other/unknown13 (23)5 (8)Hispanic
ethnicity, n (%)9 (15)4 (7)0.15Hospital outcomes and treatment exposureHospital
length of stay, median (IQR), days6 (4–9)ICU admission, n (%)42
(70)Vasoactive‐inotropic agents, n (%)30 (50)Need for invasive ventilation, n
(%)13 (22)Intravenous immunoglobulin, n (%)54 (90)Systemic steroids, n (%)55
(92)Laboratory characteristics, n/total (%)SARS‐CoV‐2 PCR (+)26/58
(45)SARS‐CoV‐2 IgG (+)52/53 (98)Organ dysfunction, median (IQR)Troponin‐I
(ng/mL)0.24 (0.03–0.91)BNP, pg/mL795 (428–1270)eGFR, mL/min per 1.73 m291
(65–110)Acute phase reactants, median (IQR)CRP, mg/dL19.9 (15.8–25.8)D‐dimer,
mg/dL4.9 (2.4–7.8)Ferritin, ng/mL738 (447–1131)Hematologic abnormalities, median
(IQR)Hemoglobin, g/dL9.0 (7.9–10.0)Platelet count, 103/µL153 (118–193)Absolute
lymphocyte count, /µL495 (300–895)Lactate dehydrogenase, U/L686
(539–896)Clinical outcome, n/total (%)New York Heart Association classification
at the last clinical visitI: 51/51 (100)II: 0III: 0IV: 0

BMI indicates body mass index; BNP, brain‐type natriuretic peptide; CRP,
C‐reactive protein; eGFR, estimated glomerular filtration rate; ICU, intensive
care unit; IQR, interquartile range; MIS‐C, multisystem inflammatory syndrome in
children; and PCR, nasopharyngeal reverse transcriptase polymerase chain
reaction test. Race was self‐reported upon registration.

PATTERNS OF IMPROVEMENT IN CARDIAC FUNCTION OVER TIME

Mean strain values over time estimated from linear mixed effects models are
illustrated in Figure 2. There was a rapid initial improvement in LVEF, GLS,
RVFWS, and LAS within the first week, followed by continued gradual improvement
through the 3‐month follow‐up period (Table 2, Figure 3, and Table S1). It is
notable that 81% of patients with myocardial injury lost the left atrial (LA)
contraction phase during the acute phase of illness (Figure 3B, white arrow). In
the immediate subacute stage, 52% lost the contraction phase; and at the 1‐month
interval, 30% continued to manifest loss of LA contraction phase. Finally, the
LA contraction phase normalized in all patients by 3 to 4 months. Diastolic
function by EDSRL did not show rapid initial improvement within the first week
compared with the other strain parameters, but still normalized by 3 months
(Figure 2D and Table S2). Compared with controls, subjects with MIS‐C had
significant impairments across all strain parameters at 1‐month follow‐up,
adjusted for heart rate and body mass index percentile (Table 3). Further
adjustment for race or ethnicity did not significantly change the results and
therefore was not included in the final models. By 3‐month follow‐up, only GLS
remained statistically significantly lower among subjects with MIS‐C compared
with controls; however, this statistical difference in GLS was small and not
clinically relevant, because it was within the range of normal published
values.16 There was no difference in the GLS/GCS ratio between acute MIS‐C and
control conditions, indicating proportionally decreased longitudinal and
circumferential contractile patterns without compensatory changes in
circumferential strain. LV segmental longitudinal strains demonstrated similar
impairments across basal, mid, and apical segments (Table 2 and Figure S1),
suggesting global rather than segmental dysfunction.

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Figure 2. Mean strain values over time, estimated from mixed effects models.

Global longitudinal strain (GLS) (A), right ventricular free wall strain (RVFWS)
(B), and peak left atrial strain (LAS) (C) improved dramatically within the
first week, then continued to improve gradually over 3‐month follow‐up. D,
Longitudinal early diastolic strain rate (EDSRL) showed delayed improvement.
Week=0 represents the day of first echocardiogram. Dotted lines represent mean
values from our control groups. Error bars represent 95% CIs for the mean
predictions, calculated using the Δ method of SEs.

John Wiley & Sons, Ltd

TABLE 2. STRAIN PARAMETERS AT EACH STAGE IN FOLLOW‐UP STUDY IN PATIENTS WITH
MIS‐C

VariablesAcute (n=60)Subacute (n=50)1‐mo follow‐up (n=39)3‐mo follow‐up
(n=25)Control (n=60)GLS, %−16.8±3.9−20.2±2.8−21.4±1.9−21.8±1.8−23.2±2.0Segmental
analysis,
%Base−15.9±4.1−19.6±3.5−21.3±2.2−21.8±2.6−22.8±2.9Mid−17.1±4.0−20.4±3.1−21.9±2.7−22.2±2.9−23.7±2.2Apex−17.2±4.5−20.9±3.5−20.9±2.8−21.2±2.7−23.0±2.6GLSR,
1/s−0.87±0.2−0.98±0.2−1.05±0.2−1.04±0.2−1.13±0.1GCS,
%−18.4±5.3−23.5±4.1−25.4±2.9−26.7±3.4−26.0±3.2GCSR,
1/s−0.99±0.4−1.21±0.3−1.39±0.2−1.33±0.2−1.41±0.3GLS/GCS ratio0.91
(0.81–1.04)0.86 (0.78–0.97)0.86 (0.76–0.93)0.81 (0.75–0.90)0.90
(0.81–0.99)EDSRL, 1/s0.93±0.30.98±0.31.17±0.31.24±0.31.37±0.4EDSRC,
1/s1.06±0.41.17±0.31.44±0.41.43±0.31.61±0.4LAS,
%25.3±8.833.8±8.337.6±4.841.7±7.943.2±7.7RVFWS,
%−21.1±6.1−24.8±4.4−25.1±3.8−26.7±4.7−27.5±4.5

Values are expressed as median (interquartile range) or mean±SD. For statistical
results on these parameters, please see Table 3 and Table S2. EDSRC indicates
circumferential early diastolic strain rate; EDSRL, longitudinal early diastolic
strain rate; GCS, global circumferential strain; GCSR, GCS rate; GLS, global
longitudinal strain; GLSR, GLS rate; LAS, left atrial strain; MIS‐C, multisystem
inflammatory syndrome in children; and RVFWS, right ventricular free wall
longitudinal strain.

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Figure 3. Global longitudinal strain (GLS) curves (A) and left atrial strain
(LAS) curves (B) in the same subject with multisystem inflammatory syndrome in
children over acute, subacute, and 3‐month follow‐up study.

Of note, there was a rapid initial improvement in both GLS and LAS within the
first week, followed by continued gradual improvement through 3‐month follow‐up.
Moreover, left atrial active contraction phase is lost in the acute phase in
this patient (white arrow).

John Wiley & Sons, Ltd

TABLE 3. PAIRWISE COMPARISONS BETWEEN MIS‐C AND CONTROLS AT 1‐ AND 3‐MONTH
FOLLOW‐UP STUDY (LINEAR REGRESSION ADJUSTED FOR BMI PERCENTILE AND HEART RATE)

Variables1‐mo follow‐up (n=39 MIS‐C)3‐mo follow‐up (n=25 MIS‐C)Conditional mean
difference*95% CIP valueConditional mean difference*95% CIP valueGLS, %−1.62−2.5
to −0.7<0.001†−1.15−2.1 to −0.20.020†EDSRL, 1/s−0.23−0.4 to −0.10.006†−0.12−0.3
to 0.10.202LAS, %−5.48−8.6 to −2.40.001†−0.73−3 to 1.50.707RVFWS, %−2.13−4.1 to
−0.10.038−0.79−0.1 to 00.487

BMI indicates body mass index; EDSRL, longitudinal early diastolic strain rate;
GLS, global longitudinal strain; LAS, left atrial strain; MIS‐C, multisystem
inflammatory syndrome in children; and RVFWS, right ventricular free wall
longitudinal strain.

*Mean difference between MIS‐C cases at each time point and 60 controls,
adjusted for BMI percentile for age and sex and heart rate.

†P values indicate statistical significance based on the Benjamini‐Hochberg
critical value for each strain parameter. P values without dagger do not meet
the threshold for statistical significance when corrected for multiple
comparisons.

In the survival curve analysis, the median time to normalization of both GLS and
LAS was 6 days (95% CI, 3–9 days) (Figure S2). Median time to normalization of
LVEF and RVFWS was 8 days (95% CI, 4–13 days) and 9 days (95% CI, 4–18 days),
respectively.

ECGs were available in 54 of 60 (90%) in the acute stage, of which 10 (19%)
showed inverted T waves in lateral/inferior leads. In these 10 patients, ECG
changes normalized during follow‐up (4 within subacute phase, other 5 within
1 month, and the last within 3 months). There was no evidence of high‐grade
atrioventricular block (ie, second‐degree atrioventricular block–Mobitz type II
or complete atrioventricular block).

IMPACT OF MYOCARDIAL INJURY ON SHORT‐TERM OUTCOMES

All deformation parameters in the acute phase were worse in patients with
biochemical evidence of myocardial injury than in those without (Figure 4).
However, GLS and LAS also improved more rapidly between the acute and subacute
phases among those with myocardial injury (P values for interaction with time of
0.015 and 0.017, respectively), such that no differences remained between injury
(+) and injury (−) patients by 1‐month follow‐up. On average, over the follow‐up
period, there was also no statistically significant effect of myocardial injury
on RVFWS or EDSRL.

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Figure 4. Mean strain values over time for patients with myocardial injury (+)
and those without injury (−), estimated from mixed effects models.

Global longitudinal strain (GLS) (A) and peak left atrial strain (LAS) (C) were
significantly decreased in patients with myocardial injury at baseline. However,
neither GLS nor LAS differed between myocardial injury (+) and (−) groups at
follow‐up because of a greater slope of improvement in the myocardial injury (+)
group (P values for interaction between myocardial injury and time were 0.015
and 0.017, respectively). Error bars represent 95% CIs for the mean predictions,
calculated using the Δ method of SEs. EDSRL (D) indicates longitudinal early
diastolic strain rate; and RVFWS, (B) right ventricular free wall strain.

MISSING DATA

White race and Hispanic ethnicity were associated with a higher likelihood of
missing subacute phase echocardiographic data, but not 1‐ or 3‐month follow‐up
echocardiograms. The dominant reason for the missing data was attributable to
the lack of follow‐up. The severity of systolic dysfunction in the acute stage
was not associated with missingness at any subsequent time point.

SERIAL CORONARY ARTERY ASSESSMENT

Four subjects (4/60, 7%) had small coronary aneurysms involving the right
coronary or left anterior descending artery in the acute phase, all of whom
received intravenous immunoglobulin. All 4 had resolution of coronary aneurysms
during follow‐up (1 during subacute stage, 2 within 1 month, and the last within
2 months). No newly progressive coronary lesions were detected over the 3‐month
observation period.

CARDIAC MAGNETIC RESONANCE IMAGING

CMR was available in 15 of 60 (25%) cases, of which 1 patient was excluded
because of the incidental finding of anomalous origin of the left coronary
artery from the right sinus of Valsalva. Of the evaluable cohort of 14 patients,
12 (86%) had biochemical evidence of myocardial injury at presentation. Five
patients underwent CMR during the subacute phase (median, 8 days [interquartile
range, 6–10 days]), all of whom had biochemical evidence of myocardial injury,
and 9 underwent CMR during follow‐up period (median, 162 days [interquartile
range, 104–265 days]) (Table 4). Two patients in the subacute phase who had
evidence of myocardial edema (1 focal, 1 global) also showed discrete and
diffuse fibrosis at the same time, despite normal LV systolic function by
strain, conventional echocardiography, and CMR. Only one patient who underwent
CMR during follow‐up period had residual edema. However, this patient had no
fibrosis and showed normal systolic function by echocardiography. No patients
had CMR studies both in the subacute stage as well as in the follow‐up stage.
There were no associated regional wall motion abnormalities by the eye‐ball
method in CMR of the affected regions, in patients with focal changes. One
patient with abnormal findings in CMR in the follow‐up stage (No. 8 in Table 4)
showed reduced strains in the affected regions. No patients showed evidence of
CAAs by CMR.

John Wiley & Sons, Ltd

TABLE 4. CARDIAC MRI FINDINGS IN PATIENTS WITH MIS‐C IN SUBACUTE AND FOLLOW‐UP
STAGES

Patient no.DaysEdemaFibrosisLVEF/GLS by echocardiography (at closest time point
to CMR), %Biochemical evidence of myocardial injury at
presentationDiscreteDiffuseSubacute phase15−−−72+−20.826Global++69+a thin
midmyocardial layer at the mid short axis
(subepicardium)−18.838−−−55+−18.7410Focal++61+midlateral FW of the LV
(subepicardium)−23.8518−−−62+−21.5Follow‐up
phase681−−−64+−21.2784−−−65+−21.58104−−−66−−19.99127NA−−66+−22.110162−−−67+−20.411204Focal−−56+Anterior
septum anterior/anterolateral
wall−18.912265−−−66−−24.613278−−−60+−22.414285−−−69+−24.2

CMR indicates cardiac magnetic resonance imaging; FW, free wall; GLS, global
longitudinal strain; LV, left ventricle; LVEF, left ventricular ejection
fraction; MIS‐C, multisystem inflammatory syndrome in children; MRI, magnetic
resonance imaging; and NA, not available. “+” indicates present, whereas, “−”
indicates absent

REPRODUCIBILITY

Intraclass correlation coefficients for interobserver reliability for GLS,
EDSRL, and LAS were 0.90, 0.92, and 0.92, respectively. Intraclass correlation
coefficients for intraobserver reliability for GLS, EDSRL, and LAS were 0.88,
0.94, and 0.97, respectively.


DISCUSSION

Our study provides a detailed characterization of the evolution of cardiac
manifestations of MIS‐C several months after onset of illness. We demonstrate
that (1) all deformation parameters improved quickly within the first week,
followed by continued gradual improvement and complete normalization by 3 to
4 months; (2) biochemical evidence of myocardial injury at presentation did not
affect short‐term echocardiographic outcomes; and (3) coronary arteries were
spared during follow‐up.

Because MIS‐C is a newly described disease, there is a paucity of follow‐up data
about the appropriate frequency and duration of cardiac monitoring. Because of
the lack of standardization, presently follow‐up care of these patients is
highly variable and has led to confusion among both the care team and patients’
families. Because we have described cardiac strain patterns in the acute and
subacute phases of MIS‐C in detail in our previous study,5 the primary emphasis
of the present study was to describe evolution of cardiac findings in MIS‐C
during short‐term, longitudinal follow‐up.

FUNCTIONAL CARDIAC OUTCOMES DURING SHORT‐TERM FOLLOW‐UP

The rapid recovery in systolic function in our cohort is consistent with recent
studies. One large multicenter study (n=539) in the United States by Feldstein
et al reported median time to normalization of LVEF of 4 days (interquartile
range, 3–8 days). Of those with follow‐up data available, 91.0% had a normal
LVEF by 30 days, and 99.4% by 90 days.3 The other most recent single‐center
study (n=46) in the United Kingdom by Penner et al showed normalization of LVEF
in all patients by 6 months.19 In these studies, however, only LVEF was used as
an index of systolic function, and strain parameters were not evaluated.
Myocardial strain is more sensitive for ventricular dysfunction in both children
and adults, even when conventional parameters, such as LVEF, are normal, and is
not influenced by demographic and clinical cofounders, such as age or body
surface area.16, 20 In the acute and subacute phases of MIS‐C, subclinical
dysfunction can be detected using strain parameters despite preserved LVEF.5, 21
In addition, strain parameters can detect the segmental pattern of cardiac
dysfunction, such that our MIS‐C cohort showed proportional decrease in
segmental strains across basal/mid/apical segments, suggesting global rather
than segmental impairment (Figure S1). In our series, there was lack of any
increase in GCS to compensate for the decrease in GLS characterized by unchanged
GLS/GCS ratio (Table 2). Using strain indexes of systolic function, another
recent single‐center study by Sanil et al demonstrated that 24% (6/25) of
patients with MIS‐C had abnormal LV GLS (<−19%) at median 10‐week follow‐up
study, which is not consistent with our present findings. This difference may be
attributed to our use of a more conservative outcome definition (GLS <−17%) and
our inclusion criteria. Sanil et al used a higher cutoff value for GLS <−19%,
which may have resulted in inclusion of more patients in the LV dysfunction
group during the follow‐up stages.22 Moreover, their study included 4 patients
who developed myocardial stunning requiring venoarterial extracorporeal membrane
oxygenation during the acute phase, whereas in our cohort patients requiring
extracorporeal membrane oxygenation support were excluded. Overall, the acuity
level of our cohort with respect to intensive care unit admission, need for
invasive ventilation, and use of vasopressors was highly comparable to that of a
larger multicenter surveillance cohort published by the “Overcoming COVID‐19
Investigators”3 and, therefore, we believe our findings to be generalizable.

To date, indexes of LV diastolic function and RV systolic function during the
follow‐up period have not been evaluated previously in MIS‐C. Our findings
demonstrate that LV diastolic and RV systolic function also improve rapidly
within the first week, followed by continued gradual improvement. All
deformation parameters reached normal levels by 3 to 4 months.

This rapid functional recovery of LV diastolic function is a distinctive feature
of MIS‐C. Many other causes of acute heart failure in children result in more
delayed recovery of diastolic function over several months or years. In Kawasaki
disease shock syndrome, diastolic dysfunction assessed by conventional
echocardiography persists for up to 1 year.23 In biopsy‐proven viral
(non–COVID‐19) myocarditis in children with normal ejection fraction (n=13),
diastolic dysfunction (lateral e′ and EDSRL) also persists over 1 year, despite
recovery of systolic function.11 In our cohort with MIS‐C, all indexes of
diastolic function normalized at the last follow‐up visit. This finding has
important implications for resumption of vigorous and competitive physical
activities and provides direct evidence to support current “consensus‐based”
recommendations.

DIASTOLIC FUNCTION IN MIS‐C

Our study was unique in that we used 2 deformation parameters, LAS and EDSRL, to
assess LV diastolic function. Noninvasive assessment of diastolic dysfunction
has not been well established in children. Conventional parameters, such as
E/e′, used in adult diagnostic algorithms incorrectly classify up to 30% of
patients with overt and often severe pediatric cardiomyopathy as having normal
diastolic function.24

Recent studies have proposed LA strain as a surrogate measure of LV diastolic
function in adults, reinforced by strong correlation between peak LA strain and
LV filling pressures in adults referred for left heart catheterization.25 This
finding was also confirmed in our previous study in children with dilated LAs.26
In addition, our previous MIS‐C study demonstrated that LAS was the single
strain parameter most strongly associated with troponin‐I levels.5 Because of
its role in atrioventricular coupling, recently there has been a concerted call
for incorporating LA strain into the adult American Society of Echocardiography
diastolic function guidelines.12 This may have utility in children as well,
including those with global myocardial dysfunction attributable to MIS‐C.

EDSRL has been used to assess diastolic function in LV in various diseases in
both adults and children.11, 27 Because of the lack of normative pediatric
reference data for EDSRL, we used the distribution in our controls to define
abnormal cutoff values (<2 SDs below normal). In our cohort with MIS‐C, EDSRL
showed a more gradual recovery pattern compared with LAS, but still normalized
within 3 months.

MYOCARDIAL INJURY AND CARDIAC OUTCOMES

We defined the biochemical evidence of myocardial injury by elevated troponin‐I
(≥0.09 ng/mL) or BNP (>800 pg/mL) because many other studies have demonstrated a
significant increase in these parameters in patients with MIS‐C and used them as
cardiac biomarkers. The median troponin‐I level in our cohort with MIS‐C was
8‐fold higher than the upper limit of normal at our institution. Despite the
high incidence of myocardial involvement described in most cohorts with MIS‐C,2
mortality was low in most studies and functional recovery was excellent. As of
May 3, 2021, the Centers for Disease Control and Prevention reported 35 deaths
of 3742 total MIS‐C cases in the United States.28 In our cohort, patients with
myocardial injury had worse deformation parameters at presentation; however,
this did not predict worse short‐term echocardiographic outcomes. This is
consistent with a recent multicenter study on MIS‐C (n=539) that showed similar
likelihood and temporal trajectory of recovery of ejection fraction, regardless
of initial severity of dysfunction.3

In contrast, elevated troponin level in adult patients with COVID‐19 is a robust
prognostic marker.29 Even a small increase in troponin I (0.03–0.09 ng/mL) in
adults with COVID‐19 (n=2736) was significantly associated with higher
in‐hospital mortality, as well as increased LV and RV dysfunction.13, 30 Higher
troponin concentrations were also associated with increased short‐term mortality
among children (n=65) with acute, fulminant myocarditis from the pre–COVID‐19
era.31 The clinical implications of troponin‐I in MIS‐C remain unclear; however,
our findings suggest that although elevated troponin levels are associated with
worse cardiac function at disease onset, they do not appear to have similar
prognostic implications in children with MIS‐C as they do in adults with
COVID‐19 or in children with fulminant viral myocarditis. Although we previously
demonstrated that increased troponin‐I was strongly associated with RVFWS in the
acute phase,5 our current study shows that irrespective of troponin elevations,
RV systolic function recovers quickly during the follow‐up phase.

CMR FINDINGS

In the subacute stage of our study, a subset of consecutive patients who
underwent clinically indicated CMR had evidence of edema, as well as discrete
and diffuse fibrosis in the setting of normal function by echocardiography. This
is consistent with a report by Theocharis et al from the United Kingdom, which
showed myocardial edema in 50% and fibrosis in 20% of MIS‐C cases (n=20) at a
median of 20 days after disease onset, regardless of cardiac function and timing
of presentation.32 The distribution patterns of edema and fibrosis were both
global and focal in our MIS‐C cohort, and 2 met criteria for myocarditis in the
subacute phase.

To date, only one case series from France showed CMR findings in a single
patient with MIS‐C during the convalescent phase (28 days after the disease
onset) who had myocardial edema without fibrosis.33 Our CMR follow‐up cohort is
also small (n=9); however, it represents a number that is higher than currently
available studies in children during the follow‐up stage. One patient in our
cohort who presented with LV dysfunction (LVEF=43%) along with elevated troponin
of 3.9 ng/mL in the acute phase had evidence of residual focal edema in the
follow‐up stage as late as 204 days after disease onset. However,
echocardiographic function had normalized by then. The implications of edema so
late after acute illness are perplexing and are different from conventional
myocarditis, where CMR markers of myocardial inflammation resolve earlier.15 In
adult patients with COVID‐19 who had recovered from their disease, there have
been reports of ongoing myocardial inflammation with edema,34, 35 and the same
may be the case in patients with MIS‐C. In adults, after recovery from COVID‐19
(with or without hospitalization), LVEF and RV ejection fraction were lower than
those in controls (LVEF: 57% versus 62%; RV ejection fraction: 54% versus 59%;
both P<0.01). In addition, 78 of 100 adult patients had abnormal CMR findings,
including myocardial edema or fibrosis at a median of 71 days after acute
infection.34 Another recent CMR study (n=26) on adults with cardiac symptoms
after recovery from COVID‐19 reported abnormal myocardial tissue
characterization in 58%, including myocardial edema, fibrosis, and impaired RV
function.35 These studies in adults did not control for preexisting conditions,
which existed in some of the subjects. Reassuringly, there was no fibrosis in
the few children who underwent follow‐up CMR. The need for a repeated CMR is
based on the echocardiographic evidence of the severe cardiac dysfunction
detected by echocardiography. Further studies are needed to determine whether
there may be any long‐term damage, including possible evolvement of fibrosis and
edema.

CORONARY ARTERY OUTCOMES

Variation in published rates of CAAs may be explained by differences in
reporting (absolute lumen dimensions versus z score) and definitions adopted for
CAAs (z score >2.0 versus z score >2.5). In our study, de novo measurements of
coronary arteries were performed by 3 designated, experienced readers, similar
to the concept of a core laboratory used in multicenter studies. Using this
method, we found that coronary arteries were spared during the short‐term
follow‐up. Only 4 patients (7%) had small CAAs in the acute phase, all of which
normalized during follow‐up. This finding was consistent with a recent large
multicenter study by Feldstein et al, which reported mild to moderate aneurysms
(13.4%), which regressed to normal dimension in 79.1% of patients by 30 days,
and in 100% by 90 days.3 However, a more recent study by Penner et al reported 2
cases with coronary aneurysms (maximum z scores of 9.2 and 2.9) who required
antiplatelet therapy for up to 6 months.19 Although most MIS‐C cases, including
those in our present cohort, have good coronary outcomes, longer‐term studies
are needed to reveal the natural history of this disease.

Researchers should also take into account the phenomenon of transient coronary
dilatation in non–Kawasaki disease, febrile illnesses, where z scores may exceed
2 but virtually never >2.5.36 Therefore, it is important that CAA is defined by
a z score of >2.5. Transient coronary dilations in febrile illnesses may reflect
a physiologic response to increased myocardial oxygen demand caused by fever,
tachycardia, myocardial inflammation, circulating inflammatory mediators, or
endothelial dysfunction.

CLINICAL IMPLICATIONS

MIS‐C frequently affects the cardiovascular system at presentation.
Nevertheless, functional recovery is excellent, and this has important
implications for the management of this population, especially as related to
physical activity and sports participation. Current recommendations about
resumption of physical activity are consensus based; however, all consensus
statements treat MIS‐C as equivalent to myocarditis and recommend a similar
gradual return to unrestricted physical activity over a period of at least
3 months.37, 38 The data from our current study would suggest that this approach
is probably conservative and safe. The more rapid recovery of diastolic function
in our current MIS‐C population compared with viral myocarditis and the lack of
late CMR findings consistent with myocarditis are both reassuring. Our numbers
are obviously small, but support the current consensus algorithms for activities
and sports in the pediatric population. This study may help provide data‐derived
consensus for discharging these patients from cardiology care, if their ECGs and
echocardiograms are normal at a 3‐month follow‐up evaluation (Figure 5).

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Figure 5. Outcome diagram showing good functional recovery and good coronary
outcomes during a 3‐month short‐term follow‐up (F/U) period.

CMR indicates cardiac magnetic resonance imaging; and MIS‐C, multisystem
inflammatory syndrome in children.

LIMITATIONS

Our current study provides a detailed characterization of short‐term cardiac
outcomes in patients with MIS‐C, and longer‐term outcomes are not available
presently. However, a shorter time frame was chosen as it is important to
provide guidelines about this newly emergent disease to frontline physicians who
are faced with these patients in their daily practice. Long‐term data will also
need to be presented when they become available in the future. As this was a
retrospective study, image acquisition was performed for clinical purposes and
was not prospectively standardized for obtaining noncompressed images using
digital imaging and communications in medicine technique. Nevertheless, frame
rates of digital imaging and communications in medicine images were similar for
both control patients and patients with MIS‐C. We wish to acknowledge that BNP
elevation can be caused by stretching of the myocardium; however, in this study,
the cutoff value of BNP greatly exceeded the 97.5 percentile in children.
Therefore, it was used as a marker of myocardial injury. We decided not to use
the exercise tests as an additional clinical outcome because few were available,
which would not allow meaningful statistical analysis. The group with MIS‐C has
significantly larger body statures and higher body mass index compared with
normal controls. This is because obesity is a known risk factor of MIS‐C. To
address this, we adjusted for differences in body mass index. Last, we
acknowledge that missing follow‐up data are a major limitation of this study.
Although baseline severity of cardiac dysfunction was not associated with
missingness of follow‐up data, there may be nonrandom missingness that could
result in biased estimates.


CONCLUSIONS

Lack of knowledge about the short‐term consequences of MIS‐C has led to
uncertainty among physicians in making recommendations about follow‐up. Our
detailed characterization of short‐term cardiac outcomes provides evidence that
functional recovery and coronary outcomes are good. Moreover, our use of more
sensitive deformation parameters provides further reassurance that there is no
persistent subclinical dysfunction. These findings may inform early guidelines
for outpatient management strategies and recommendations for returning to
competitive sports. The echocardiographic parameters described in this study may
form the basis of future long‐term follow‐up studies.


SOURCES OF FUNDING

Dr Chang was supported by the National Institutes of Health/National Heart,
Lung, and Blood Institute (K23‐HL148539).


DISCLOSURES

None.


ACKNOWLEDGMENTS

We wish to express our deepest appreciation for the brave sonographers of our
institution, who have acquired the images used for this study, during this
ominous pandemic.


FOOTNOTES

* Correspondence to: Anirban Banerjee, MD, Division of Cardiology, Children’s
Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104.
E‐mail: banerjeea@email.chop.edu


Supplemental Material for this article is available at
https://www.ahajournals.org/doi/suppl/10.1161/JAHA.121.023251

For Sources of Funding and Disclosures, see page 14.


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   10.1016/S0140‐6736(20)31103‐XCrossrefMedlineGoogle Scholar
 * 2 Valverde I, Singh Y, Sanchez‐de‐Toledo J, Theocharis P, Chikermane A, Di
   Filippo S, Kuciñska B, Mannarino S, Tamariz‐Martel A, Gutierrez‐Larraya F, et
   al. Acute cardiovascular manifestations in 286 children with multisystem
   inflammatory syndrome associated with COVID‐19 infection in Europe.
   Circulation. 2021; 143:21–32. doi:
   10.1161/CIRCULATIONAHA.120.050065LinkGoogle Scholar
 * 3 Feldstein LR, Tenforde MW, Friedman KG, Newhams M, Rose EB, Dapul H, Soma
   VL, Maddux AB, Mourani PM, Bowens C, et al. Characteristics and outcomes of
   US children and adolescents with multisystem inflammatory syndrome in
   children (MIS‐C) compared with severe acute COVID‐19. JAMA. 2021;
   325:1074–1087. doi: 10.1001/jama.2021.2091CrossrefMedlineGoogle Scholar
 * 4 Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, Barranco
   MA, Maxted AM, Rosenberg ES, Easton D, et al. Multisystem inflammatory
   syndrome in children in New York State. N Engl J Med. 2020; 383:347–358. doi:
   10.1056/NEJMoa2021756CrossrefMedlineGoogle Scholar
 * 5 Matsubara D, Kauffman HL, Wang Y, Calderon‐Anyosa R, Nadaraj S, Elias MD,
   White TJ, Torowicz DL, Yubbu P, Giglia TM, et al. Echocardiographic findings
   in pediatric multisystem inflammatory syndrome associated with COVID‐19 in
   the United States. J Am Coll Cardiol. 2020; 76:1947–1961. doi:
   10.1016/j.jacc.2020.08.056CrossrefMedlineGoogle Scholar
 * 6 Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, Ramnarayan P,
   Fraisse A, Miller O, Davies P, et al. Clinical characteristics of 58 children
   with a pediatric inflammatory multisystem syndrome temporally associated with
   SARS‐CoV‐2. JAMA. 2020; 324:259–269. doi:
   10.1001/jama.2020.10369CrossrefMedlineGoogle Scholar
 * 7 Information for healthcare providers about multisystem inflammatory
   syndrome in children (MIS‐C) | CDC. Available at:
   https://www.cdc.gov/mis‐c/hcp/. Accessed June 1, 2021.Google Scholar
 * 8 Multisystem inflammatory syndrome in children and adolescents temporally
   related to COVID‐19. Available at:
   https://www.who.int/news‐room/commentaries/detail/multisystem‐inflammatory‐syndrome‐in‐children‐and‐adolescents‐with‐covid‐19.
   Accessed June 1, 2021.Google Scholar
 * 9 Lang RM, Badano LP, Mor‐Avi V, Afilalo J, Armstrong A, Ernande L,
   Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al. Recommendations
   for cardiac chamber quantification by echocardiography in adults: an update
   from the American Society of Echocardiography and the European Association of
   Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015; 16:233–270.
   doi: 10.1093/ehjci/jev014CrossrefMedlineGoogle Scholar
 * 10 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M,
   Baker AL, Jackson MA, Takahashi M, Shah PB, et al. Diagnosis, treatment, and
   long‐term management of Kawasaki disease: a scientific statement for health
   professionals from the American Heart Association. Circulation. 2017;
   135:e927–e999. doi: 10.1161/CIR.0000000000000484LinkGoogle Scholar
 * 11 Khoo NS, Smallhorn JF, Atallah J, Kaneko S, Mackie AS, Paterson I. Altered
   left ventricular tissue velocities, deformation and twist in children and
   young adults with acute myocarditis and normal ejection fraction. J Am Soc
   Echocardiogr. 2012; 25:294–303. doi:
   10.1016/j.echo.2011.10.010CrossrefMedlineGoogle Scholar
 * 12 Singh A, Addetia K, Maffessanti F, Mor‐Avi V, Lang RM. LA strain for
   categorization of LV diastolic dysfunction. JACC Cardiovasc Imaging. 2017;
   10:735–743. doi: 10.1016/j.jcmg.2016.08.014CrossrefMedlineGoogle Scholar
 * 13 Lala A, Johnson KW, Januzzi JL, Russak AJ, Paranjpe I, Richter F, Zhao S,
   Somani S, Van Vleck T, Vaid A, et al. Prevalence and impact of myocardial
   injury in patients hospitalized with COVID‐19 infection. J Am Coll Cardiol.
   2020; 76:533–546. doi: 10.1016/j.jacc.2020.06.007CrossrefMedlineGoogle
   Scholar
 * 14 Cantinotti M, Law Y, Vittorini S, Crocetti M, Marco M, Murzi B, Clerico A.
   The potential and limitations of plasma BNP measurement in the diagnosis,
   prognosis, and management of children with heart failure due to congenital
   cardiac disease: an update. Heart Fail Rev. 2014; 19:727–742. doi:
   10.1007/s10741‐014‐9422‐2CrossrefMedlineGoogle Scholar
 * 15 Ferreira VM, Schulz‐Menger J, Holmvang G, Kramer CM, Carbone I, Sechtem U,
   Kindermann I, Gutberlet M, Cooper LT, Liu P, et al. Cardiovascular magnetic
   resonance in nonischemic myocardial inflammation. J Am Coll Cardiol. 2018;
   72:3158–3176. doi: 10.1016/j.jacc.2018.09.072CrossrefMedlineGoogle Scholar
 * 16 Levy PT, Machefsky A, Sanchez AA, Patel MD, Rogal S, Fowler S, Yaeger L,
   Hardi A, Holland MR, Hamvas A, et al. Reference ranges of left ventricular
   strain measures by two‐dimensional speckle‐tracking echocardiography in
   children: a systematic review and meta‐analysis. J Am Soc Echocardiogr. 2016;
   29:209–225.e6. doi: 10.1016/j.echo.2015.11.016CrossrefMedlineGoogle Scholar
 * 17 Levy PT, Sanchez Mejia AA, Machefsky A, Fowler S, Holland MR, Singh GK.
   Normal ranges of right ventricular systolic and diastolic strain measures in
   children: a systematic review and meta‐analysis. J Am Soc Echocardiogr. 2014;
   27:549–560.e3. doi: 10.1016/j.echo.2014.01.015CrossrefMedlineGoogle Scholar
 * 18 D’Souza R, Wang Y, Calderon‐Anyosa RJC, Montero AE, Banerjee MM, Ekhomu O,
   Matsubara D, Mercer‐Rosa L, Agger P, Sato T, et al. Decreased right
   ventricular longitudinal strain in children with hypoplastic left heart
   syndrome during staged repair and follow‐up: does it have implications in
   clinically stable patients?Int J Cardiovasc Imaging. 2020; 36:1667–1677. doi:
   10.1007/s10554‐020‐01870‐0CrossrefMedlineGoogle Scholar
 * 19 Penner J, Abdel‐Mannan O, Grant K, Maillard S, Kucera F, Hassell J, Eyre
   M, Berger Z, Hacohen Y, Moshal K, et al. 6‐Month multidisciplinary follow‐up
   and outcomes of patients with paediatric inflammatory multisystem syndrome
   (PIMS‐TS) at a UK tertiary paediatric hospital: a retrospective cohort study.
   Lancet Child Adolesc Health. 2021; 5:473–482. doi:
   10.1016/S2352‐4642(21)00138‐3CrossrefMedlineGoogle Scholar
 * 20 Kostakou PM, Kostopoulos VS, Tryfou ES, Giannaris VD, Rodis IE, Olympios
   CD, Kouris NT. Subclinical left ventricular dysfunction and correlation with
   regional strain analysis in myocarditis with normal ejection fraction: a new
   diagnostic criterion. Int J Cardiol. 2018; 259:116–121. doi:
   10.1016/j.ijcard.2018.01.058CrossrefMedlineGoogle Scholar
 * 21 Kobayashi R, Dionne A, Ferraro A, Harrild D, Newburger J, VanderPluym C,
   Gauvreau K, Son MB, Lee P, Baker A, et al. Detailed assessment of left
   ventricular function in multisystem inflammatory syndrome in children using
   strain analysis. CJC Open. 2021; 3:880–887. doi:
   10.1016/j.cjco.2021.02.012CrossrefMedlineGoogle Scholar
 * 22 Sanil Y, Misra A, Safa R, Blake JM, Eddine AC, Balakrishnan P, Garcia RU,
   Taylor R, Dentel JN, Ang J, et al. Echocardiographic indicators associated
   with adverse clinical course and cardiac sequelae in multisystem inflammatory
   syndrome in children with coronavirus disease 2019. J Am Soc Echocardiogr.
   2021; 34:862–876. doi: 10.1016/j.echo.2021.04.018CrossrefMedlineGoogle
   Scholar
 * 23 Kanegaye JT, Wilder MS, Molkara D, Frazer JR, Pancheri J, Tremoulet AH,
   Watson VE, Best BM, Burns JC. Recognition of a Kawasaki disease shock
   syndrome. Pediatrics. 2009; 123:e783–e789. doi:
   10.1542/peds.2008‐1871CrossrefMedlineGoogle Scholar
 * 24 Dragulescu A, Mertens L, Friedberg MK. Interpretation of left ventricular
   diastolic dysfunction in children with cardiomyopathy by echocardiography:
   problems and limitations. Circ Cardiovasc Imaging. 2013; 6:254–261. doi:
   10.1161/CIRCIMAGING.112.000175LinkGoogle Scholar
 * 25 Kurt M, Wang J, Torre‐Amione G, Nagueh SF. Left atrial function in
   diastolic heart failure. Circ Cardiovasc Imaging. 2009; 2:10–15. doi:
   10.1161/CIRCIMAGING.108.813071LinkGoogle Scholar
 * 26 Hope KD, Wang Y, Banerjee MM, Montero AE, Pandian NG, Banerjee A. Left
   atrial mechanics in children: insights from new applications of strain
   imaging. Int J Cardiovasc Imaging. 2019; 35:57–65. doi:
   10.1007/s10554‐018‐1429‐7CrossrefMedlineGoogle Scholar
 * 27 Morris DA, Takeuchi M, Nakatani S, Otsuji Y, Belyavskiy E, Aravind Kumar
   R, Frydas A, Kropf M, Kraft R, Marquez E, et al. Lower limit of normality and
   clinical relevance of left ventricular early diastolic strain rate for the
   detection of left ventricular diastolic dysfunction. Eur Heart J Cardiovasc
   Imaging. 2018; 19:905–915. doi: 10.1093/ehjci/jex185CrossrefMedlineGoogle
   Scholar
 * 28 Health department‐reported cases of multisystem inflammatory syndrome in
   children (MIS‐C) in the United States | CDC. Available at:
   https://www.cdc.gov/mis‐c/cases/index.html. Accessed June 1, 2021.Google
   Scholar
 * 29 Sandoval Y, Januzzi JL, Jaffe AS. Cardiac troponin for assessment of
   myocardial injury in COVID‐19. J Am Coll Cardiol. 2020; 76:1244–1258. doi:
   10.1016/j.jacc.2020.06.068CrossrefMedlineGoogle Scholar
 * 30 Giustino G, Croft LB, Stefanini GG, Bragato R, Silbiger JJ, Vicenzi M,
   Danilov T, Kukar N, Shaban N, Kini A, et al. Characterization of myocardial
   injury in patients with COVID‐19. J Am Coll Cardiol. 2020; 76:2043–2055. doi:
   10.1016/j.jacc.2020.08.069CrossrefMedlineGoogle Scholar
 * 31 Al‐Biltagi M, Issa M, Hagar HA, Abdel‐Hafez M, Aziz NA. Circulating
   cardiac troponins levels and cardiac dysfunction in children with acute and
   fulminant viral myocarditis: circulating cardiac troponins levels and cardiac
   dysfunction. Acta Paediatr. 2010; 99:1510–1516. doi:
   10.1111/j.1651‐2227.2010.01882.xCrossrefMedlineGoogle Scholar
 * 32 Theocharis P, Wong J, Pushparajah K, Mathur SK, Simpson JM, Pascall E,
   Cleary A, Stewart K, Adhvaryu K, Savis A, et al. Multimodality cardiac
   evaluation in children and young adults with multisystem inflammation
   associated with COVID‐19. Eur Heart J Cardiovasc Imaging. 2021; 22:896–903.
   doi: 10.1093/ehjci/jeaa212CrossrefMedlineGoogle Scholar
 * 33 Blondiaux E, Parisot P, Redheuil A, Tzaroukian L, Levy Y, Sileo C,
   Schnuriger A, Lorrot M, Guedj R, Ducou le Pointe H. Cardiac MRI in children
   with multisystem inflammatory syndrome associated with COVID‐19. Radiology.
   2020; 297:E283–E288. doi: 10.1148/radiol.2020202288CrossrefMedlineGoogle
   Scholar
 * 34 Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J,
   Shchendrygina A, Escher F, Vasa‐Nicotera M, Zeiher AM, et al. Outcomes of
   cardiovascular magnetic resonance imaging in patients recently recovered from
   coronavirus disease 2019 (COVID‐19). JAMA Cardiol. 2020; 5:1265–1273. doi:
   10.1001/jamacardio.2020.3557CrossrefMedlineGoogle Scholar
 * 35 Huang L, Zhao P, Tang D, Zhu T, Han R, Zhan C, Liu W, Zeng H, Tao Q, Xia
   L. Cardiac involvement in patients recovered from COVID‐2019 identified using
   magnetic resonance imaging. JACC Cardiovasc Imaging. 2020; 13:2330–2339. doi:
   10.1016/j.jcmg.2020.05.004CrossrefMedlineGoogle Scholar
 * 36 Bratincsak A, Reddy VD, Purohit PJ, Tremoulet AH, Molkara DP, Frazer JR,
   Dyar D, Bush RA, Sim JY, Sang N, et al. Coronary artery dilation in acute
   Kawasaki disease and acute illnesses associated with fever. Pediatr Infect
   Dis J. 2012; 31:924–926. doi:
   10.1097/INF.0b013e31826252b3CrossrefMedlineGoogle Scholar
 * 37 Dean PN, Jackson LB, Paridon SM. Returning to play after coronavirus
   infection: pediatric cardiologists’ perspective—American College of
   Cardiology. Published July 14, 2020. Available at:
   https://www.acc.org/latest‐in‐cardiology/articles/2020/07/13/13/37/returning‐to‐play‐after‐coronavirus‐infection.
   Accessed June 1, 2021.Google Scholar
 * 38 Kim JH, Levine BD, Phelan D, Emery MS, Martinez MW, Chung EH, Thompson PD,
   Baggish AL. Coronavirus disease 2019 and the athletic heart: emerging
   perspectives on pathology, risks, and return to play. JAMA Cardiol. 2021;
   6:219–227. doi: 10.1001/jamacardio.2020.5890CrossrefMedlineGoogle Scholar


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REFERENCES

 * 1 Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M,
   Bonanomi E, D'Antiga L. An outbreak of severe Kawasaki‐like disease at the
   Italian epicentre of the SARS‐CoV‐2 epidemic: an observational cohort study.
   Lancet. 2020; 395:1771–1778. doi:
   10.1016/S0140‐6736(20)31103‐XCrossrefMedlineGoogle Scholar
 * 2 Valverde I, Singh Y, Sanchez‐de‐Toledo J, Theocharis P, Chikermane A, Di
   Filippo S, Kuciñska B, Mannarino S, Tamariz‐Martel A, Gutierrez‐Larraya F, et
   al. Acute cardiovascular manifestations in 286 children with multisystem
   inflammatory syndrome associated with COVID‐19 infection in Europe.
   Circulation. 2021; 143:21–32. doi:
   10.1161/CIRCULATIONAHA.120.050065LinkGoogle Scholar
 * 3 Feldstein LR, Tenforde MW, Friedman KG, Newhams M, Rose EB, Dapul H, Soma
   VL, Maddux AB, Mourani PM, Bowens C, et al. Characteristics and outcomes of
   US children and adolescents with multisystem inflammatory syndrome in
   children (MIS‐C) compared with severe acute COVID‐19. JAMA. 2021;
   325:1074–1087. doi: 10.1001/jama.2021.2091CrossrefMedlineGoogle Scholar
 * 4 Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, Barranco
   MA, Maxted AM, Rosenberg ES, Easton D, et al. Multisystem inflammatory
   syndrome in children in New York State. N Engl J Med. 2020; 383:347–358. doi:
   10.1056/NEJMoa2021756CrossrefMedlineGoogle Scholar
 * 5 Matsubara D, Kauffman HL, Wang Y, Calderon‐Anyosa R, Nadaraj S, Elias MD,
   White TJ, Torowicz DL, Yubbu P, Giglia TM, et al. Echocardiographic findings
   in pediatric multisystem inflammatory syndrome associated with COVID‐19 in
   the United States. J Am Coll Cardiol. 2020; 76:1947–1961. doi:
   10.1016/j.jacc.2020.08.056CrossrefMedlineGoogle Scholar
 * 6 Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, Ramnarayan P,
   Fraisse A, Miller O, Davies P, et al. Clinical characteristics of 58 children
   with a pediatric inflammatory multisystem syndrome temporally associated with
   SARS‐CoV‐2. JAMA. 2020; 324:259–269. doi:
   10.1001/jama.2020.10369CrossrefMedlineGoogle Scholar
 * 7 Information for healthcare providers about multisystem inflammatory
   syndrome in children (MIS‐C) | CDC. Available at:
   https://www.cdc.gov/mis‐c/hcp/. Accessed June 1, 2021.Google Scholar
 * 8 Multisystem inflammatory syndrome in children and adolescents temporally
   related to COVID‐19. Available at:
   https://www.who.int/news‐room/commentaries/detail/multisystem‐inflammatory‐syndrome‐in‐children‐and‐adolescents‐with‐covid‐19.
   Accessed June 1, 2021.Google Scholar
 * 9 Lang RM, Badano LP, Mor‐Avi V, Afilalo J, Armstrong A, Ernande L,
   Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al. Recommendations
   for cardiac chamber quantification by echocardiography in adults: an update
   from the American Society of Echocardiography and the European Association of
   Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015; 16:233–270.
   doi: 10.1093/ehjci/jev014CrossrefMedlineGoogle Scholar
 * 10 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M,
   Baker AL, Jackson MA, Takahashi M, Shah PB, et al. Diagnosis, treatment, and
   long‐term management of Kawasaki disease: a scientific statement for health
   professionals from the American Heart Association. Circulation. 2017;
   135:e927–e999. doi: 10.1161/CIR.0000000000000484LinkGoogle Scholar
 * 11 Khoo NS, Smallhorn JF, Atallah J, Kaneko S, Mackie AS, Paterson I. Altered
   left ventricular tissue velocities, deformation and twist in children and
   young adults with acute myocarditis and normal ejection fraction. J Am Soc
   Echocardiogr. 2012; 25:294–303. doi:
   10.1016/j.echo.2011.10.010CrossrefMedlineGoogle Scholar
 * 12 Singh A, Addetia K, Maffessanti F, Mor‐Avi V, Lang RM. LA strain for
   categorization of LV diastolic dysfunction. JACC Cardiovasc Imaging. 2017;
   10:735–743. doi: 10.1016/j.jcmg.2016.08.014CrossrefMedlineGoogle Scholar
 * 13 Lala A, Johnson KW, Januzzi JL, Russak AJ, Paranjpe I, Richter F, Zhao S,
   Somani S, Van Vleck T, Vaid A, et al. Prevalence and impact of myocardial
   injury in patients hospitalized with COVID‐19 infection. J Am Coll Cardiol.
   2020; 76:533–546. doi: 10.1016/j.jacc.2020.06.007CrossrefMedlineGoogle
   Scholar
 * 14 Cantinotti M, Law Y, Vittorini S, Crocetti M, Marco M, Murzi B, Clerico A.
   The potential and limitations of plasma BNP measurement in the diagnosis,
   prognosis, and management of children with heart failure due to congenital
   cardiac disease: an update. Heart Fail Rev. 2014; 19:727–742. doi:
   10.1007/s10741‐014‐9422‐2CrossrefMedlineGoogle Scholar
 * 15 Ferreira VM, Schulz‐Menger J, Holmvang G, Kramer CM, Carbone I, Sechtem U,
   Kindermann I, Gutberlet M, Cooper LT, Liu P, et al. Cardiovascular magnetic
   resonance in nonischemic myocardial inflammation. J Am Coll Cardiol. 2018;
   72:3158–3176. doi: 10.1016/j.jacc.2018.09.072CrossrefMedlineGoogle Scholar
 * 16 Levy PT, Machefsky A, Sanchez AA, Patel MD, Rogal S, Fowler S, Yaeger L,
   Hardi A, Holland MR, Hamvas A, et al. Reference ranges of left ventricular
   strain measures by two‐dimensional speckle‐tracking echocardiography in
   children: a systematic review and meta‐analysis. J Am Soc Echocardiogr. 2016;
   29:209–225.e6. doi: 10.1016/j.echo.2015.11.016CrossrefMedlineGoogle Scholar
 * 17 Levy PT, Sanchez Mejia AA, Machefsky A, Fowler S, Holland MR, Singh GK.
   Normal ranges of right ventricular systolic and diastolic strain measures in
   children: a systematic review and meta‐analysis. J Am Soc Echocardiogr. 2014;
   27:549–560.e3. doi: 10.1016/j.echo.2014.01.015CrossrefMedlineGoogle Scholar
 * 18 D’Souza R, Wang Y, Calderon‐Anyosa RJC, Montero AE, Banerjee MM, Ekhomu O,
   Matsubara D, Mercer‐Rosa L, Agger P, Sato T, et al. Decreased right
   ventricular longitudinal strain in children with hypoplastic left heart
   syndrome during staged repair and follow‐up: does it have implications in
   clinically stable patients?Int J Cardiovasc Imaging. 2020; 36:1667–1677. doi:
   10.1007/s10554‐020‐01870‐0CrossrefMedlineGoogle Scholar
 * 19 Penner J, Abdel‐Mannan O, Grant K, Maillard S, Kucera F, Hassell J, Eyre
   M, Berger Z, Hacohen Y, Moshal K, et al. 6‐Month multidisciplinary follow‐up
   and outcomes of patients with paediatric inflammatory multisystem syndrome
   (PIMS‐TS) at a UK tertiary paediatric hospital: a retrospective cohort study.
   Lancet Child Adolesc Health. 2021; 5:473–482. doi:
   10.1016/S2352‐4642(21)00138‐3CrossrefMedlineGoogle Scholar
 * 20 Kostakou PM, Kostopoulos VS, Tryfou ES, Giannaris VD, Rodis IE, Olympios
   CD, Kouris NT. Subclinical left ventricular dysfunction and correlation with
   regional strain analysis in myocarditis with normal ejection fraction: a new
   diagnostic criterion. Int J Cardiol. 2018; 259:116–121. doi:
   10.1016/j.ijcard.2018.01.058CrossrefMedlineGoogle Scholar
 * 21 Kobayashi R, Dionne A, Ferraro A, Harrild D, Newburger J, VanderPluym C,
   Gauvreau K, Son MB, Lee P, Baker A, et al. Detailed assessment of left
   ventricular function in multisystem inflammatory syndrome in children using
   strain analysis. CJC Open. 2021; 3:880–887. doi:
   10.1016/j.cjco.2021.02.012CrossrefMedlineGoogle Scholar
 * 22 Sanil Y, Misra A, Safa R, Blake JM, Eddine AC, Balakrishnan P, Garcia RU,
   Taylor R, Dentel JN, Ang J, et al. Echocardiographic indicators associated
   with adverse clinical course and cardiac sequelae in multisystem inflammatory
   syndrome in children with coronavirus disease 2019. J Am Soc Echocardiogr.
   2021; 34:862–876. doi: 10.1016/j.echo.2021.04.018CrossrefMedlineGoogle
   Scholar
 * 23 Kanegaye JT, Wilder MS, Molkara D, Frazer JR, Pancheri J, Tremoulet AH,
   Watson VE, Best BM, Burns JC. Recognition of a Kawasaki disease shock
   syndrome. Pediatrics. 2009; 123:e783–e789. doi:
   10.1542/peds.2008‐1871CrossrefMedlineGoogle Scholar
 * 24 Dragulescu A, Mertens L, Friedberg MK. Interpretation of left ventricular
   diastolic dysfunction in children with cardiomyopathy by echocardiography:
   problems and limitations. Circ Cardiovasc Imaging. 2013; 6:254–261. doi:
   10.1161/CIRCIMAGING.112.000175LinkGoogle Scholar
 * 25 Kurt M, Wang J, Torre‐Amione G, Nagueh SF. Left atrial function in
   diastolic heart failure. Circ Cardiovasc Imaging. 2009; 2:10–15. doi:
   10.1161/CIRCIMAGING.108.813071LinkGoogle Scholar
 * 26 Hope KD, Wang Y, Banerjee MM, Montero AE, Pandian NG, Banerjee A. Left
   atrial mechanics in children: insights from new applications of strain
   imaging. Int J Cardiovasc Imaging. 2019; 35:57–65. doi:
   10.1007/s10554‐018‐1429‐7CrossrefMedlineGoogle Scholar
 * 27 Morris DA, Takeuchi M, Nakatani S, Otsuji Y, Belyavskiy E, Aravind Kumar
   R, Frydas A, Kropf M, Kraft R, Marquez E, et al. Lower limit of normality and
   clinical relevance of left ventricular early diastolic strain rate for the
   detection of left ventricular diastolic dysfunction. Eur Heart J Cardiovasc
   Imaging. 2018; 19:905–915. doi: 10.1093/ehjci/jex185CrossrefMedlineGoogle
   Scholar
 * 28 Health department‐reported cases of multisystem inflammatory syndrome in
   children (MIS‐C) in the United States | CDC. Available at:
   https://www.cdc.gov/mis‐c/cases/index.html. Accessed June 1, 2021.Google
   Scholar
 * 29 Sandoval Y, Januzzi JL, Jaffe AS. Cardiac troponin for assessment of
   myocardial injury in COVID‐19. J Am Coll Cardiol. 2020; 76:1244–1258. doi:
   10.1016/j.jacc.2020.06.068CrossrefMedlineGoogle Scholar
 * 30 Giustino G, Croft LB, Stefanini GG, Bragato R, Silbiger JJ, Vicenzi M,
   Danilov T, Kukar N, Shaban N, Kini A, et al. Characterization of myocardial
   injury in patients with COVID‐19. J Am Coll Cardiol. 2020; 76:2043–2055. doi:
   10.1016/j.jacc.2020.08.069CrossrefMedlineGoogle Scholar
 * 31 Al‐Biltagi M, Issa M, Hagar HA, Abdel‐Hafez M, Aziz NA. Circulating
   cardiac troponins levels and cardiac dysfunction in children with acute and
   fulminant viral myocarditis: circulating cardiac troponins levels and cardiac
   dysfunction. Acta Paediatr. 2010; 99:1510–1516. doi:
   10.1111/j.1651‐2227.2010.01882.xCrossrefMedlineGoogle Scholar
 * 32 Theocharis P, Wong J, Pushparajah K, Mathur SK, Simpson JM, Pascall E,
   Cleary A, Stewart K, Adhvaryu K, Savis A, et al. Multimodality cardiac
   evaluation in children and young adults with multisystem inflammation
   associated with COVID‐19. Eur Heart J Cardiovasc Imaging. 2021; 22:896–903.
   doi: 10.1093/ehjci/jeaa212CrossrefMedlineGoogle Scholar
 * 33 Blondiaux E, Parisot P, Redheuil A, Tzaroukian L, Levy Y, Sileo C,
   Schnuriger A, Lorrot M, Guedj R, Ducou le Pointe H. Cardiac MRI in children
   with multisystem inflammatory syndrome associated with COVID‐19. Radiology.
   2020; 297:E283–E288. doi: 10.1148/radiol.2020202288CrossrefMedlineGoogle
   Scholar
 * 34 Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J,
   Shchendrygina A, Escher F, Vasa‐Nicotera M, Zeiher AM, et al. Outcomes of
   cardiovascular magnetic resonance imaging in patients recently recovered from
   coronavirus disease 2019 (COVID‐19). JAMA Cardiol. 2020; 5:1265–1273. doi:
   10.1001/jamacardio.2020.3557CrossrefMedlineGoogle Scholar
 * 35 Huang L, Zhao P, Tang D, Zhu T, Han R, Zhan C, Liu W, Zeng H, Tao Q, Xia
   L. Cardiac involvement in patients recovered from COVID‐2019 identified using
   magnetic resonance imaging. JACC Cardiovasc Imaging. 2020; 13:2330–2339. doi:
   10.1016/j.jcmg.2020.05.004CrossrefMedlineGoogle Scholar
 * 36 Bratincsak A, Reddy VD, Purohit PJ, Tremoulet AH, Molkara DP, Frazer JR,
   Dyar D, Bush RA, Sim JY, Sang N, et al. Coronary artery dilation in acute
   Kawasaki disease and acute illnesses associated with fever. Pediatr Infect
   Dis J. 2012; 31:924–926. doi:
   10.1097/INF.0b013e31826252b3CrossrefMedlineGoogle Scholar
 * 37 Dean PN, Jackson LB, Paridon SM. Returning to play after coronavirus
   infection: pediatric cardiologists’ perspective—American College of
   Cardiology. Published July 14, 2020. Available at:
   https://www.acc.org/latest‐in‐cardiology/articles/2020/07/13/13/37/returning‐to‐play‐after‐coronavirus‐infection.
   Accessed June 1, 2021.Google Scholar
 * 38 Kim JH, Levine BD, Phelan D, Emery MS, Martinez MW, Chung EH, Thompson PD,
   Baggish AL. Coronavirus disease 2019 and the athletic heart: emerging
   perspectives on pathology, risks, and return to play. JAMA Cardiol. 2021;
   6:219–227. doi: 10.1001/jamacardio.2020.5890CrossrefMedlineGoogle Scholar

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https://doi.org/10.1161/JAHA.121.023251

PMID: 35043684

 * Manuscript receivedSeptember 18, 2021
 * Manuscript acceptedNovember 3, 2021
 * Originally publishedJanuary 19, 2022


Keywords
 * multisystem inflammatory syndrome in children
 * cardiac magnetic resonance imaging
 * echocardiography
 * strain
 * cardiac function
 * coronary artery

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Subjects
 * Echocardiography
 * Magnetic Resonance Imaging (MRI)


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