COVID-19 vaccination and cardiac dysfunction

Table 1 Incidence and clinical manifestations of myocarditis after coronavirus disease 2019 mRNA vaccination

Ref.	Type of vaccine	Study population	Incidence	Cardiac assessment methods	Main findings and clinical outcomes
Witberg et al[11], Israel	Pfizer-BioNTech	54/2558421 (21-63 yr)	2.13/100000	Clinical presentation, ECG, ECHO, MRI, Troponin T	Myocarditis = 10.69/100000 in male ages 16-29 yr, 25.92% had LV dysfunction, 76% = mild, 22% = intermediate, 1 case had cardiogenic shock, 1 case died of unknown cause, 0.51/100000 after 1st dose and 2.15/100000 after 2nd dose
Mevorach et al[12], Israel	Pfizer-BioNTech	136/9289765 (≥ 16 yr)	1.46/100000	Clinical presentation, ECHO, MRI, Troponin T, Endomyocardial biopsy	Myocarditis = 15.07/100000 in male ages 16-19 yr, 0.35/100000 after 1st dose, 2.28/100000 after 2nd dose, 94.85% = mild, 4.41% = intermediate, 1 case was fatal, endo-interstitial edema with neutrophils and mononuclear-cells infiltrates with no giant cells
Montgomery et al[13], United States	Pfizer-BioNTech/Moderna	23/2810000 (20-51 yr)	0.82/100000	Clinical presentation, ECG, ECHO, MRI, Troponin T	Myocarditis = 1.88/100000 after 1st dose, 3.49/100000 after 2nd dose, and 4.36/100000 in male after 2nd dose
Perez et al[14], United States	Pfizer-BioNTech/Moderna/Johnson and Johnson	7/175472 (12-106 yr)	55.35/100000, Person-yr	Clinical presentation, ECG, ECHO, MRI, Troponin T	The overall incidence rate was 55.35 (22.25–114.00) per 100000 person-yr during the 2 wk after a dose of vaccine. The IRR for myocarditis following COVID-19 mRNA vaccination was increased for males at 6.69 (2.35–15.52), but it was not statistically significant for females at 1.41 (0.03–8.45)
Das et al[15], United States	Pfizer-BioNTech	25/7735071 (12-17 yr)	0.32/100000	Clinical presentation, ECG, ECHO, MRI, Troponin T, CRP	Myocarditis = 0.04/100000 after 1st dose, 0.28/100000 after 2nd dose, and 0.26/100000 in male after 2nd dose
Li et al[16], United States	Pfizer-BioNTech/Moderna/Janssen	Age ≥ 12 yr	0.598/100000	VAERS	Pfizer–BioNTech had a higher incidence rate of 0.670/100000 than the rate of 0.498/100000 found for Moderna. The incidence rate following the 2nd dose was twice that of the 1st dose and was the highest in adolescents aged 12-17 yr, at 2.094/100000. The Janssen vaccine was not associated with myocarditis or pericarditis
Patone et al[17], United Kingdom	Pfizer-BioNTech/Moderna/AstraZeneca	1615/38615491 (Age ≥ 16 yr)	4.18/100000	NIMS	The IRR of myocarditis = 1.76, 1.45, 8.38 after 1st dose of AstraZeneca, Pfizer-BioNTech, Moderna. IRR of myocarditis = 1.75, 23.10 after 2nd dose of Pfizer-BioNTech, Moderna. There was an increase in the risk of myocarditis within 1 wk after 1st dose of adenovirus and mRNA vaccines and a higher increased risk after 2nd dose of both mRNA vaccines, especially in under 40 yr
Simone et al[18], United States	Pfizer-BioNTech/Moderna	15/2392924 (Age ≥ 18 yr)	0.63/100000	KPSC members with clinical presentation, ECG, ECHO, Troponin I	Myocarditis = 0.08/100000 after 1st dose, 0.58/100000 after 2nd dose over a 10-d period, all were men aged 20-32 yr. The IRR of myocarditis = 0.38 after 1st dose and 2.7 after 2nd dose
Nygaard et al[19], Denmark	Pfizer-BioNTech	15/261334 (12-17 yr)	5.74/100000	Clinical presentation, ECG, ECHO, MRI, Troponin	Myocarditis = 3.06/100000 after 1st dose, 2.68/100000 after 2nd dose mostly in male (M:F = 6:1)
Husby et al[20], Denmark	Pfizer-BioNTech/Moderna	269/4931775 (Age ≥ 12 yr)	5.45/100000	Danish Vaccination Register	HR of myocarditis/pericarditis = 1.34, 3.92 within 28 d from the vaccination of Pfizer-BioNTech, Moderna respectively. Myocarditis or pericarditis occurred at 1.4/100000 for Pfizer-BioNTech and 4.2/100000 for Moderna. Vaccination with Moderna vaccine was associated with an increased risk of myocarditis or pericarditis, especially in aged 12-39 yr
Diaz et al[21], United States	Pfizer-BioNTech/Moderna/Janssen	57/2000287 (26-70 yr)	2.85/100000	Clinical presentation, ECG, ECHO, Troponin	Myocarditis = 1.0/100000 and pericarditis = 1.8/100000. Myocarditis and pericarditis were observed after the COVID-19 vaccination. Myocarditis developed rapidly in younger patients, mostly after the 2nd dose. Pericarditis affected older patients later, after either the 1st or 2nd dose
Chouchana et al[22], WHO	Pfizer-BioNTech/Moderna	2277/716576 reports	NA	VigiBase	Over all myocarditis = 3.57/100000 with 12–17 yr = 3.69/100000, 18–29 yr = 1.97/100000, and ≥ 30 yr = 0.21/100000. Younger male aged 12–17 yr were more prone to report myocarditis or pericarditis with 22.3/100000. The median time to onset for myocarditis was 3 d after vaccine injection
Barda et al[23], Israel	Pfizer-BioNTech	21/938812	2.23/100000	Clinical presentation, ECG, ECHO, Troponin	Vaccination was most strongly associated with an elevated risk of myocarditis [risk ratio, 3.24 (1.55-12.44)]. Alternatively, SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis [risk ratio, 18.28 (3.95-25.12)]. The BNT162b2-mRNA vaccine increased the incidence of a few adverse events over a 42-d follow-up period

ECG: Electrocardiography; ECHO: Echocardiography; HR: Hazard ratio; IRR: Incidence rate ratio; KPSC: Kaiser Permanente Southern California; M:F: Male to female; MRI: Magnetic resonance imaging; NA: Not available; NIMS: The English National Immunisation; ROR: Reporting odds ratio; VAERS: Vaccine Adverse Events Reporting System; VigiBase: World Health Organization (WHO) global safety database; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 2 Characteristic of acute myocarditis patients after coronavirus disease 2019 mRNA vaccination

Ref.	Type of vaccine	No. of myocarditiscases	Male/Female (%)	Median age in yr (IQR)	Myocarditis after 1st dose (%)	Myocarditis after 2nd dose (%)	Clinical severity F/I/M
Witberg et al[11], Israel	Pfizer-BioNTech	54	51/3 (94/6)	27 (21–35)	17 (31.48)	37 (68.52)	1/12/41
Mevorach et al[12], Israel	Pfizer-BioNTech	136	118/18 (87/13)	- (16-> 30)	19 (13.97)	117 (86.03)	1/6/129
Montgomery et al[13], United States	Pfizer-BioNTech/Moderna	23	23/0 (100/0)	25 (20-51)	3 (13.04)	20 (86.96)	0/7/16
Perez et al[14], United States	Pfizer-BioNTech/Moderna	7	6/1 (86/14)	44 (22-71)	1 (14.29)	6 (85.71)	0/6/1
Das et al[15], United States	Pfizer-BioNTech	25	22/3 (88/12)	15 (12-17)	3 (12.00)	22 (88.00)	0/22/3
Simone et al[18], United States	Pfizer-BioNTech/Moderna	15	15/0 (100/0)	25 (20-32)	2 (13.33)	13 (86.67)	0/15/0
Nygaard et al[19], Denmark	Pfizer-BioNTech	15	13/2 (87/12)	17 (13-17)	8 (53.33)	7 (46.67)	0/1/14
Diaz et al[21], United States	Pfizer-BioNTech/Moderna	20	15/5 (75/25)	36 (26-48)	4 (20.00)	16 (80.00)	2/17/1

F/I/M: Fulminant/intermediate/mild; IQR: Interquartile range.

Table 3 Clinical presentation of the patients with acute myocarditis after coronavirus disease 2019 mRNA vaccination

	Clinical presentation of acute myocarditis
1	Chest pain, Myalgia, Fatigue, Fever
2	Abnormal ECG: ST-elevation, Non-specific ST/T changes, PR depression, T-wave inversion, Ventricular fibrillation
3	Elevation of cardiac troponin
4	Elevation of CRP
5	Abnormal ECHO: LVEF reduction
6	Abnormal cardiac MRI: Myocardial inflammation, Myocardial edema
7	Abnormal cardiac spectral CT: Delayed iodine enhancement

CRP: C-reactive protein; CT: Computerized tomography; ECG: Electrocardiogram; ECHO: Echocardiogram; LVEF: Left ventricular ejection fraction; MRI: Magnetic resonance imaging.

Table 4 Gross and histopathological findings of the heart after coronavirus disease 2019 mRNA vaccination

Ref.	No. of cases (age, sex)/vaccine	Gross findings	Histopathological findings
Ameratunga et al[24]	1 (57, F)/Pfizer-BioNTech	The heart was normal without pericardial effusion and intra-cardiac thrombosis. There was a large thymoma mass (710 g) in the left pleural cavity	The heart sections showed fulminant necrotizing eosinophilic myocarditis. There were multifocal aggregates of lymphoid cells, histiocytes, and abundant eosinophils with focal myocyte necrosis in the free walls of both ventricles, interventricular septum, and around the conduction system (sino-atrial and atrioventricular nodes)
Choi et al[25]	1 (22, M)/Pfizer-BioNTech	The heart weighed 470 g with multiple petechial hemorrhages on its surface. The pericardium was smooth with no fibrin deposition or exudate. The coronary arteries were patent, and the heart valves were unremarkable	The myocardial sections showed a diffuse inflammatory infiltration with neutrophils and histiocytes predominance. The inflammatory infiltrates dominant in the atria and around the sinoatrial and atrioventricular nodes with no inflammatory cells in the ventricular muscles
Schneider et al[26]	1 (65, M)/Pfizer-BioNTech	The heart showed severe coronary sclerosis, massive cardiac hypertrophy, myocardial infarction scars	The myocardial sections showed myocarditis with lymphocytic and plasmacytoid infiltration of the perivascular space and the myocardium

F: Female; M: Male.