1. Su JR, McNeil MM, Welsh KJ, Marquez PL, Ng C, Yan M, et al. Myopericarditis after vac
cination, vaccine adverse event reporting system (VAERS), 1990–2018. Vaccine 2021;
39:839–845.
2. Bozkurt B, Kamat I, Hotez PJ. Myocarditis with COVID-19 mRNA vaccines. Circulation
2021;144:471–484.
3. Mevorach D, Anis E, Cedar N, Bromberg M, Haas EJ, Nadir E, et al. Myocarditis after
BNT162b2 mRNA vaccine against Covid-19 in Israel. N Engl J Med 2021;385:
2140–2149.
4. Verma AK, Lavine KJ, Lin CY. Myocarditis after Covid-19 mRNA vaccination. N Engl J
Med 2021;385:1332–1334.
5. Lim Y, Kim MC, Kim KH, Jeong IS, Cho YS, Choi YD, et al. Case report: acute fulminant
myocarditis and cardiogenic shock after messenger RNA coronavirus disease 2019 vac
cination requiring extracorporeal cardiopulmonary resuscitation. Front Cardiovasc Med
2021;8:758996.
6. Centers for Disease Control and Prevention. Myocarditis and pericarditis following
mRNA COVID-19 vaccination. 2021. https://www.cdc.gov/coronavirus/2019-ncov/
vaccines/safety/myocarditis.html. Accessed 5 January 2022.
7. Muthukumar A, Narasimhan M, Li QZ, Mahimainathan L, Hitto I, Fuda F, et al. In-depth
evaluation of a case of presumed myocarditis after the second dose of COVID-19
mRNA vaccine. Circulation 2021;144:487–498.
8. Pan JA, Lee YJ, Salerno M. Diagnostic performance of extracellular volume, native T1,
and T2 mapping versus Lake Louise Criteria by cardiac magnetic resonance for detec
tion of acute myocarditis: a meta-analysis. Circ Cardiovasc Imaging 2018;11:e007598.
9. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, et al. Current
state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a
position statement of the European Society of Cardiology Working Group on
Myocardial and Pericardial Diseases. Eur Heart J 2013;34:2636–2648, 2648a–2648d.
10. Ehrlich P, Klingel K, Ohlmann-Knafo S, Hüttinger S, Sood N, Pickuth D. Biopsy-proven
lymphocytic myocarditis following first mRNA COVID-19 vaccination in a 40-year-old
male: case report. Clin Res Cardiol 2021;110:1855–1859.
11. Ammirati E, Frigerio M, Adler ED, Basso C, Birnie DH, Brambatti M, et al. Management
of acute myocarditis and chronic inflammatory cardiomyopathy: an expert consensus
document. Circ Heart Fail 2020;13:e007405.
12. Bergamaschi C, Terpos E, Rosati M, Angel M, Bear J, Stellas D, et al. Systemic IL-15,
IFN-γ, and IP-10/CXCL10 signature associated with effective immune response to
SARS-CoV-2 in BNT162b2 mRNA vaccine recipients. Cell Rep 2021;36:109504.
13. Yue Y, Gui J, Ai W, Xu W, Xiong S. Direct gene transfer with IP-10 mutant ameliorates
mouse CVB3-induced myocarditis by blunting Th1 immune responses. PLoS One 2011;
6:e18186.
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immunosuppressive agents. In this regard, according to the centers for
disease control and prevention (CDC) working case definition for
acute myocarditis, either CMR or EMB is essential.6 Specifically in
most reported cases of suspected post-COVID-19 vaccination myo
carditis, the diagnosis of myocardial inflammation was based on CMR
findings due to its lower invasiveness compared with that of EMB.7
However, the drawback of CMR is its low diagnostic accuracy and
low specificity.8 Therefore, EMB is necessary to obtain an accurate diag
nosis of acute myocarditis, specifically fulminant myocarditis. In fact, ex
pert consensus highly recommends EMB as the gold standard for the
diagnosis of fulminant myocarditis.9 The cases of a few patients in
whom EMB was performed for suspected post-COVID-19 vaccination
myocarditis have been reported previously;4,10 in these studies, the
histopathological and immunohistological findings were similar to those
of lymphocytic myocarditis demonstrating primary T-cell and macro
phage infiltration, which are in line with the current patient case.
Cytokine analysis is widely used to understand the functional al
terations of the host immune system. Recent assays are designed
to quantify multiple cytokines in various matrices, including serum
samples and tissue culture supernatants, and obtain more accessibil
ity. We consider that this analysis can provide us with crucial clues to
unveil the pathogenesis of inflammatory heart disease including myo
carditis. Generally, lymphocytic myocarditis is attributed to immunemediated myocardial damage, including virus infections, in systemic
inflammatory diseases.11 In the current patient case, cytokine analysis
showed notable increases in IP-10 (CXCL10), MCP-3 (CCL7), and
MIG (CXCL9) levels compared with those in the reference groups,
which are categorized as Th1-type chemokines that preferentially
promote cellular immunity by activating the chemotaxis of CXCR3+ cells
including activated T lymphocytes (CD8), B lymphocytes, and
monocytes. Meanwhile, compared with those in the reference
group, we observed only a subtle increase in the IL-4 and IL-13 levels,
which are categorized as Th2-type chemokines, and comparable le
vels of the other cytokines measured (Bio-Plex Pro Human Cytokine
Screening Panel, 48-Plex). Recently, COVID-19 mRNA (BNT162b2)
vaccination has been reported to induce cytokine signatures featur
ing IP-10 (CXCL10) in addition to IL-15 and interferon (IFN)-γ.12
Similarly, IP-10 has been reported to be induced in heart tissue in
fected with coxsackievirus B3 (CVB3) and to cause myocardial in
jury.13 Furthermore, MCP-3 (CCL7) and MIG (CXL9) have been
reported to induce histiocyte chemotaxis, followed by the develop
ment of CVB3 myocarditis via the Th1 immune response.7,14 In the
current patient case, negative antibody tests against coxsackievirus
confirmed that fulminant myocarditis was caused by COVID-19
mRNA vaccination. We believe that elevated levels of these cyto
kines in the Th1 immune response are involved in the pathogenesis
of myocarditis related to COVID-19 mRNA vaccination.
Interestingly, similar to this form of myocarditis, CVB3 myocarditis
also shows sex differences, with increased severity in males.15 The
potential underlying mechanism is the inhibition of antiinflammatory cells by testosterone, followed by its involvement in
a Th1-type immune response.2,16 A similar mechanism may explain
sex differences in myocarditis related to COVID-19 mRNA
vaccination.
14. Westermann D, Savvatis K, Lindner D, Zietsch C, Becher PM, Hammer E, et al. Reduced
degradation of the chemokine MCP-3 by matrix metalloproteinase-2 exacerbates myo
cardial inflammation in experimental viral cardiomyopathy. Circulation 2011;124:
2082–2093.
M. Fujii et al.
15. Huber SA, Pfaeffle B. Differential Th1 and Th2 cell responses in male and female BALB/c
mice infected with coxsackievirus group B type 3. J Virol 1994;68:5126–5132.
16. Lasrado N, Reddy J. An overview of the immune mechanisms of viral myocarditis. Rev
Med Virol 2020;30:1–14.
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