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Myocarditis Following COVID-19 Vaccination

  • Constantin A. Marschner
    Affiliations
    Department of Medical Imaging, Toronto General Hospital, Peter Munk Cardiac Center, University Health Network (UHN), University of Toronto, Toronto

    Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany
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  • Kirsten E. Shaw
    Affiliations
    Abbott Northwestern Hospital, Department of Graduate Medical Education, Minneapolis, Minnesota, USA
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  • Felipe Sanchez Tijmes
    Affiliations
    Department of Medical Imaging, Toronto General Hospital, Peter Munk Cardiac Center, University Health Network (UHN), University of Toronto, Toronto

    Department of Medical Imaging, Clinica Santa Maria, Universidad de los Andes, Santiago, Chile
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  • Matteo Fronza
    Affiliations
    Department of Medical Imaging, Toronto General Hospital, Peter Munk Cardiac Center, University Health Network (UHN), University of Toronto, Toronto
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  • Sharmila Khullar
    Affiliations
    Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto
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  • Michael A. Seidman
    Affiliations
    Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto

    Laboratory Medicine Program, University Health Network, Toronto
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  • Paaladinesh Thavendiranathan
    Affiliations
    Department of Medical Imaging, Toronto General Hospital, Peter Munk Cardiac Center, University Health Network (UHN), University of Toronto, Toronto

    Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network (UHN), University of Toronto, Toronto
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  • Jacob A. Udell
    Affiliations
    Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network (UHN), University of Toronto, Toronto

    Cardiovascular Division, Women’s College Hospital, University of Toronto, Toronto
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  • Rachel M. Wald
    Affiliations
    Department of Medical Imaging, Toronto General Hospital, Peter Munk Cardiac Center, University Health Network (UHN), University of Toronto, Toronto

    Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network (UHN), University of Toronto, Toronto
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  • Kate Hanneman
    Correspondence
    Address for Correspondence: Kate Hanneman MD MPH Toronto General Hospital, University Health Network 1 PMB-298, 585 University Avenue Toronto, Ontario M5G 2N2 Phone: (416) 340-4800 ext. 3790 Fax: (416) 593-0502
    Affiliations
    Department of Medical Imaging, Toronto General Hospital, Peter Munk Cardiac Center, University Health Network (UHN), University of Toronto, Toronto
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      Key Words

      Abbreviations:

      ACE2 (Angiotensin-converting enzyme 2), Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine), BNP (Brain natriuretic peptide), BNT162b2 mRNA (Pfizer-BioNTech COVID-19 vaccine), CDC (U.S. Centers of Disease Control and Prevention), CMR (Cardiac magnetic resonance imaging), COVID-19 (Coronavirus disease 2019), CT (Computed tomography), ECG (Electrocardiography), ECV (Extracellular volume), EUA (Emergency use authorization), FDA (U.S. Food and Drug Administration), FDG-PET (Fluorodeoxyglucose positron emission tomography), H&E (Hematoxylin and eosin), LGE (Late gadolinium enhancement), LLC (Lake Louise Criteria), LVEF (Left ventricular ejection fraction), mRNA (Messenger ribonucleic acid), mRNA-1273 (Moderna COVID-19 vaccine), NSAIDs (Nonsteroidal anti-inflammatory drugs), SARS-CoV-2 (Severe acute respiratory syndrome coronavirus-2)

      Key Points

      • Myocarditis following mRNA-based COVID-19 vaccines is rare; however, adolescent and young adult males are at highest risk.
      • Chest pain is the most common symptom, with typical onset within a few days of vaccine administration.
      • CMR plays an important role in the diagnosis of acute myocarditis following vaccination, with typical findings of subepicardial late gadolinium enhancement and co-localizing edema at the basal inferior lateral wall.
      • The disease course of myocarditis following COVID-19 vaccination is typically transient and mild, with resolution of symptoms within 1-3 weeks in most patients.
      • However, longer term follow-up is needed to determine whether imaging abnormalities persist, to evaluate for adverse outcomes, and to understand the risk associated with subsequent vaccination.

      Introduction

      Following the discovery of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in December 2019, there has been intense focus on the development of vaccines to limit the contagion and severity of coronavirus disease 2019 (COVID-19). On December 11, 2020, the U.S. Food and Drug Administration (FDA) issued emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 vaccine (BNT162b2 mRNA). Since then, the FDA has approved the Pfizer-BioNTech COVID-19 vaccine and has authorized two other vaccines for emergency use, Moderna (mRNA-1273) and Janssen/Johnson & Johnson (Ad26.COV2.S). The Janssen/Johnson & Johnson vaccine is an adenovirus vector vaccine, whereas the other two are messenger ribonucleic acid (mRNA) vaccines. As of April 2022, over 11.5 billion COVID-19 vaccine doses have been administered worldwide.
      Several side effects have been reported after administration of COVID-19 vaccines, the majority of which are mild and self-limited. These include pain at the injection site, lymphadenopathy ipsilateral to the site of injection, fever, chills, myalgias, headache and fatigue (
      • Hanneman K.
      • Iwanochko R.M.
      • Thavendiranathan P.
      Evolution of Lymphadenopathy at PET/MRI after COVID-19 Vaccination.
      ). Serious side effects have been reported in a very small proportion of individuals following COVID-19 vaccination. These include thrombosis with thrombocytopenia syndrome (TTS) following administration of viral vector vaccines and myocarditis and pericarditis following administration of mRNA-based vaccines (
      • See I.
      • Su J.R.
      • Lale A.
      • Woo E.J.
      • Guh A.Y.
      • Shimabukuro T.T.
      • et al.
      US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021.
      ,
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Sanchez Tijmes F.
      • Thavendiranathan P.
      • Udell J.A.
      • Seidman M.A.
      • Hanneman K.
      Cardiac MRI Assessment of Nonischemic Myocardial Inflammation: State of the Art Review and Update on Myocarditis Associated with COVID-19 Vaccination.
      ).
      Myocarditis is an inflammatory disease of the myocardium without an ischemic cause, which can be diagnosed by histological, immunological and imaging criteria (
      • Caforio A.L.
      • Pankuweit S.
      • Arbustini E.
      • Basso C.
      • Gimeno-Blanes J.
      • Felix S.B.
      • 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.
      ). Pericarditis refers to non-ischemic inflammation of the pericardium. The term myopericarditis is used when both the myocardium and pericardium are inflamed. Myocarditis following vaccination had been described very rarely prior to the introduction of COVID-19 vaccines, including following smallpox and anthrax vaccines (
      • Su J.R.
      • McNeil M.M.
      • Welsh K.J.
      • Marquez P.L.
      • Ng C.
      • Yan M.
      • et al.
      Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018.
      ). Although rare, there has been intense interest in myocarditis following COVID-19 vaccination, particularly given the higher incidence of this adverse event in young men and concerns about the potential for long-term sequelae.
      The purpose of the review is to evaluate the current literature related to myocarditis following COVID-19 vaccination, including the incidence, risk factors, clinical presentation, imaging findings, proposed pathophysiologic mechanisms, treatment and prognosis.
      Definition of Vaccine Associated Myocarditis
      There is no test or investigation that can establish causality for vaccine associated myocarditis or pericarditis. These associations are based on a close temporal relationship between vaccine administration and the onset of symptoms, usually defined as within 14 days although ranges of up to a month have been reported in the literature (
      • Husby A.
      • Hansen J.V.
      • Fosbol E.
      • Thiesson E.M.
      • Madsen M.
      • Thomsen R.W.
      • et al.
      SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study.
      ,
      • Mevorach D.
      • Anis E.
      • Cedar N.
      • Bromberg M.
      • Haas E.J.
      • Nadir E.
      • et al.
      Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.
      ,
      • Patone M.
      • Mei X.W.
      • Handunnetthi L.
      • Dixon S.
      • Zaccardi F.
      • Shankar-Hari M.
      • et al.
      Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection.
      ,
      • Perez Y.
      • Levy E.R.
      • Joshi A.Y.
      • Virk A.
      • Rodriguez-Porcel M.
      • Johnson M.
      • et al.
      Myocarditis Following COVID-19 mRNA Vaccine: A Case Series and Incidence Rate Determination.
      ). The U.S. Centers of Disease Control and Prevention (CDC) has established case definitions of acute myocarditis and pericarditis, including probable or confirmed acute myocarditis and probable acute pericarditis, summarized in Table 1 (
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ).
      Table 1Centers for Disease Control and Prevention working case definitions for acute myocarditis and acute pericarditis. Adapted from Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices — United States, June 2021. MMWR Morb Mortal Wkly Rep 2021;70:977–982.
      Table thumbnail fx1

       Incidence

      In the United States, most of the data on the incidence of adverse events following vaccination has been gleaned from the Vaccine Adverse Events Reporting System (VAERS). As of January 7, 2022, VAERS had received 2,478 reports of myocarditis and 1,900 reports of pericarditis following COVID-19 vaccination (

      United States Department of Health and Human Services (DHHS), Public Health Service (PHS), Centers for Disease Control (CDC) / Food and Drug Administration (FDA), Vaccine Adverse Event Reporting System (VAERS) 1990 - 01/07/2022, CDC WONDER On-line Database [cited 2022 January 16]. Available from: http://wonder.cdc.gov/vaers.

      ). Of note, the VAERS is a passive adverse event reporting system with limitations including reporting bias.
      Post-vaccine myocarditis has been documented worldwide, with no clear identified pattern of increased prevalence based on geographic region. Reported rates from different healthcare organizations across the world are similar, including large population-based studies from Israel and California (
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • et al.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ,
      • Witberg G.
      • Barda N.
      • Hoss S.
      • Richter I.
      • Wiessman M.
      • Aviv Y.
      • et al.
      Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.
      ). A recent systematic review estimated that the overall incidence of myopericarditis following COVID-19 vaccination is 18 per million vaccine doses (

      Ling RR, Ramanathan K, Tan FL, Tai BC, Somani J, Fisher D, MacLaren G. Myopericarditis following COVID-19 vaccination and non- COVID-19 vaccination: a systematic review and meta-analysis. Lancet Respir Med 2022. Apr 11:S2213-2600(22)00059-5. doi: 10.1016/S2213-2600(22)00059-5.

      ). Compared with COVID-19 vaccines, the incidence of myopericarditis was higher following vaccination for small pox (132 per million vaccine doses) and did not differ significantly with the incidence of myopericarditis following influenza vaccination (1.3 per million vaccine dose) or other non-small pox vaccination (57 per million vaccine doses) (

      Ling RR, Ramanathan K, Tan FL, Tai BC, Somani J, Fisher D, MacLaren G. Myopericarditis following COVID-19 vaccination and non- COVID-19 vaccination: a systematic review and meta-analysis. Lancet Respir Med 2022. Apr 11:S2213-2600(22)00059-5. doi: 10.1016/S2213-2600(22)00059-5.

      ).

       Sex and Age Differences

      The risk of myocarditis associated with mRNA-based COVID-19 vaccination is highest in males between 12 and 29 years of age following administration of the second dose (
      • Mevorach D.
      • Anis E.
      • Cedar N.
      • Bromberg M.
      • Haas E.J.
      • Nadir E.
      • et al.
      Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.
      ,
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • et al.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ,
      • Witberg G.
      • Barda N.
      • Hoss S.
      • Richter I.
      • Wiessman M.
      • Aviv Y.
      • et al.
      Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.
      ,
      • Hajjo R.
      • Sabbah D.A.
      • Bardaweel S.K.
      • Tropsha A.
      Shedding the Light on Post-Vaccine Myocarditis and Pericarditis in COVID-19 and Non-COVID-19 Vaccine Recipients.
      ,
      • Oster M.E.
      • Shay D.K.
      • Su J.R.
      • Gee J.
      • Creech C.B.
      • Broder K.R.
      • et al.
      Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021.
      ). As of June 2021, crude reporting rates of myocarditis following COVID-19 vaccination based on VAERS data were 40.6 cases per million second doses among males aged 12-29 years and 4.2 cases per million second doses among females aged 12-29 years (
      • Gargano J.W.
      • Wallace M.
      • Hadler S.C.
      • Langley G.
      • Su J.R.
      • Oster M.E.
      • et al.
      Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021.
      ). The striking sex difference in adolescents and young adults has led to proposed pathophysiologic mechanisms related to sex hormones and has raised questions about the potential for under-diagnosis of myocarditis in women compared to men (
      • Mevorach D.
      • Anis E.
      • Cedar N.
      • Bromberg M.
      • Haas E.J.
      • Nadir E.
      • et al.
      Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.
      ).
      Rates of myocarditis following COVID-19 vaccination are much lower in younger children between 5 and 11 years of age and adults over 30 years of age (
      • Gargano J.W.
      • Wallace M.
      • Hadler S.C.
      • Langley G.
      • Su J.R.
      • Oster M.E.
      • et al.
      Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021.
      ). As of December 19, 2021, reported rates of myocarditis based on VAERS data per 1 million doses of Pfizer-BioNTech COVID-19 vaccines administered were only 4 for males aged 5-11 years compared to 46 for males aged 12-15 years and 70 for males aged 16-17 years after the second dose. For females, rates were 2, 4, and 8 in the same age ranges, respectively (

      Su JR. COVID-19 vaccine safety updates: Primary series in children and adolescents ages 5–11 and 12–15 years, and booster doses in adolescents ages 16–24 years 2022 [cited 2022 January 20]. Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-01-05/02-covid-su-508.pdf.

      ). The vaccine formulation of the Pfizer mRNA vaccine for ages 5-11 years of age is one third the dose of the formulation for those aged 12 years and older, which raises the possibility of a weight-based dose response relationship in younger adolescents who have lower body weight compared to adults.

       Risk with Different Vaccinations

      Among mRNA-based COVID-19 vaccines, myocarditis is more common following the Moderna vaccine compared to the Pfizer-BioNTech COVID-19 vaccine, although absolute cases numbers vary depending on local availability of each vaccine (
      • Husby A.
      • Hansen J.V.
      • Fosbol E.
      • Thiesson E.M.
      • Madsen M.
      • Thomsen R.W.
      • et al.
      SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study.
      ,
      • Montgomery J.
      • Ryan M.
      • Engler R.
      • Hoffman D.
      • McClenathan B.
      • Collins L.
      • et al.
      Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.
      ). A study of more than 2.5 million people who received the Pfizer-BioNTech COVID-19 vaccine demonstrated an estimated incidence of myocarditis of 2.1 cases per 100,000 persons (
      • Witberg G.
      • Barda N.
      • Hoss S.
      • Richter I.
      • Wiessman M.
      • Aviv Y.
      • et al.
      Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.
      ), while a study of nearly 500,000 people vaccinated with the Moderna vaccine demonstrated an incidence of 4.2 cases per 100,000 persons (
      • Husby A.
      • Hansen J.V.
      • Fosbol E.
      • Thiesson E.M.
      • Madsen M.
      • Thomsen R.W.
      • et al.
      SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study.
      ). A large population-based study in Denmark found that the rates of myocarditis among individuals aged 12-39 years were 1.6 per 100,000 individuals for Pfizer-BioNTech and 5.7 per 100,000 individuals for Moderna (
      • Husby A.
      • Hansen J.V.
      • Fosbol E.
      • Thiesson E.M.
      • Madsen M.
      • Thomsen R.W.
      • et al.
      SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study.
      ).
      Myocarditis is much more common following the second dose compared to the first, but has also been reported following the first dose particularly in those with a prior history of COVID-19 infection (
      • Sanchez Tijmes F.
      • Thavendiranathan P.
      • Udell J.A.
      • Seidman M.A.
      • Hanneman K.
      Cardiac MRI Assessment of Nonischemic Myocardial Inflammation: State of the Art Review and Update on Myocarditis Associated with COVID-19 Vaccination.
      ). There are limited data on the risk of myocarditis following third and subsequent booster doses (
      • Aviram G.
      • Viskin D.
      • Topilsky Y.
      • Sadon S.
      • Shalmon T.
      • Taieb P.
      • et al.
      Myocarditis Associated With COVID-19 Booster Vaccination.
      ,
      • Sanchez Tijmes F.
      • Zamorano A.
      • Thavendiranathan P.
      • Hanneman K.
      Imaging of Myocarditis Following mRNA COVID-19 Booster Vaccination.
      ). However, the risk after the third dose appears to be lower than following the second dose (

      Ling RR, Ramanathan K, Tan FL, Tai BC, Somani J, Fisher D, MacLaren G. Myopericarditis following COVID-19 vaccination and non- COVID-19 vaccination: a systematic review and meta-analysis. Lancet Respir Med 2022. Apr 11:S2213-2600(22)00059-5. doi: 10.1016/S2213-2600(22)00059-5.

      ,
      • Friedensohn L.
      • Levin D.
      • Fadlon-Derai M.
      • Gershovitz L.
      • Fink N.
      • Glassberg E.
      • et al.
      Myocarditis Following a Third BNT162b2 Vaccination Dose in Military Recruits in Israel.
      ). History of prior exposure is likely relevant as well as shorter interval between doses (
      • Buchan S.A.
      • Seo C.Y.
      • Johnson C.
      • Alley S.
      • Kwong J.C.
      • Nasreen S.
      • et al.
      Epidemiology of myocarditis and pericarditis following mRNA vaccines in Ontario, Canada: by vaccine product, schedule and interval.
      ). There are a few case reports of recurrent myocarditis following administration of mRNA-based COVID-19 vaccines (
      • Minocha P.K.
      • Better D.
      • Singh R.K.
      • Hoque T.
      Recurrence of Acute Myocarditis Temporally Associated with Receipt of the mRNA Coronavirus Disease 2019 (COVID-19) Vaccine in a Male Adolescent.
      ,
      • Umei T.C.
      • Kishino Y.
      • Shiraishi Y.
      • Inohara T.
      • Yuasa S.
      • Fukuda K.
      Recurrence of myopericarditis following mRNA COVID-19 vaccination in a male adolescent.
      ). However, the risk of recurrence of myocarditis following receipt of additional doses of mRNA COVID-19 vaccines in individuals with a history of confirmed myocarditis is currently unknown (

      Summary of NACI advice on vaccination with COVID-19 vaccines following myocarditis (with or without pericarditis) [cited 2022 January 28]. Available from: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/summary-advice-vaccination-covid-19-vaccines-following-myocarditis-with-without-pericarditis.html.

      ). One pre-print article suggests that the risk of myocarditis among individuals who received the Moderna vaccine for the second dose was higher for those who had a heterologous as opposed to homologous vaccine schedule (i.e. higher in those who had received a COVID-19 vaccine other than the Moderna vaccine for their first dose) (
      • Buchan S.A.
      • Seo C.Y.
      • Johnson C.
      • Alley S.
      • Kwong J.C.
      • Nasreen S.
      • et al.
      Epidemiology of myocarditis and pericarditis following mRNA vaccines in Ontario, Canada: by vaccine product, schedule and interval.
      ).

       Risk relative to COVID-19 infection

      Infection with SARS-CoV-2 can also result in myocardial inflammation, which is associated with adverse outcomes in hospitalized patients, and should be balanced against the risk of vaccine-related complications (
      • Guo T.
      • Fan Y.
      • Chen M.
      • Wu X.
      • Zhang L.
      • He T.
      • et al.
      Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19).
      ). Overall, the rates of myocarditis following SARS-CoV-2 infection are much higher than after vaccination (
      • Gargano J.W.
      • Wallace M.
      • Hadler S.C.
      • Langley G.
      • Su J.R.
      • Oster M.E.
      • et al.
      Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021.
      ). Data from the largest integrated health care organization in Israel indicate that SARS-CoV-2 infection is associated with an excess risk of myocarditis when compared to age and risk-matched controls (risk ratio 18.3 and risk difference 11.0 events per 100,000 persons) that is much higher than the excess risk of myocarditis following administration of Pfizer-BioNTech COVID-19 vaccine (risk ratio 3.2 and risk difference 2.7 events per 100,000 persons) (
      • Barda N.
      • Dagan N.
      • Ben-Shlomo Y.
      • Kepten E.
      • Waxman J.
      • Ohana R.
      • et al.
      Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.
      ). Similarly, higher risk of myocarditis after SARS-CoV-2 infection compared to COVID-19 vaccination was recently demonstrated in a study in England that evaluated over 38 million individuals aged ≥ 16 years who had received at least one dose of a COVID-19 vaccine (
      • Patone M.
      • Mei X.W.
      • Handunnetthi L.
      • Dixon S.
      • Zaccardi F.
      • Shankar-Hari M.
      • et al.
      Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection.
      ). The extent of abnormalities on cardiac magnetic resonance imaging (CMR) are also less severe in myocarditis following COVID-19 vaccination compared to myocarditis following SARS-CoV-2 infection (
      • Fronza M.T.
      • Thavendiranathan P.
      • Chan V.
      • Rani Karur G.
      • Udell J.
      • Wald R.
      • Hong R.
      • Hanneman K.
      Myocardial injury pattern by MRI in COVID-19 Vaccine Associated Myocarditis.
      ).

       Clinical Presentation

       Symptoms

      The clinical presentation of myocarditis following COVID-19 vaccination is similar to that of myocarditis due to other causes (Table 1). Chest pain is the most frequently reported presenting symptom (
      • Montgomery J.
      • Ryan M.
      • Engler R.
      • Hoffman D.
      • McClenathan B.
      • Collins L.
      • et al.
      Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.
      ,
      • Engler R.J.
      • Nelson M.R.
      • Collins Jr., L.C.
      • Spooner C.
      • Hemann B.A.
      • Gibbs B.T.
      • et al.
      A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination.
      ,
      • Halsell J.S.
      • Riddle J.R.
      • Atwood J.E.
      • Gardner P.
      • Shope R.
      • Poland G.A.
      • et al.
      Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel.
      ,
      • Mei R.
      • Raschi E.
      • Forcesi E.
      • Diemberger I.
      • De Ponti F.
      • Poluzzi E.
      Myocarditis and pericarditis after immunization: Gaining insights through the Vaccine Adverse Event Reporting System.
      ). However, as with myocarditis from other causes, myocarditis following COVID-19 vaccination can present with variable symptoms ranging from subclinical presentations to acute arrythmia, heart failure or rarely cardiogenic shock (
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Witberg G.
      • Barda N.
      • Hoss S.
      • Richter I.
      • Wiessman M.
      • Aviv Y.
      • et al.
      Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.
      ,
      • Montgomery J.
      • Ryan M.
      • Engler R.
      • Hoffman D.
      • McClenathan B.
      • Collins L.
      • et al.
      Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.
      ).

       Timing after Vaccination

      Most patients with myocarditis following COVID-19 vaccination demonstrate symptom onset within the first week after vaccination, with the vast majority presenting within the first 4 days (
      • Montgomery J.
      • Ryan M.
      • Engler R.
      • Hoffman D.
      • McClenathan B.
      • Collins L.
      • et al.
      Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.
      ,
      • Heymans S.
      • Cooper L.T.
      Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms.
      ,
      • Das B.B.
      • Moskowitz W.B.
      • Taylor M.B.
      • Palmer A.
      Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination: What Do We Know So Far?.
      ,
      • Matta A.
      • Kunadharaju R.
      • Osman M.
      • Jesme C.
      • McMiller Z.
      • Johnson E.M.
      • et al.
      Clinical Presentation and Outcomes of Myocarditis Post mRNA Vaccination: A Meta-Analysis and Systematic Review.
      ). This is similar to myocarditis following non-COVID vaccination where symptom onset is usually less than two weeks after vaccine administration (

      United States Department of Health and Human Services (DHHS), Public Health Service (PHS), Centers for Disease Control (CDC) / Food and Drug Administration (FDA), Vaccine Adverse Event Reporting System (VAERS) 1990 - 01/07/2022, CDC WONDER On-line Database [cited 2022 January 16]. Available from: http://wonder.cdc.gov/vaers.

      ,
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • et al.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ).

       Histopathology and Pathophysiology

       Histopathology

      Endomyocardial biopsy is not frequently performed in the setting of acute myocarditis but is indicated in patients with suspected myocarditis when diagnostic confirmation will alter therapy, in cases of hemodynamic instability or with clinical deterioration despite supportive care (
      • Leone O.
      • Veinot J.P.
      • Angelini A.
      • Baandrup U.T.
      • Basso C.
      • Berry G.
      • et al.
      consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology.
      ). A negative endomyocardial biopsy does not exclude the diagnosis of myocarditis given sampling imprecision associated with spatial heterogeneity (patchiness) of the disease (
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Leone O.
      • Veinot J.P.
      • Angelini A.
      • Baandrup U.T.
      • Basso C.
      • Berry G.
      • et al.
      consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology.
      ,
      • Baughman K.L.
      Diagnosis of myocarditis: death of Dallas criteria.
      ,
      • Chow L.H.
      • Radio S.J.
      • Sears T.D.
      • McManus B.M.
      Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis.
      ). However, it should also be noted that cardiac dysfunction mimicking myocarditis may result from a systemic increase in cytokine production, which does not have a histological correlate (
      • Baughman K.L.
      Diagnosis of myocarditis: death of Dallas criteria.
      ,
      • Luk A.
      • Clarke B.
      • Dahdah N.
      • Ducharme A.
      • Krahn A.
      • McCrindle B.
      • et al.
      Myocarditis and Pericarditis After COVID-19 mRNA Vaccination: Practical Considerations for Care Providers.
      ,
      • Rali A.S.
      • Ranka S.
      • Shah Z.
      • Sauer A.J.
      Mechanisms of Myocardial Injury in Coronavirus Disease 2019.
      ,
      • Switzer C.
      • Loeb M.
      Evaluating the relationship between myocarditis and mRNA vaccination.
      ).
      There are very few reports of histologically documented myocarditis following COVID-19 vaccination in the literature to date. Lymphocytic myocarditis is the predominant pattern observed in biopsied and autopsied hearts and occurs most frequently in adolescents and young adult males who present with mild, self-limited disease (
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Switzer C.
      • Loeb M.
      Evaluating the relationship between myocarditis and mRNA vaccination.
      ,
      • Ehrlich P.
      • Klingel K.
      • Ohlmann-Knafo S.
      • Huttinger S.
      • Sood N.
      • Pickuth D.
      • et al.
      Biopsy-proven lymphocytic myocarditis following first mRNA COVID-19 vaccination in a 40-year-old male: case report.
      ,
      • Jain S.S.
      • Steele J.M.
      • Fonseca B.
      • Huang S.
      • Shah S.
      • Maskatia S.A.
      • et al.
      COVID-19 Vaccination-Associated Myocarditis in Adolescents.
      ). In rare instances it may manifest as a fulminant, potentially fatal disease with no sex predilection (
      • Abbate A.
      • Gavin J.
      • Madanchi N.
      • Kim C.
      • Shah P.R.
      • Klein K.
      • et al.
      Fulminant myocarditis and systemic hyperinflammation temporally associated with BNT162b2 mRNA COVID-19 vaccination in two patients.
      ,
      • Lim Y.
      • Kim M.C.
      • Kim K.H.
      • Jeong I.S.
      • Cho Y.S.
      • Choi Y.D.
      • et al.
      Case Report: Acute Fulminant Myocarditis and Cardiogenic Shock After Messenger RNA Coronavirus Disease 2019 Vaccination Requiring Extracorporeal Cardiopulmonary Resuscitation.
      ,
      • Verma A.K.
      • Lavine K.J.
      • Lin C.Y.
      Myocarditis after Covid-19 mRNA Vaccination.
      ). Depending upon the timing of histological assessment, a pattern of healing myocarditis may be present. Ameratunga et al. report a 57-year old woman who died of fulminant necrotizing eosinophilic myocarditis three days after a first dose of the Pfizer-BioNTech COVID-19 vaccine (
      • Ameratunga R.
      • Woon S.T.
      • Sheppard M.N.
      • Garland J.
      • Ondruschka B.
      • Wong C.X.
      • et al.
      First Identified Case of Fatal Fulminant Necrotizing Eosinophilic Myocarditis Following the Initial Dose of the Pfizer-BioNTech mRNA COVID-19 Vaccine (BNT162b2, Comirnaty): an Extremely Rare Idiosyncratic Hypersensitivity Reaction.
      ). Interestingly, myocarditis following other viral vaccines, such as smallpox, measles-mumps-rubella, varicella, oral polio, yellow fever, influenza, hepatitis A and B, and human papillomavirus is usually of the eosinophilic pattern, albeit not typically necrotizing (
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Luk A.
      • Clarke B.
      • Dahdah N.
      • Ducharme A.
      • Krahn A.
      • McCrindle B.
      • et al.
      Myocarditis and Pericarditis After COVID-19 mRNA Vaccination: Practical Considerations for Care Providers.
      ,
      • Switzer C.
      • Loeb M.
      Evaluating the relationship between myocarditis and mRNA vaccination.
      ). Different histologic patterns of myocarditis are summarized in Figure 1.
      Figure thumbnail gr1
      Figure 1Examples of different histologic patterns of vaccine associated myocarditis. (A) Lymphocytic myocarditis, the most common pattern reported in COVID-19 vaccination associated myocarditis, is characterized by a dense mononuclear infiltrate and associated myocyte damage. (B) Healing myocarditis is more typically characterized by a looser and more mixed inflammatory infiltrate and with underlying damage already entering stages of repair (matrix formation). (C) Eosinophilic myocarditis, the pattern typically associated with other vaccinations, is characterized by a patchy infiltrate of eosinophils with relatively little cardiomyocyte damage. All images are hematoxylin and eosin (H&E) stained slides, digital image capture (Leica DM2500 microscope, 200x original magnification with 10x Plan ocular and 20x FluorTar objective, OMAX 18MP camera, Toupview software, post-processing in GNU Image Manipulator Program 2.0), scale bar as indicated (100 μm).
      Potential mechanisms of myocarditis following mRNA vaccination
      A number of possible mechanisms for mRNA-related myocarditis have emerged, Figure 2 (
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Heymans S.
      • Cooper L.T.
      Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms.
      ,
      • Switzer C.
      • Loeb M.
      Evaluating the relationship between myocarditis and mRNA vaccination.
      ,
      • Kadkhoda K.
      Post RNA-based COVID vaccines myocarditis: Proposed mechanisms.
      ). Most focus on humoral (antibody-mediated) immunity, which is in keeping with the increased prevalence of myocarditis following the second dose of COVID-19 vaccines. One hypothesis involves molecular mimicry between the mRNA vaccine-encoded SARS-CoV2 spike glycoprotein and self-antigens in individuals with pre-existing immune dysregulation, leading to polyclonal B cell expansion, immune complex formation, and inflammation. Alternate explanations involve binding of mRNA vaccine encoded viral spike glycoprotein to the surface of cardiomyocytes via angiotensin-converting enzyme 2 (ACE2) receptors or deposited immune complexes, thus directly acting as an antigenic trigger for inflammation. Yet another hypothesis involves production of antibodies targeting the anti-spike protein antibodies (i.e. anti-antibodies), which mimic the spike protein, bind cardiac ACE2 receptors, form immune complexes, and activate the classical complement pathway. Humoral mechanisms, however, fail to explain the case of a 40-year-old man with biopsy-proven lymphocytic myocarditis in the absence of serum SARS-CoV2 neutralizing antibodies six days after receiving a first dose of the Pfizer-BioNTech mRNA COVID-19 vaccine (
      • Ehrlich P.
      • Klingel K.
      • Ohlmann-Knafo S.
      • Huttinger S.
      • Sood N.
      • Pickuth D.
      • et al.
      Biopsy-proven lymphocytic myocarditis following first mRNA COVID-19 vaccination in a 40-year-old male: case report.
      ). Consequently, a subset of post-vaccine myocarditis might be caused by an innate inflammatory response to the mRNA-encoded viral spike glycoprotein. Testosterone could play a role in the inhibition of anti-inflammatory cells or the stimulation of immune responses mediated by Th1-lymphocytes (
      • Lazaros G.
      • Klein A.L.
      • Hatziantoniou S.
      • Tsioufis C.
      • Tsakris A.
      • Anastassopoulou C.
      The Novel Platform of mRNA COVID-19 Vaccines and Myocarditis: Clues into the Potential Underlying Mechanism.
      ).
      Figure thumbnail gr2
      Figure 2Potential Mechanisms of Myocarditis Following COVID-19 mRNA Vaccination. Overview of the potential mechanisms of myocarditis related to mRNA-based COVID-19 vaccination. Th1, helper T-cell; ACE, angiotensin converting enzyme. Created with BioRender.com.
      Two additional mechanisms not described in the literature still warrant consideration. Theoretically, vaccine mRNA can enter circulation, rather than being directly expressed at the injection site, and could become expressed in cardiomyocytes and thus trigger direct cell-mediated responses against spike protein (
      • Rijkers G.T.
      • Weterings N.
      • Obregon-Henao A.
      • Lepolder M.
      • Dutt T.S.
      • van Overveld F.J.
      • et al.
      Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 Vaccines.
      ). In addition, despite chemical modifications and liposome delivery to prevent such, exogenous RNA can trigger the innate immune response, causing activation of the cellular inflammasome and acting as an adjuvant to antigen mediated responses (
      • Milano G.
      • Gal J.
      • Creisson A.
      • Chamorey E.
      Myocarditis and COVID-19 mRNA vaccines: a mechanistic hypothesis involving dsRNA.
      ).

       Role of Cardiac Imaging

      A summary of diagnostic test findings in acute myocarditis is provided in Table 2. Cardiac imaging plays an important role in establishing a diagnosis of myocarditis and pericarditis, excluding other potential causes of symptoms, and risk-stratifying patients.
      Table 2Diagnostic Test Findings in Acute Myocarditis
      TestTypical FindingsStrengthsLimitations
      Cardiac Imaging
      CMR• Typically evaluated using the revised Lake Louise Criteria

      • T2-based criteria for myocardial edema include high native T2 and regional T2-hyperintensity

      • T1-based criteria for myocardial injury include high native T1, high ECV, and non-ischemic pattern LGE

      • +/- Impaired regional and global ventricular function

      • +/- Pericardial effusion, edema and enhancement
      • High diagnostic sensitivity and specificity for acute myocarditis

      • Useful in ruling out other potential diagnoses, such as stress-induced cardiomyopathy

      • Useful in risk-stratification

      • Useful to demonstrate resolution of edema at follow-up
      • Limited availability

      • Relatively long examination time
      Echocardiography• Impaired regional and global ventricular function

      • Pericardial effusion

      • +/- Focal echogenicity

      • +/- Left-ventricular dilatation

      • +/- Impaired strain
      • Widely availability

      • Relatively low cost

      • Relatively short examination time
      • Low sensitivity and specificity for myocarditis

      • Operator dependent
      Cardiac CT• Pericardial effusion or thickening

      • +/- Myocardial wall thickening

      • Late iodine enhancement
      • Useful in ruling out other potential diagnoses that might present similarly, such as stress-induced cardiomyopathy• Exposure to ionizing radiation

      • Low specificity for acute myocarditis
      Cardiac PET• Focal FDG-uptake indicates myocardial inflammation• Metabolic information

      • Potentially useful in monitoring treatment response
      • Limited availability

      • Exposure to ionizing radiation
      Chest Radiography• Possible cardiomegaly

      • Pericardial effusion

      • Pulmonary edema in the setting of heart failure
      • Widely availability

      • Low cost

      • Very short examination time

      • Useful in ruling out other causes of symptoms
      • Finding are not specific for myocarditis
      Other Investigations
      Troponin• Elevated values indicate myocyte injury• Elevated in almost all patients with acute myocarditis

      • Widely available
      • Requires blood draw

      • Not specific for acute myocarditis
      BNP• Elevated values are associated with heart failure• Widely available• Requires blood draw

      • Not specific for acute myocarditis
      ECG• ST-segment and T-wave abnormalities• Widely available

      • Relatively quick

      • Useful in ruling out other potential diagnoses that might present similarly
      • Not specific for acute myocarditis
      Endomyocardial biopsy• Inflammatory infiltrates within the myocardium associated with myocyte damage/necrosis of non-ischaemic origin

      • Newer criteria may utilize immunohistochemical techniques
      • Reference standard for definitive diagnosis of myocarditis

      • High specificity
      • Invasive with risk of complications

      • Low sensitivity for acute myocarditis due to sampling error and patchy disease
      Abbreviations: BNP – Brain Natriuretic Peptide; CMR – Cardiac Magnetic Resonance; CT – Computed Tomography; ECG – Echocardiography; ECV – Extracellular Volume; FDG – Fluorodeoxyglucose; LGE – Late Gadolinium Enhancement; PET – Positron Emission Tomography

       Echocardiography

      Transthoracic echocardiography is often the first cardiac imaging modality performed in the setting of suspected myocarditis, allowing for assessment of cardiac size and function and associated findings including the presence of a pericardial effusion. Although most findings in the setting of myocarditis are not specific, focal echogenicity, particularly in the lateral and inferior wall, and the presence of pericardial effusions have been shown to be sensitive for acute myopericarditis in young adults (
      • Saricam E.
      • Saglam Y.
      • Hazirolan T.
      Clinical evaluation of myocardial involvement in acute myopericarditis in young adults.
      ). Speckle tracking based myocardial strain is also a potentially sensitive method to identify acute myocarditis with echocardiography (
      • Hsiao J.F.
      • Koshino Y.
      • Bonnichsen C.R.
      • Yu Y.
      • Miller Jr., F.A.
      • Pellikka P.A.
      • et al.
      Speckle tracking echocardiography in acute myocarditis.
      ). Impaired ventricular function is a predictor of poor outcomes, and echocardiography is also useful in follow-up to ensure recovery of function (
      • van den Heuvel F.M.A.
      • Vos J.L.
      • van Bakel B.
      • Duijnhouwer A.L.
      • van Dijk A.P.J.
      • Dimitriu-Leen A.C.
      • et al.
      Comparison between myocardial function assessed by echocardiography during hospitalization for COVID-19 and at 4 months follow-up.
      ).

       Cardiac CT

      Cardiac computed tomography (CT) is infrequently used in the evaluation of suspected myocarditis but can be helpful in excluding other potential etiologies of acute chest pain, including obstructive coronary artery disease. In the setting of an inability to perform CMR, late iodine enhancement on CT could be considered, given high sensitivity and positive predictive value for acute myocarditis (
      • Bouleti C.
      • Baudry G.
      • Iung B.
      • Arangalage D.
      • Abtan J.
      • Ducrocq G.
      • et al.
      Usefulness of Late Iodine Enhancement on Spectral CT in Acute Myocarditis.
      ).

       Cardiac PET

      Cardiac fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in the evaluation of cardiac inflammation and is most often used clinically in the setting of cardiac sarcoidosis (
      • Genovesi D.
      • Bauckneht M.
      • Altini C.
      • Popescu C.E.
      • Ferro P.
      • Monaco L.
      • et al.
      The role of positron emission tomography in the assessment of cardiac sarcoidosis.
      ). However, focal cardiac FDG-uptake on PET has also been described in the setting of myocardial inflammation due to other causes including COVID-19 infection (
      • Hanneman K.
      • Houbois C.
      • Schoffel A.
      • Gustafson D.
      • Iwanochko R.M.
      • Wintersperger B.J.
      • et al.
      Combined Cardiac Fluorodeoxyglucose-Positron Emission Tomography/Magnetic Resonance Imaging Assessment of Myocardial Injury in Patients Who Recently Recovered From COVID-19.
      ). Combined cardiac PET/MR adds complementary information and increases the sensitivity for mild or borderline myocarditis compared to CMR, although not widely available (
      • Hanneman K.
      • Houbois C.
      • Schoffel A.
      • Gustafson D.
      • Iwanochko R.M.
      • Wintersperger B.J.
      • et al.
      Combined Cardiac Fluorodeoxyglucose-Positron Emission Tomography/Magnetic Resonance Imaging Assessment of Myocardial Injury in Patients Who Recently Recovered From COVID-19.
      ,
      • Chen W.
      • Jeudy J.
      Assessment of Myocarditis: Cardiac MR, PET/CT, or PET/MR?.
      ,
      • Cheung E.
      • Ahmad S.
      • Aitken M.
      • Chan R.
      • Iwanochko R.M.
      • Balter M.
      • et al.
      Combined simultaneous FDG-PET/MRI with T1 and T2 mapping as an imaging biomarker for the diagnosis and prognosis of suspected cardiac sarcoidosis.
      ,
      • Hanneman K.
      • Kadoch M.
      • Guo H.H.
      • Jamali M.
      • Quon A.
      • Iagaru A.
      • et al.
      Initial Experience With Simultaneous 18F-FDG PET/MRI in the Evaluation of Cardiac Sarcoidosis and Myocarditis.
      ).

       CMR

      CMR is the most important imaging modality for diagnosis of acute myocarditis. The Lake Louise Criteria (LCC) are most commonly used for evaluation of suspected myocarditis on CMR. These criteria were initially established in 2009 and were revised in 2018 to incorporate parametric mapping (
      • Ferreira V.M.
      • Schulz-Menger J.
      • Holmvang G.
      • Kramer C.M.
      • Carbone I.
      • Sechtem U.
      • et al.
      Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations.
      ). The revised criteria indicate a high likelihood of non-ischemic myocardial inflammation when at least one of each of the T1- and T2-based criteria are met. T1-based criteria include increased native T1, increased extracellular volume (ECV), or presence of non-ischemic pattern late gadolinium enhancement (LGE). T2-based criteria include increased native T2, regional T2-hyperintensity, or increased myocardial T2 signal intensity ratio compared to skeletal muscle on T2-weighted imaging. Regional and global left ventricular dysfunction and findings associated with pericarditis (including presence of a pericardial effusion and pericardial enhancement) are supportive criteria but are not required.
      Although the presence of both T1- and T2-based criteria is associated with the highest specificity for active myocardial inflammation, the presence of only one criterion could still be consistent with a diagnosis of myocarditis, particularly if imaging was delayed after symptom onset or performed after immunosuppressive treatment is started (in which case edema might no longer be detectable) (
      • Sanchez Tijmes F.
      • Thavendiranathan P.
      • Udell J.A.
      • Seidman M.A.
      • Hanneman K.
      Cardiac MRI Assessment of Nonischemic Myocardial Inflammation: State of the Art Review and Update on Myocarditis Associated with COVID-19 Vaccination.
      ). Given the importance of establishing a diagnosis of myocarditis, CMR should ideally be performed as soon as possible after the onset of symptoms. This may be particularly relevant in the setting of myocarditis following COVID-19 vaccination given reports of very rapid resolution of symptoms and the potential implications of a diagnosis on recommendations for future vaccination (
      • Sanchez Tijmes F.
      • Thavendiranathan P.
      • Udell J.A.
      • Seidman M.A.
      • Hanneman K.
      Cardiac MRI Assessment of Nonischemic Myocardial Inflammation: State of the Art Review and Update on Myocarditis Associated with COVID-19 Vaccination.
      ).
      In acute myocarditis in general, LGE most commonly occurs in a subepicardial pattern and is often located at the basal inferior lateral wall. Mid-wall and septal patterns of LGE are less common but are associated with a worse prognosis (
      • Grani C.
      • Eichhorn C.
      • Biere L.
      • Murthy V.L.
      • Agarwal V.
      • Kaneko K.
      • et al.
      Prognostic Value of Cardiac Magnetic Resonance Tissue Characterization in Risk Stratifying Patients With Suspected Myocarditis.
      ). Myocardial edema is usually focal, however diffuse changes have also been described (
      • Luetkens J.A.
      • Isaak A.
      • Zimmer S.
      • Nattermann J.
      • Sprinkart A.M.
      • Boesecke C.
      • et al.
      Diffuse Myocardial Inflammation in COVID-19 Associated Myocarditis Detected by Multiparametric Cardiac Magnetic Resonance Imaging.
      ). In the acute setting, LGE co-localizing with edema is often associated with functional recovery as edema improves over time (
      • Aquaro G.D.
      • Ghebru Habtemicael Y.
      • Camastra G.
      • Monti L.
      • Dellegrottaglie S.
      • Moro C.
      • et al.
      Prognostic Value of Repeating Cardiac Magnetic Resonance in Patients With Acute Myocarditis.
      ). However, isolated LGE without edema often reflects fibrosis, which is a risk-marker for major cardiac events including sudden cardiac death and heart failure (
      • Aquaro G.D.
      • Ghebru Habtemicael Y.
      • Camastra G.
      • Monti L.
      • Dellegrottaglie S.
      • Moro C.
      • et al.
      Prognostic Value of Repeating Cardiac Magnetic Resonance in Patients With Acute Myocarditis.
      ). Native T1, T2 and ECV allow for quantification of myocardial tissue changes and are all elevated in the setting of myocardial edema. On the other hand, elevation of T1 and ECV in the setting of normal T2 values are suggestive of healed myocarditis with fibrosis but no active edema (
      • Sanchez Tijmes F.
      • Thavendiranathan P.
      • Udell J.A.
      • Seidman M.A.
      • Hanneman K.
      Cardiac MRI Assessment of Nonischemic Myocardial Inflammation: State of the Art Review and Update on Myocarditis Associated with COVID-19 Vaccination.
      ).
      The pattern of CMR findings in myocarditis following COVID-19 vaccination is similar to myocarditis due to other causes, although the extent and severity of abnormalities tends to be milder (
      • Sanchez Tijmes F.
      • Thavendiranathan P.
      • Udell J.A.
      • Seidman M.A.
      • Hanneman K.
      Cardiac MRI Assessment of Nonischemic Myocardial Inflammation: State of the Art Review and Update on Myocarditis Associated with COVID-19 Vaccination.
      ). Typical findings in the acute phase include subepicardial LGE and co-localizing edema at the basal to mid inferolateral wall, Figure 3. Compared with other causes of myocarditis, patients with vaccine associated myocarditis have higher left ventricular ejection fraction, less extensive LGE, and less frequent involvement of the septum (
      • Fronza M.T.
      • Thavendiranathan P.
      • Chan V.
      • Rani Karur G.
      • Udell J.
      • Wald R.
      • Hong R.
      • Hanneman K.
      Myocardial injury pattern by MRI in COVID-19 Vaccine Associated Myocarditis.
      ).
      Figure thumbnail gr3
      Figure 3COVID-19 vaccine associated myocarditis. Short-axis 1.5 T MRI images of a young adult man with myocarditis following mRNA COVID-19 vaccine administration demonstrating (A) subepicardial late gadolinium enhancement (LGE) at the basal to mid inferior lateral wall (red arrows), with corresponding (B) hyperintensity on T2-weighted imaging (orange arrows), (C) abnormal high native T1 (1274 ms, maximum region of interest), and (D) abnormal high native T2 (65 ms, maximum region of interest).
      Follow-up CMR is often performed 3-6 months after acute myocarditis to evaluate for recovery of left ventricular function, resolution of edema, and any residual scarring, although there are no established guidelines defining the optimal timing of follow-up imaging (
      • Tschope C.
      • Ammirati E.
      • Bozkurt B.
      • Caforio A.L.P.
      • Cooper L.T.
      • Felix S.B.
      • et al.
      Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.
      ). There is limited follow-up CMR data in myocarditis following vaccination (
      • Fronza M.
      • Thavendiranathan P.
      • Karur G.R.
      • Abdel-Qadir H.
      • Udell J.A.
      • Wald R.M.
      • Hanneman K.
      Cardiac MRI and Clinical Follow-Up in COVID-19 Vaccine Associated Myocarditis.
      ,

      Schauer J, Buddhe S, Gulhane A, Sagiv E, Studer M, Colyer J, et al. Persistent Cardiac MRI Findings in a Cohort of Adolescents with post COVID-19 mRNA vaccine myopericarditis. J Pediatr. 2022. Mar 26;S0022-3476(22)00282-7. doi: 10.1016/j.jpeds.2022.03.032.

      ,
      • Rosner C.M.
      • Atkins M.
      • Saeed I.M.
      • de Lemos J.A.
      • Khera A.
      • Maghsoudi A.
      • et al.
      Patients With Myocarditis Associated With COVID-19 Vaccination.
      ,
      • Cavalcante J.L.
      • Shaw K.E.
      • Gossl M.
      Cardiac Magnetic Resonance Imaging Midterm Follow Up of COVID-19 Vaccine–Associated Myocarditis.
      ). In a case series of 13 adults with acute myocarditis following COVID-19 vaccination, intermediate term follow-up CMR at a median of 5 months demonstrated resolution of myocardial edema, normalization of left ventricular function and interval decrease in LGE extent, Figure 4 (
      • Fronza M.
      • Thavendiranathan P.
      • Karur G.R.
      • Abdel-Qadir H.
      • Udell J.A.
      • Wald R.M.
      • Hanneman K.
      Cardiac MRI and Clinical Follow-Up in COVID-19 Vaccine Associated Myocarditis.
      ). However, minimal residual LGE without edema was present in 8/13 patients at follow-up, likely reflecting myocardial fibrosis. Similarly, in a case series of 16 pediatric patients with myocarditis following COVID-19 vaccination, follow-up CMR at a median of 3 months demonstrated normalization of LVEF and interval decrease in LGE extent (

      Schauer J, Buddhe S, Gulhane A, Sagiv E, Studer M, Colyer J, et al. Persistent Cardiac MRI Findings in a Cohort of Adolescents with post COVID-19 mRNA vaccine myopericarditis. J Pediatr. 2022. Mar 26;S0022-3476(22)00282-7. doi: 10.1016/j.jpeds.2022.03.032.

      ). However, minimal LGE persisted in 11/16 and global longitudinal strain remained impaired in 12/16. Longer-term follow-up in larger cohorts of patients is needed to understand the sequelae of myocarditis following vaccination and the ability of imaging abnormalities to identify patients who are at risk of adverse cardiac events.
      Figure thumbnail gr4
      Figure 4Baseline and Follow-up CMR in COVID-19 vaccine associated myocarditis. Short-axis cardiac MRI images in a young adult man with myocarditis following the second dose of mRNA-1273. Baseline MRI at 1.5T demonstrates subepicardial late gadolinium enhancement (LGE) at the basal inferior and inferolateral wall (red arrows) with corresponding high T2-signal in keeping with edema (yellow arrows), high regional native T1 (green arrows) and high regional T2 (blue arrows). Follow-up cardiac MRI performed 4 months later at 3T demonstrates interval decrease in LGE extent (orange arrow) with resolution of edema and normalization of T1 and T2 values.

       Other Investigations

      Other diagnostic investigations used frequently in the setting of myocarditis and pericarditis include electrocardiography (ECG) and assessment of cardiac blood biomarkers. ECG findings in myocarditis are non-specific but can include ST-segment elevation, T-wave inversions, and ectopic beats (
      • Halsell J.S.
      • Riddle J.R.
      • Atwood J.E.
      • Gardner P.
      • Shope R.
      • Poland G.A.
      • et al.
      Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel.
      ,
      • Das B.B.
      • Moskowitz W.B.
      • Taylor M.B.
      • Palmer A.
      Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination: What Do We Know So Far?.
      ,
      • Kindermann I.
      • Barth C.
      • Mahfoud F.
      • Ukena C.
      • Lenski M.
      • Yilmaz A.
      • et al.
      Update on myocarditis.
      ). While these findings have low sensitivity for myocarditis, ECG is frequently used in patients with suspected myocarditis to evaluate for alternative causes of cardiac symptoms (
      • Kindermann I.
      • Barth C.
      • Mahfoud F.
      • Ukena C.
      • Lenski M.
      • Yilmaz A.
      • et al.
      Update on myocarditis.
      ). In the setting of pericarditis, typical ECG changes include concave upward ST-segment elevation, upright T waves in the leads with ST-segment elevation, and PR depression. ECG findings in the setting of myocarditis and pericarditis following COVID-19 vaccination are similar to other causes (
      • Montgomery J.
      • Ryan M.
      • Engler R.
      • Hoffman D.
      • McClenathan B.
      • Collins L.
      • et al.
      Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.
      ,
      • Kindermann I.
      • Barth C.
      • Mahfoud F.
      • Ukena C.
      • Lenski M.
      • Yilmaz A.
      • et al.
      Update on myocarditis.
      ).
      Although not specific to myocarditis, elevated troponin levels, indicating myocyte injury, are almost always present in the setting of acute myocarditis (
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Montgomery J.
      • Ryan M.
      • Engler R.
      • Hoffman D.
      • McClenathan B.
      • Collins L.
      • et al.
      Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.
      ,
      • Engler R.J.
      • Nelson M.R.
      • Collins Jr., L.C.
      • Spooner C.
      • Hemann B.A.
      • Gibbs B.T.
      • et al.
      A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination.
      ,
      • Shaw K.E.
      • Cavalcante J.L.
      • Han B.K.
      • Gossl M.
      Possible Association Between COVID-19 Vaccine and Myocarditis: Clinical and CMR Findings.
      ). The degree of troponin elevation varies and is dependent on the severity of myocardial injury and timing of evaluation in relation to symptom onset. Elevated brain natriuretic peptide (BNP) levels indicate increased ventricular stretch and are elevated in the setting of heart failure. BNP is often assessed in patients with suspected myocarditis when heart failure symptoms are present. However, elevations of BNP are not included in the CDC working case definitions of probable or confirmed acute myocarditis, and values are not consistently evaluated or reported. Other testing, such as acute and convalescent viral testing (e.g. SARS-CoV-2, coxsackievirus, etc.), should be considered when clinically appropriate to exclude other potential causes of myocarditis.

       Management

      Currently, there are no specific management recommendations for myocarditis following COVID-19 vaccination. Care is largely supportive following guidelines for myocarditis due to other causes (
      • Luk A.
      • Clarke B.
      • Dahdah N.
      • Ducharme A.
      • Krahn A.
      • McCrindle B.
      • et al.
      Myocarditis and Pericarditis After COVID-19 mRNA Vaccination: Practical Considerations for Care Providers.
      ). Treatment is typically focused on addressing potential sequelae such as heart failure or arrhythmia as per guideline-directed medical therapy. For patients with very mild symptoms with rapid improvement, therapy can often be deferred.
      Individuals are typically safe to return to their normal daily activities after their symptoms improve. However, the optimal duration of exercise restriction is unknown. The American Heart Association and American College of Cardiology Foundation have recommended 3-6 months of restriction from competitive sports following myocarditis. Repeat evaluation of serum biomarkers, 24-hour Holter monitor, and echocardiography are recommended prior to return to exercise in order to ensure normal ventricular function, resolution of active inflammation, and absence of arrhythmias (72).
      Although there is no clear evidence on risk associated with subsequent vaccination, current guidelines suggest that further doses of mRNA COVID-19 vaccines should be deferred among individuals who experienced myocarditis within 6 weeks of receiving a previous dose of an mRNA COVID-19 vaccine (

      Summary of NACI advice on vaccination with COVID-19 vaccines following myocarditis (with or without pericarditis) [cited 2022 January 28]. Available from: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/summary-advice-vaccination-covid-19-vaccines-following-myocarditis-with-without-pericarditis.html.

      ).

       Clinical Course and Adverse Outcomes

      Myocarditis following COVID-19 vaccination is typically associated with a transient, mild course, with complete resolution of symptoms within 1-3 weeks in the vast majority of patients (
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Montgomery J.
      • Ryan M.
      • Engler R.
      • Hoffman D.
      • McClenathan B.
      • Collins L.
      • et al.
      Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.
      ,
      • Engler R.J.
      • Nelson M.R.
      • Collins Jr., L.C.
      • Spooner C.
      • Hemann B.A.
      • Gibbs B.T.
      • et al.
      A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination.
      ,
      • Das B.B.
      • Moskowitz W.B.
      • Taylor M.B.
      • Palmer A.
      Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination: What Do We Know So Far?.
      ). Patients with more severe disease with ventricular dysfunction might require hospitalization, although most reports indicate that patients who do require hospitalization typically require a short stay of less than 5 days (
      • Montgomery J.
      • Ryan M.
      • Engler R.
      • Hoffman D.
      • McClenathan B.
      • Collins L.
      • et al.
      Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.
      ,
      • Das B.B.
      • Moskowitz W.B.
      • Taylor M.B.
      • Palmer A.
      Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination: What Do We Know So Far?.
      ). Patients rarely require intensive care unit admission or re-admission following hospital discharge (
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • et al.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ).
      Although most patients with myocarditis after COVID-19 vaccination have a mild course, there are limited long-term follow-up data given the relatively recent introduction of these vaccines. Improvement or normalization of ejection fraction and resolution of symptoms in nearly all patients with myocarditis following COVID-19 vaccination has been demonstrated at short-interval follow-up (
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • et al.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ). Limited intermediate term (∼5-6 months) follow-up data has demonstrated normalization of troponin levels, no residual cardiac symptoms or functional impairment, and no adverse cardiac events (
      • Fronza M.
      • Thavendiranathan P.
      • Karur G.R.
      • Abdel-Qadir H.
      • Udell J.A.
      • Wald R.M.
      • Hanneman K.
      Cardiac MRI and Clinical Follow-Up in COVID-19 Vaccine Associated Myocarditis.
      ,
      • Rosner C.M.
      • Atkins M.
      • Saeed I.M.
      • de Lemos J.A.
      • Khera A.
      • Maghsoudi A.
      • et al.
      Patients With Myocarditis Associated With COVID-19 Vaccination.
      ). Although these data are reassuring, further studies with long-term clinical and imaging follow-up are needed. Additional study is also needed to determine the risk with subsequent vaccine doses and other potential risk factors including prior history of myocarditis.

      Summary

      Myocarditis is an established but rare adverse event following administration of mRNA-based COVID-19 vaccines, most commonly diagnosed in male adolescents and young adults. Symptoms typically develop within a few days of vaccine administration. Most patients have mild abnormalities on cardiac imaging with rapid clinical improvement with standard treatment, which is reassuring. However, longer term follow-up is needed to determine whether imaging abnormalities persist, to evaluate for adverse outcomes, and to understand the risk associated with subsequent vaccination.

      Clinics Care Points

      • Myocarditis following mRNA-based COVID-19 vaccines is rare; however, adolescent and young adult males are at highest risk.
      • Chest pain is the most common symptom, with typical onset within a few days of vaccine administration.
      • CMR plays an important role in the diagnosis of acute myocarditis following vaccination, with typical findings of subepicardial late gadolinium enhancement and co-localizing edema at the basal inferior lateral wall.
      • The disease course of myocarditis following COVID-19 vaccination is typically transient and mild, with resolution of symptoms within 1-3 weeks in most patients.
      • However, longer term follow-up is needed to determine whether imaging abnormalities persist, to evaluate for adverse outcomes, and to understand the risk associated with subsequent vaccination.

      Uncited reference

      • Maron B.J.
      • Udelson J.E.
      • Bonow R.O.
      • Nishimura R.A.
      • Ackerman M.J.
      • Estes 3rd, N.A.
      • et al.
      Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology.
      .

      References

        • Hanneman K.
        • Iwanochko R.M.
        • Thavendiranathan P.
        Evolution of Lymphadenopathy at PET/MRI after COVID-19 Vaccination.
        Radiology. 2021; 299: E282
        • See I.
        • Su J.R.
        • Lale A.
        • Woo E.J.
        • Guh A.Y.
        • Shimabukuro T.T.
        • et al.
        US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021.
        JAMA. 2021; 325: 2448-2456
        • Bozkurt B.
        • Kamat I.
        • Hotez P.J.
        Myocarditis With COVID-19 mRNA Vaccines.
        Circulation. 2021; 144: 471-484
        • Sanchez Tijmes F.
        • Thavendiranathan P.
        • Udell J.A.
        • Seidman M.A.
        • Hanneman K.
        Cardiac MRI Assessment of Nonischemic Myocardial Inflammation: State of the Art Review and Update on Myocarditis Associated with COVID-19 Vaccination.
        Radiol Cardiothorac Imaging. 2021; 3e210252
        • Caforio A.L.
        • Pankuweit S.
        • Arbustini E.
        • Basso C.
        • Gimeno-Blanes J.
        • Felix S.B.
        • 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 (48a-48d): 2636-2648
        • Su J.R.
        • McNeil M.M.
        • Welsh K.J.
        • Marquez P.L.
        • Ng C.
        • Yan M.
        • et al.
        Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018.
        Vaccine. 2021; 39: 839-845
        • Husby A.
        • Hansen J.V.
        • Fosbol E.
        • Thiesson E.M.
        • Madsen M.
        • Thomsen R.W.
        • et al.
        SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study.
        BMJ. 2021; 375e068665
        • Mevorach D.
        • Anis E.
        • Cedar N.
        • Bromberg M.
        • Haas E.J.
        • Nadir E.
        • et al.
        Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.
        N Engl J Med. 2021; 385: 2140-2149
        • Patone M.
        • Mei X.W.
        • Handunnetthi L.
        • Dixon S.
        • Zaccardi F.
        • Shankar-Hari M.
        • et al.
        Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection.
        Nat Med. 2021;
        • Perez Y.
        • Levy E.R.
        • Joshi A.Y.
        • Virk A.
        • Rodriguez-Porcel M.
        • Johnson M.
        • et al.
        Myocarditis Following COVID-19 mRNA Vaccine: A Case Series and Incidence Rate Determination.
        Clin Infect Dis. 2021; (doi.org/10.1093/cid/ciab926)
      1. United States Department of Health and Human Services (DHHS), Public Health Service (PHS), Centers for Disease Control (CDC) / Food and Drug Administration (FDA), Vaccine Adverse Event Reporting System (VAERS) 1990 - 01/07/2022, CDC WONDER On-line Database [cited 2022 January 16]. Available from: http://wonder.cdc.gov/vaers.

        • Simone A.
        • Herald J.
        • Chen A.
        • Gulati N.
        • Shen A.Y.
        • Lewin B.
        • et al.
        Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
        JAMA Intern Med. 2021; 181: 1668-1670
        • Witberg G.
        • Barda N.
        • Hoss S.
        • Richter I.
        • Wiessman M.
        • Aviv Y.
        • et al.
        Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.
        N Engl J Med. 2021; 385: 2132-2139
      2. Ling RR, Ramanathan K, Tan FL, Tai BC, Somani J, Fisher D, MacLaren G. Myopericarditis following COVID-19 vaccination and non- COVID-19 vaccination: a systematic review and meta-analysis. Lancet Respir Med 2022. Apr 11:S2213-2600(22)00059-5. doi: 10.1016/S2213-2600(22)00059-5.

        • Hajjo R.
        • Sabbah D.A.
        • Bardaweel S.K.
        • Tropsha A.
        Shedding the Light on Post-Vaccine Myocarditis and Pericarditis in COVID-19 and Non-COVID-19 Vaccine Recipients.
        Vaccines. 2021; 9
        • Oster M.E.
        • Shay D.K.
        • Su J.R.
        • Gee J.
        • Creech C.B.
        • Broder K.R.
        • et al.
        Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021.
        JAMA. 2022; 327: 331-340
        • Gargano J.W.
        • Wallace M.
        • Hadler S.C.
        • Langley G.
        • Su J.R.
        • Oster M.E.
        • et al.
        Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021.
        MMWR Morb Mortal Wkly Rep. 2021; 70: 977-982
      3. Su JR. COVID-19 vaccine safety updates: Primary series in children and adolescents ages 5–11 and 12–15 years, and booster doses in adolescents ages 16–24 years 2022 [cited 2022 January 20]. Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-01-05/02-covid-su-508.pdf.

        • Montgomery J.
        • Ryan M.
        • Engler R.
        • Hoffman D.
        • McClenathan B.
        • Collins L.
        • et al.
        Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.
        JAMA Cardiol. 2021; 6: 1202-1206
        • Aviram G.
        • Viskin D.
        • Topilsky Y.
        • Sadon S.
        • Shalmon T.
        • Taieb P.
        • et al.
        Myocarditis Associated With COVID-19 Booster Vaccination.
        Circ Cardiovasc Imaging. 2022; 15e013771
        • Sanchez Tijmes F.
        • Zamorano A.
        • Thavendiranathan P.
        • Hanneman K.
        Imaging of Myocarditis Following mRNA COVID-19 Booster Vaccination.
        Radiology: Cardiothoracic Imaging. 2022; 4 (doi.org/10.1148/ryct.220019)e220019
        • Friedensohn L.
        • Levin D.
        • Fadlon-Derai M.
        • Gershovitz L.
        • Fink N.
        • Glassberg E.
        • et al.
        Myocarditis Following a Third BNT162b2 Vaccination Dose in Military Recruits in Israel.
        JAMA. 2022 Mar 17; e224425https://doi.org/10.1001/jama.2022.4425
        • Buchan S.A.
        • Seo C.Y.
        • Johnson C.
        • Alley S.
        • Kwong J.C.
        • Nasreen S.
        • et al.
        Epidemiology of myocarditis and pericarditis following mRNA vaccines in Ontario, Canada: by vaccine product, schedule and interval.
        medRxiv. 2021; (12.02.21267156): 2021
        • Minocha P.K.
        • Better D.
        • Singh R.K.
        • Hoque T.
        Recurrence of Acute Myocarditis Temporally Associated with Receipt of the mRNA Coronavirus Disease 2019 (COVID-19) Vaccine in a Male Adolescent.
        J Pediatr. 2021; 238: 321-323
        • Umei T.C.
        • Kishino Y.
        • Shiraishi Y.
        • Inohara T.
        • Yuasa S.
        • Fukuda K.
        Recurrence of myopericarditis following mRNA COVID-19 vaccination in a male adolescent.
        CJC Open. 2022 Mar; 4: 350-352https://doi.org/10.1016/j.cjco.2021.12.002
      4. Summary of NACI advice on vaccination with COVID-19 vaccines following myocarditis (with or without pericarditis) [cited 2022 January 28]. Available from: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/summary-advice-vaccination-covid-19-vaccines-following-myocarditis-with-without-pericarditis.html.

        • Guo T.
        • Fan Y.
        • Chen M.
        • Wu X.
        • Zhang L.
        • He T.
        • et al.
        Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19).
        JAMA Cardiol. 2020; 5: 811-818
        • Barda N.
        • Dagan N.
        • Ben-Shlomo Y.
        • Kepten E.
        • Waxman J.
        • Ohana R.
        • et al.
        Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.
        N Engl J Med. 2021; 385: 1078-1090
        • Fronza M.T.
        • Thavendiranathan P.
        • Chan V.
        • Rani Karur G.
        • Udell J.
        • Wald R.
        • Hong R.
        • Hanneman K.
        Myocardial injury pattern by MRI in COVID-19 Vaccine Associated Myocarditis.
        Radiology. 2022 Feb 15; : 212559https://doi.org/10.1148/radiol.212559
        • Engler R.J.
        • Nelson M.R.
        • Collins Jr., L.C.
        • Spooner C.
        • Hemann B.A.
        • Gibbs B.T.
        • et al.
        A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination.
        PLoS One. 2015; 10e0118283
        • Halsell J.S.
        • Riddle J.R.
        • Atwood J.E.
        • Gardner P.
        • Shope R.
        • Poland G.A.
        • et al.
        Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel.
        JAMA. 2003; 289: 3283-3289
        • Mei R.
        • Raschi E.
        • Forcesi E.
        • Diemberger I.
        • De Ponti F.
        • Poluzzi E.
        Myocarditis and pericarditis after immunization: Gaining insights through the Vaccine Adverse Event Reporting System.
        Int J Cardiol. 2018; 273: 183-186
        • Heymans S.
        • Cooper L.T.
        Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms.
        Nat Rev Cardiol. 2022; 19 (doi.org/10.1038/s41569-021-00662-w): 75077
        • Das B.B.
        • Moskowitz W.B.
        • Taylor M.B.
        • Palmer A.
        Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination: What Do We Know So Far?.
        Children (Basel). 2021; 8: 607
        • Matta A.
        • Kunadharaju R.
        • Osman M.
        • Jesme C.
        • McMiller Z.
        • Johnson E.M.
        • et al.
        Clinical Presentation and Outcomes of Myocarditis Post mRNA Vaccination: A Meta-Analysis and Systematic Review.
        Cureus. 2021; 13e19240
        • Leone O.
        • Veinot J.P.
        • Angelini A.
        • Baandrup U.T.
        • Basso C.
        • Berry G.
        • et al.
        consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology.
        Cardiovasc Pathol. 2012. 2011; 21: 245-274
        • Baughman K.L.
        Diagnosis of myocarditis: death of Dallas criteria.
        Circulation. 2006; 113: 593-595
        • Chow L.H.
        • Radio S.J.
        • Sears T.D.
        • McManus B.M.
        Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis.
        J Am Coll Cardiol. 1989; 14: 915-920
        • Luk A.
        • Clarke B.
        • Dahdah N.
        • Ducharme A.
        • Krahn A.
        • McCrindle B.
        • et al.
        Myocarditis and Pericarditis After COVID-19 mRNA Vaccination: Practical Considerations for Care Providers.
        Can J Cardiol. 2021; 37: 1629-1634
        • Rali A.S.
        • Ranka S.
        • Shah Z.
        • Sauer A.J.
        Mechanisms of Myocardial Injury in Coronavirus Disease 2019.
        Card Fail Rev. 2020; 6: e15
        • Switzer C.
        • Loeb M.
        Evaluating the relationship between myocarditis and mRNA vaccination.
        Expert Rev Vaccines. 2022; 21: 83-89
        • Ehrlich P.
        • Klingel K.
        • Ohlmann-Knafo S.
        • Huttinger S.
        • Sood N.
        • Pickuth D.
        • et al.
        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
        • Jain S.S.
        • Steele J.M.
        • Fonseca B.
        • Huang S.
        • Shah S.
        • Maskatia S.A.
        • et al.
        COVID-19 Vaccination-Associated Myocarditis in Adolescents.
        Pediatrics. 2021; 148
        • Abbate A.
        • Gavin J.
        • Madanchi N.
        • Kim C.
        • Shah P.R.
        • Klein K.
        • et al.
        Fulminant myocarditis and systemic hyperinflammation temporally associated with BNT162b2 mRNA COVID-19 vaccination in two patients.
        Int J Cardiol. 2021; 340: 119-121
        • Lim Y.
        • Kim M.C.
        • Kim K.H.
        • Jeong I.S.
        • Cho Y.S.
        • Choi Y.D.
        • et al.
        Case Report: Acute Fulminant Myocarditis and Cardiogenic Shock After Messenger RNA Coronavirus Disease 2019 Vaccination Requiring Extracorporeal Cardiopulmonary Resuscitation.
        Front Cardiovasc Med. 2021; 8: 758996
        • Verma A.K.
        • Lavine K.J.
        • Lin C.Y.
        Myocarditis after Covid-19 mRNA Vaccination.
        N Engl J Med. 2021; 385: 1332-1334
        • Ameratunga R.
        • Woon S.T.
        • Sheppard M.N.
        • Garland J.
        • Ondruschka B.
        • Wong C.X.
        • et al.
        First Identified Case of Fatal Fulminant Necrotizing Eosinophilic Myocarditis Following the Initial Dose of the Pfizer-BioNTech mRNA COVID-19 Vaccine (BNT162b2, Comirnaty): an Extremely Rare Idiosyncratic Hypersensitivity Reaction.
        J Clin Immunol. 2022 Jan 3; : 1-7https://doi.org/10.1007/s10875-021-01187-0
        • Kadkhoda K.
        Post RNA-based COVID vaccines myocarditis: Proposed mechanisms.
        Vaccine. 2022; 40: 406-407
        • Lazaros G.
        • Klein A.L.
        • Hatziantoniou S.
        • Tsioufis C.
        • Tsakris A.
        • Anastassopoulou C.
        The Novel Platform of mRNA COVID-19 Vaccines and Myocarditis: Clues into the Potential Underlying Mechanism.
        Vaccine. 2021; 39: 4925-4927
        • Rijkers G.T.
        • Weterings N.
        • Obregon-Henao A.
        • Lepolder M.
        • Dutt T.S.
        • van Overveld F.J.
        • et al.
        Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 Vaccines.
        Vaccines (Basel). 2021; 9
        • Milano G.
        • Gal J.
        • Creisson A.
        • Chamorey E.
        Myocarditis and COVID-19 mRNA vaccines: a mechanistic hypothesis involving dsRNA.
        Future Virol. 2022; 17: 191-196
        • Saricam E.
        • Saglam Y.
        • Hazirolan T.
        Clinical evaluation of myocardial involvement in acute myopericarditis in young adults.
        BMC Cardiovasc Disord. 2017; 17: 129
        • Hsiao J.F.
        • Koshino Y.
        • Bonnichsen C.R.
        • Yu Y.
        • Miller Jr., F.A.
        • Pellikka P.A.
        • et al.
        Speckle tracking echocardiography in acute myocarditis.
        Int J Cardiovasc Imaging. 2013; 29: 275-284
        • van den Heuvel F.M.A.
        • Vos J.L.
        • van Bakel B.
        • Duijnhouwer A.L.
        • van Dijk A.P.J.
        • Dimitriu-Leen A.C.
        • et al.
        Comparison between myocardial function assessed by echocardiography during hospitalization for COVID-19 and at 4 months follow-up.
        Int J Cardiovasc Imaging. 2021; 37: 3459-3467
        • Bouleti C.
        • Baudry G.
        • Iung B.
        • Arangalage D.
        • Abtan J.
        • Ducrocq G.
        • et al.
        Usefulness of Late Iodine Enhancement on Spectral CT in Acute Myocarditis.
        JACC Cardiovasc Imaging. 2017; 10: 826-827
        • Genovesi D.
        • Bauckneht M.
        • Altini C.
        • Popescu C.E.
        • Ferro P.
        • Monaco L.
        • et al.
        The role of positron emission tomography in the assessment of cardiac sarcoidosis.
        Br J Radiol. 2019; 92: 20190247
        • Hanneman K.
        • Houbois C.
        • Schoffel A.
        • Gustafson D.
        • Iwanochko R.M.
        • Wintersperger B.J.
        • et al.
        Combined Cardiac Fluorodeoxyglucose-Positron Emission Tomography/Magnetic Resonance Imaging Assessment of Myocardial Injury in Patients Who Recently Recovered From COVID-19.
        JAMA Cardiol. 2022; 7 (Mar 1): 298-308https://doi.org/10.1001/jamacardio.2021.5505
        • Chen W.
        • Jeudy J.
        Assessment of Myocarditis: Cardiac MR, PET/CT, or PET/MR?.
        Curr Cardiol Rep. 2019; 21: 76
        • Cheung E.
        • Ahmad S.
        • Aitken M.
        • Chan R.
        • Iwanochko R.M.
        • Balter M.
        • et al.
        Combined simultaneous FDG-PET/MRI with T1 and T2 mapping as an imaging biomarker for the diagnosis and prognosis of suspected cardiac sarcoidosis.
        Eur J Hybrid Imaging. 2021; 5: 24
        • Hanneman K.
        • Kadoch M.
        • Guo H.H.
        • Jamali M.
        • Quon A.
        • Iagaru A.
        • et al.
        Initial Experience With Simultaneous 18F-FDG PET/MRI in the Evaluation of Cardiac Sarcoidosis and Myocarditis.
        Clin Nucl Med. 2017; 42: e328-e334
        • Ferreira V.M.
        • Schulz-Menger J.
        • Holmvang G.
        • Kramer C.M.
        • Carbone I.
        • Sechtem U.
        • et al.
        Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations.
        J Am Coll Cardiol. 2018; 72: 3158-3176
        • Grani C.
        • Eichhorn C.
        • Biere L.
        • Murthy V.L.
        • Agarwal V.
        • Kaneko K.
        • et al.
        Prognostic Value of Cardiac Magnetic Resonance Tissue Characterization in Risk Stratifying Patients With Suspected Myocarditis.
        J Am Coll Cardiol. 2017; 70: 1964-1976
        • Luetkens J.A.
        • Isaak A.
        • Zimmer S.
        • Nattermann J.
        • Sprinkart A.M.
        • Boesecke C.
        • et al.
        Diffuse Myocardial Inflammation in COVID-19 Associated Myocarditis Detected by Multiparametric Cardiac Magnetic Resonance Imaging.
        Circ Cardiovasc Imaging. 2020; 13e010897
        • Aquaro G.D.
        • Ghebru Habtemicael Y.
        • Camastra G.
        • Monti L.
        • Dellegrottaglie S.
        • Moro C.
        • et al.
        Prognostic Value of Repeating Cardiac Magnetic Resonance in Patients With Acute Myocarditis.
        J Am Coll Cardiol. 2019; 74: 2439-2448
        • Tschope C.
        • Ammirati E.
        • Bozkurt B.
        • Caforio A.L.P.
        • Cooper L.T.
        • Felix S.B.
        • et al.
        Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.
        Nat Rev Cardiol. 2021; 18: 169-193
        • Fronza M.
        • Thavendiranathan P.
        • Karur G.R.
        • Abdel-Qadir H.
        • Udell J.A.
        • Wald R.M.
        • Hanneman K.
        Cardiac MRI and Clinical Follow-Up in COVID-19 Vaccine Associated Myocarditis.
        Radiology. 2022; ([Accepted, in press])
      5. Schauer J, Buddhe S, Gulhane A, Sagiv E, Studer M, Colyer J, et al. Persistent Cardiac MRI Findings in a Cohort of Adolescents with post COVID-19 mRNA vaccine myopericarditis. J Pediatr. 2022. Mar 26;S0022-3476(22)00282-7. doi: 10.1016/j.jpeds.2022.03.032.

        • Rosner C.M.
        • Atkins M.
        • Saeed I.M.
        • de Lemos J.A.
        • Khera A.
        • Maghsoudi A.
        • et al.
        Patients With Myocarditis Associated With COVID-19 Vaccination.
        J Am Coll Cardiol. 2022; 79: 1317-1319
        • Cavalcante J.L.
        • Shaw K.E.
        • Gossl M.
        Cardiac Magnetic Resonance Imaging Midterm Follow Up of COVID-19 Vaccine–Associated Myocarditis.
        JACC Cardiovascular Imaging. 2022; (Mar 16): 2022https://doi.org/10.1016/j.jcmg.2022.01.008
        • Kindermann I.
        • Barth C.
        • Mahfoud F.
        • Ukena C.
        • Lenski M.
        • Yilmaz A.
        • et al.
        Update on myocarditis.
        J Am Coll Cardiol. 2012; 59: 779-792
        • Shaw K.E.
        • Cavalcante J.L.
        • Han B.K.
        • Gossl M.
        Possible Association Between COVID-19 Vaccine and Myocarditis: Clinical and CMR Findings.
        JACC Cardiovasc Imaging. 2021; 14: 1856-1861
        • Maron B.J.
        • Udelson J.E.
        • Bonow R.O.
        • Nishimura R.A.
        • Ackerman M.J.
        • Estes 3rd, N.A.
        • et al.
        Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology.
        Circulation. 2015; 132: e273-e280