RESEARCH LETTER Myocarditis Temporally Associated With COVID-19 Vaccination Carolyn M. Rosner, MSN, NP-C, MBA; Leonard Genovese , MD; Behnam N. Tehrani, MD; Melany Atkins, MD, MRMD; Hooman Bakhshi, MD; Saquib Chaudhri, MD, MBA; Abdulla A. Damluji, MD, PhD, MPH; James A. de Lemos, MD; Shashank S. Desai, MD, MBA; Abbas Emaminia, MD; Michael Casey Flanagan , MD; Amit Khera, MD; Alireza Maghsoudi Matthew W. Sherwood , MD; Shashank S. Sinha, MD, MSc; Christopher M. O’Connor, MD; Christopher R. deFilippi , MD; Girum Mekonnen, MD, MPH; Alagarraju Muthukumar, MD; Ibrahim M. Saeed , MD; , MD The global coronavirus disease 2019 (COVID-19) pandemic brought significant mortality with more than 3 million deaths worldwide since January 2020.1 Concerted efforts focused on the time-sensitive develop- ment of vaccines yielded 3 COVID-19 vaccines receiving provisional US Food and Drug Administration approval: Pfizer-BioNTech COVID-19 (BNT162b2; Pfizer, Inc; Phil- adelphia, PA), Moderna (mRNA-1273; ModernaTX, Inc; Cambridge, MA), and Janssen (Ad.26.COV2.S; Johnson and Johnson; New Brunswick, NJ).1 All vaccines dem- onstrated excellent safety and clinical efficacy profiles in clinical trials. As of June 5, 2021, more than 170 million individuals in the United States and 894 million individuals worldwide had received at least 1 dose of a COVID-19 vac- cine. Notwithstanding isolated rare serious adverse events, they have been well tolerated and associated with decreas- ing burden of disease in areas with high vaccination rates.2 Myopericarditis has been reported as a rare vaccination complication.3 We present a case series of 7 patients hos- pitalized for acute myocarditis-like illness after COVID-19 vaccination, from 2 US medical centers in Falls Church, VA, and Dallas, TX. All were men <40 years of age and of White or Hispanic race/ethnicity (Table). Only 1 patient reported previous history of COVID-19 infection. Six patients received an mRNA vaccine (Moderna or Pfizer/BioNTech), and 1 received the adenovirus vaccine (Johnson and John- son). All patients presented 3 to 7 days after vaccination with acute onset chest pain and biochemical evidence of myocardial injury, by cTnI ([cardiac troponin I]; Abbott Diag- nostics, Lake Forest, IL) (mean peak, 15.77 ng/mL; median peak, 12.01 ng/mL) or elevated high-sensitivity cTnI (Abbott Diagnostics) (peak, 7000 ng/L). All were hemodynamically stable and none had a pericardial friction rub or rash. ECG patterns varied from normal to ST segment elevation. Three patients underwent invasive coronary angiography, and none had evidence of obstructive coronary artery disease. Echocardiograms showed left ventricular ejection fraction ranging from 35% to 62%, with 5 of 7 having some degree of hypokinesis. Patients underwent cardiac magnetic reso- nance imaging between 3 and 37 days after vaccination, including multiplanar SSFP sequences, short axis T1 and T2 stacks, T1 mapping when available and multiplanar myocar- dial late gadolinium enhancement. Multifocal subepicardial late gadolinium enhancement was present in 7 of 7 patients and additional midmyocardial late gadolinium enhancement was 4 of 7 patients. There was corresponding myocardial edema in 3 of 7 patients. Two patients who underwent car- diac magnetic resonance imaging >7 days from presenta- tion had no edema, with an additional patient’s T2 images limited by artifact. One patient underwent endomyocardial biopsy without pathological evidence of myocarditis. No patients reported palpitations, and there was no evidence of sustained arrhythmias. No patients had evidence of an active viral illness or autoimmune disease, and 6 of 7 had poly- merase chain reaction testing for acute COVID-19 infection during hospitalization (all 6 were negative). Assessment of COVID-19 serology was obtained for 6 of 7 patients, with 4 of 6 showing presence of spike protein IgG antibodies. Key Words: COVID-19 ◼ COVID-19 vaccines ◼ myocarditis Correspondence to: Christopher deFilippi, MD, Inova Heart and Vascular Institute, Inova Fairfax Medical Campus, 3300 Gallows Road, Falls Church, VA 22042. Email christopher.defilippi@inova.org This manuscript was sent to Vera Bittner, Senior Guest Editor, for review by expert referees, editorial decision, and final disposition. The podcast and transcript are available as a Data Supplement at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.121.055891. For Sources of Funding and Disclosures, see page 503. © 2021 American Heart Association, Inc. 502 August 10, 2021 Circulation. 2021;144:502–505. DOI: 10.1161/CIRCULATIONAHA.121.055891 Circulation Circulation is available at www.ahajournals.org/journal/circ D o w n l o a d e d f r o m h t t p : / / a h a j o u r n a l s . o r g b y o n O c t o b e r 4 , 2 0 2 2 Nonstandard Abbreviations and Acronyms COVID-19 coronavirus disease 2019 cTnI cardiac troponin I Treatment varied and included β-blocker and anti-inflam- matory medication. Hospital length of stay was 3±1 days, and all patients’ symptoms resolved by hospital discharge. All cases were reported to the Vaccine Adverse Event Report- ing System and the Centers for Disease Control. Institutional review board approval was obtained for this report. The data that support the findings of this study are available from the corresponding author on reasonable request. In 1990, the United States established the Vaccine Adverse Event Reporting System and from 1990 to 2018, myopericarditis comprised 0.1% of all adverse events reported.3 To date, while anecdotes of potential myocar- ditis from COVID-19 vaccines have been reported in the lay media4 and the US Centers for Disease Control and Prevention has acknowledged investigation of potential cases, to our knowledge there are no reported case series of myocarditis-like illness associated with COVID-19 vac- cination in adults. Our series of 7 male COVID-19 vaccina- tion recipients who presented with myocarditis-like illness supports a potential causal association with vaccination given the temporal relationship, clinical presentation, and cardiac magnetic resonance imaging findings. Although endomyocardial biopsy was negative in the single case in which it was performed, this may represent sampling bias, given the patchy nature of myocardial inflammation in myocarditis.5 Of the 2 patients without measurable spike protein IgG, both presented shortly after their first vaccine dose. This antibody response is not unexpected but may indicate an alternate vaccine-related immune mechanism or absence of causality with the vaccine. Additional study is needed to confirm whether the rate of myocarditis-like illness is higher after vaccination than the background rate of myocarditis among similarly aged individuals in the population. Globally, myocarditis is diag- nosed in approximately 10 to 20 individuals per 100 000 person-years.5 Moreover, careful immunophenotyping stud- ies are needed to investigate potential mechanisms of vac- cine-associated myocardial injury. Such studies could help determine populations at higher risk of this potential out- come and possible treatment strategies and should inform clinicians of the possibility of a myocarditis-like illness in patients with appropriate symptoms in the first few days after COVID-19 vaccination. Treatment considerations for myocarditis include anti-inflammatory medications and the addition of guideline-directed medical therapy if left ven- tricular ejection fraction is reduced,5 although no data spe- cific to vaccine-associated myocarditis are available. The clinical course of vaccine-associated myocar- ditis-like illness appears favorable, with resolution of symptoms in all patients. Given the potential morbidity of COVID-19 infection even in younger adults, the risk– benefit decision for vaccination remains highly favorable. Vaccine adverse event reporting remains of high impor- tance and further studies are needed to elucidate the pathophysiological mechanism to potentially identify or prevent future occurrences. ARTICLE INFORMATION The data that support the findings of this study and research materials, as well as experimental procedures and protocols, are available from the corresponding author upon reasonable request. Affiliations Division of Cardiology, Inova Heart and Vascular Institute, Fairfax, VA (C.M.R., L.G., B.N.T., M.A., H.B., S.C., A.A.D., S.S.D., A.E., G.M., A. Maghsoudi, I.M.S., M.C.F., M.W.S., S.S.S., C.M.O’C., C.R.d.F.). Fairfax Radiology Centers, VA (M.A.). Departments of In- ternal Medicine and Pathology, University of Texas Southwestern Medical Center, Dallas, TX (J.A.d.L., A.K., A. Muthukumar). Virginia Heart, Falls Church, VA (I.M.S., A. Maghsoudi). Division of Cardiology, Duke University, Durham, NC (C.M.O’C.). Acknowledgments The authors acknowledge the Dudley Family for their continued contributions and support of the Inova Dudley Family Center for Cardiovascular Innovation. The authors also acknowledge Kee Hyo Kang, Dr Lucy Nam, and Holly O’Donnell for their laboratory contributions and support of this project. Sources of Funding Dr Damluji receives research funding from the Pepper Scholars Program of the Johns Hopkins University Claude D. Pepper Older Americans Independence Cen- ter funded by the National Institute on Aging (P30-AG021334) and a Mentored Patient-Oriented Research Career Development Award from the National Heart, Lung, and Blood Institute (K23-HL153771-01). Dr deFilippi receives funding from the National Center for Advancing Translational Science of the National Institutes of Health (award UL1TR003015). Disclosures Dr Tehrani is a consultant for Medtronic, and is on the advisory board for Abbott Medical and Retriever Medical. Dr Atkins is on the advisory board for Arterys. Dr de Lemos has received grant support from Abbott Diagnostics and Roche Diagnostics and consulting income from Siemen’s Health Care Diagnostics, Or- tho Clinical Diagnostics, and Quidel, Inc. Dr Desai serves on the Advisory Board at Abbott Medical. Dr. Muthukumar has received grant support from Abbott and Roche Diagnostics. Dr deFilippi receives research funding to Inova from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics; and consults for FujiRebio, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics. The other authors report no conflicts. REFERENCES 1. Damluji AA, Christenson RH, deFilippi C. Clinical application of serologic test- ing for coronavirus disease 2019 in contemporary cardiovascular practice. J Am Heart Assoc. 2021;10:e019506. doi: 10.1161/JAHA.120.019506 2. Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, Sudre CH, Nguyen LH, Drew DA, Merino J, et al. Vaccine side-effects and SARS-CoV-2 infec- tion after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis. 2021;7:939–949. 3. Su JR, McNeil MM, Welsh KJ, Marquez PL, Ng C, Yan M, Cano MV. Myo- pericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018. Vaccine. 2021;39:839–845. doi: 10.1016/j.vaccine. 2020.12.046 4. Mandavilli A. C.D.C. is investigating a heart problem in a few young vac- cine recipients. The New York Times. May 22, 2021. https://www.nytimes. com/2021/05/22/health/cdc-heart-teens-vaccination.html?smid=em- share. Accessed May 25, 2021. 5. Tschöpe C, Ammirati E, Bozkurt B, Caforio ALP, Cooper LT, Felix SB, Hare JM, Heidecker B, Heymans S, Hübner N, et al. Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Nat Rev Cardiol. 2021;18:169–193. doi: 10.1038/s41569-020-00435-x Circulation. 2021;144:502–505. DOI: 10.1161/CIRCULATIONAHA.121.055891 August 10, 2021 503 C O R R E S P O N D E N C E Rosner et al Myocarditis After COVID-19 Vaccination D o w n l o a d e d f r o m h t t p : / / a h a j o u r n a l s . o r g b y o n O c t o b e r 4 , 2 0 2 2 Table. Patient Characteristics and Outcomes Age, y Sex Race/ethnicity Vaccine type mRNA Adenovirus Days from administration to presentation Presenting symptoms Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 White White White Hispanic White White 28 M White 5 Y (J&J) 39 M 3 39 M 4 24 M 7 19 M 2 20 M 3 23 M 3 Y (Pf, 2nd) Y (Mod, 2nd) Y (Pf, 1st) Y (Pf, 2nd) Y (Pf, 2nd) Y (Pf, 2nd) History of previous COVID-19 infection Denied/remote negative PCR Denied/ negative PCR Denied/ negative PCR Denied/ negative PCR Denied/ negative PCR Yes/ negative PCR Denied/ negative PCR Chest pain at rest, nonpleuritic, non- exertional; no fevers, cough- ing, or shortness of breath Sudden onset 7 out of 10 chest pain 2 days after vaccine, associ- ated with short- ness of breath; worse when ly- ing flat and with inspiration Fever, chills, short- ness of breath, and chest heaviness/pain symptoms Intermittent, positional chest pain with left arm numbness and tingling Midsternal sharp chest pain, waxing/ and po- sitional; relieved with leaning forward Midsternal chest pain with deep inspira- tion. Subjective fevers, diffuse myalgia, and headache starting day of vaccination; sudden onset of sharp chest pain the night before admission that persisted at 3 out of 10 intensity, worsened when lying flat Blood pressure, mm Hg 145/82 116/76 103/70 114/56 108/71 121/78 131/80 Vital signs at presentation Temperature, °C Heart rate, bpm Respirations, per min Chest x-ray findings 37 70 18 36.6 93 18 36.9 79 16 No acute pulmo- nary disease No acute pro- cess No detectable active cardiopulmonary disease 36.9 69 36.5 77 16 18 No acute ab- normality No acute dis- ease 37.9 112 18 37.1 96 16 No acute abnor- mality No evidence of acute car- diopulmonary disease ECG findings ST changes Rhythm Echocardiogram Left ventricular ejection fraction Left ventricular end-diastolic internal dimension Intraventricular septal dia- stolic thickness (2D) 1-mm ST elevation in II, V5–V6 PR depression in II, aVF, V4–V6 T wave inver- sion V1 No acute ST seg- ment changes No acute ST segment changes Nonspecific ST-T changes 1-mm ST eleva- tion V2–V5 Diffuse ST eleva- tions Normal sinus rhythm Normal sinus rhythm Normal sinus rhythm Normal sinus rhythm Normal sinus rhythm Sinus tachy- cardia Sinus tachycardia 6 days postvac- cine 3 days postvac- cine 4 days postvaccine 7 days postvac- cine 2 days postvac- cine 5 days post- vaccine 4 days postvac- cine 51% 35% to 40% 61% 53% 55% 50% to 55% 58% 4.8 cm 4.9 cm 4.4 cm 5.2 cm 4.7 cm 4.34 cm 5.0 cm 1.0 cm 1.1 cm 1.0 cm 1.0 cm 0.6 cm 1.1 cm 1.0 cm Regional wall motion abnor- malities Mild global hypo- kinesis None None None None Mild global left ventricular hypokinesis; mildly decreased right ventricular function Mild hypoki- nesis in the mid- to distal anteroseptum and apex Diastolic function Normal Normal Normal Normal Normal Normal Normal Cardiac magnetic resonance imaging 37 days postvac- cine 11 days post- vaccine 5 days postvaccine 7 days postvac- cine 3 days postvac- cine 6 days post- vaccine 3 days postvac- cine Left ventricular ejection fraction 50% (no regional wall motion abnor- malities) 56% (no region- al wall motion abnormalities) 52% (no regional wall motion abnor- malities) 48% (no regional wall motion abnor- malities) 50% (no region- al wall motion abnormalities) 52% (subtle api- cal septal and apical lateral hypokinesis) 50% (no regional wall motion ab- normalities) (Continued ) 504 August 10, 2021 Circulation. 2021;144:502–505. DOI: 10.1161/CIRCULATIONAHA.121.055891 E C N E D N O P S E R R O C Rosner et al Myocarditis After COVID-19 Vaccination D o w n l o a d e d f r o m h t t p : / / a h a j o u r n a l s . o r g b y o n O c t o b e r 4 , 2 0 2 2 Table. Continued LGE Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Patchy mild sub- epicardial LGE throughout the mid- to apical left ventricular walls; no pericardial thickening or en- hancement Subepicardial LGE along the anterior and lateral walls; no pericardial thickening or ef- fusion Multifocal sub- epicardial and midmyocardial LGE; prominence of the pericardium overlying the anterior wall with enhancement Midmyocardial LGE in the sep- tal and inferior walls; subepi- cardial LGE in the anterior, lateral, and in- ferior walls; no pericardial effusion Multifocal patchy subepi- cardial and mid- myocardial LGE within the lateral and in- ferolateral walls; no pericardial thickening or enhancement Subepicardial LGE within the lateral, infero- lateral, and an- terolateral walls with global left ventricular apex; no peri- cardial thicken- ing or effusion Basal antero- septal mid wall delayed enhancement; trace pericardial enhancement T1 mapping 1046 ms 1000 ms T2 No definitive edema No definitive edema Suboptimal T2 WI secondary to band- ing artifact and respi- ratory motion Myocardial edema in the lateral and infe- rior walls Myocardial edema in lateral wall at the level of the base Subtle inferior wall myocardial edema 1125 ms No definitive edema White blood cell count 8.08 9.01 8.28 11.14 8.33 10.56 9.46 Cardiac troponin I ng/mL (<0.04 ng/mL) 3.55 17.08 <0.01 8 Presentation Peak Postdischarge cTnI, ng/L (<17 ng/L) Presentation Peak Postdischarge B-type natriuretic peptide, pg/mL ND Erythrocyte sedimentation rate peak, mm/h SARS-CoV-2 antibody 3.41 13.00 0.037 97 23 4.24 11.01 <0.01 22 8 5.1 C-reactive protein peak, mg/dL 1.3 11.70 Antinuclear antibody screen Negative Negative Negative Negative Spike IgG Negative*‡ Positive* Positive‡ Negative§ Positive* Nucleocapsid IgG Negative† Negative† ND ND Negative† Respiratory viral panel∥ ND ND Negative Negative Negative 0.37 0.37 ND <10 4 0.1 ND 4.49 44.80 0.19 57.2 ND 3.1 0.48 8.36 ND 29 10 8.2 ND ND ND 2601 7000 6 68 32 7.3 ND Positive† Negative† Negative except Coxsackie B4 (IgG 1:320) Coronary angiography findings ND ND ND ND No evidence of coronary artery disease No evidence of coronary artery disease Clinical course Treatment(s) Hospitalization duration 2 days 4 days 3 days 2 days 3 days 4 days 2 days β-blocker, angio- tensin receptor blocker, statin 3 days IV steroids Colchicine, ibuprofen, fa- motidine Colchicine, ibuprofen, fa- motidine Ibuprofen, fa- motidine β-blocker, col- chicine β-blocker, angioten- sin-converting en- zyme inhibitor, aspi- rin, and clopidogrel (2 doses, stopped on discharge) T1 mapping refers to native T1 values obtained by the Modified Look-Locker Inversion recovery pulse sequence. T2 images were acquired by T2 mapping or short axis T2- weighted fat saturated sequence. 2D indicates two dimensional; COVID-19, coronavirus disease 2019; cTnI, high sensitivity cardiac troponin I; IgG, immunoglobulin G; IgM, immunoglobulin M; IV, intravenous; J&J, Johnson and Johnson (New Brunswick, NJ); LGE, late gadolinium enhancement; Mod, Moderna vaccine (mRNA-1273; Cambridge, MA); ND, testing not obtained; PCR, polymerase chain reaction; Pf, Pfizer-BioNTech COVID-19 vaccine (BNT162b2; Philadelphia, PA); and SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. *Performed using Siemens Healthineers Dimension EXL SARS-CoV-2 IgG assay. †Performed using Abbott ARCHITECT SARS-CoV-2 IgG. ‡Performed using DiaSorin LIAISON SARS-CoV-2 S1/S2 IgG assay. §Performed using Healgen COVID-19 IgG/IgM Rapid Test Cassette. ∥Respiratory viral panel was performed using the FilmArray BioFire Respiratory Panel 2.1 and contains qualitative detection of respiratory pathogen nucleic acid for the following viruses: adenovirus, coronavirus 229E, coronavirus HKU1, coronavirus NL63, coronavirus OC43, SARS-CoV-2, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A/H1, influenza AH1 2009, influenza A/H3, influenza B, parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, respiratory syncytial virus, Bordetella pertussis, Bordetella parapertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. Circulation. 2021;144:502–505. DOI: 10.1161/CIRCULATIONAHA.121.055891 August 10, 2021 505 Negative except my- coplasma IgG; Cox- sackie B1, B2, B3 (IgG 1:8) and B4, B5, B6 (IgG 1:16) No obstructive coro- nary artery disease; proximal circumflex; mild 30% stenosis C O R R E S P O N D E N C E Rosner et al Myocarditis After COVID-19 Vaccination D o w n l o a d e d f r o m h t t p : / / a h a j o u r n a l s . o r g b y o n O c t o b e r 4 , 2 0 2 2