Overwhelming evidence substantiates that the immunogenicity of the COVID-19 mRNA vaccine can trigger many rare cardiovascular and blood disease reactions, including myocarditis, pericardial effusion, myocardial infarction, atypical Kawasaki disease, arterial thrombosis, cutaneous small vessel vasculitis, large vessel vasculitis, etc. [7, 8, 9, 10, 11, 12, 14]. In a study on 27 patients with cardiac inflammation caused by COVID-19 vaccine, most complained of chest pain, palpitations, joint pain and dyspnea, exhibiting elevated cardiac troponin I (HS cTnI) levels, and 77.8% of patients had ST-segment elevation or T wave inversion in electrocardiogram (ECG) (Table 1a,1b, Ref. [5, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37]). Amir et al. [20] retrospectively collected 15 cases of myocarditis related to the BNT162b2 mRNA COVID-19 vaccine in five major children’s medical centers in Israel. The majority of patients were male, exhibiting symptoms and signs of myocardial involvement (such as chest pain and arrhythmia), 93.3% of patients had elevated troponin levels, 13.3% of patients had pericardial effusion, 20% of patients had ventricular dysfunction, and 86.7% of patients had nonspecific ST/T changes in ECG [20]. Puchalski et al. [21] retrospectively analyzed five adolescents with body mass index (BMI) values of 24.8 to 30 (4 obese and 1 overweight) vaccinated with Pfizer mRNA vaccine, which exhibited retrosternal chest pain (n = 5), elevated body temperature (n = 4), diarrhea and shoulder pain (n = 1), and dry cough (n = 1). Troponin levels were significantly increased in all cases and decreased rapidly a few days later. Echocardiography showed that the left ventricular ejection fraction ranged from 61 to 72% [21]. Six cases of myocarditis were reported out of nearly 200000 citizens vaccinated with the mRNA COVID-19 vaccine in Italy. All six patients were hospitalized due to fever and elevated troponin and were treated with colchicine and ibuprofen. One patient exhibited atrial tachycardia, and another showed right ventricular involvement. Only a female patient was diagnosed with myocarditis and pericardial effusion. The median high-sensitivity troponin and C-reactive protein (CRP) levels in these 6 patients were 2373 ng/mL and 4 $\pm$ 1.8 mg/L [22]. The University of Ulm in Germany reported four cases diagnosed with pericarditis or myocarditis after mRNA vaccination after a mean duration of 7.5 $\pm$ 6.5 days, exhibiting chest and back tingling (n = 4), fever (n = 2), abnormal ECG findings (n = 2), and increased high-sensitivity troponin T (hs-TnT) (n = 4). Two patients underwent endomyocardial biopsy and were diagnosed with non-giant cell myocarditis [23]. In the United States, where nearly 10 million people were immunized with the COVID-19 mRNA vaccine in 2021, 1626 cases of myocarditis have been reported with a median age of 21 years (16–31 years) and the median duration of symptoms of 2 days (1–3 days), consisting predominantly of males (82%), mainly adolescents [38]. The symptoms of myocarditis caused by the COVID-19 vaccine are generally mild and do not need hospitalization, but some patients will have heart failure and need heart transplantation, and death may occur in serious cases [38]. To sum up, myocarditis is a rare complication of immunization with the COVID-19 mRNA vaccine, often presenting with chest pain, fever, diarrhea, dyspnea and other symptoms. Generally, the disease is mild and can be generally cured after hospitalization.

COVID-19 disease and COVID-19 mRNA vaccine immunization have been associated with myocarditis; however, significant heterogeneity surrounds the degree of myocardial lesions and histopathology. The following cases can support this view. COVID-19 induced myocarditis is also considered to be a relatively rare disease. Macrophage and T cell infiltrations have been documented in the dead patients with myocarditis and autopsy and the analysis of samples stained with eosin methylene blue (EMB). Myocarditis involving macrophage and T cell infiltration were also observed in the non-infectious death (control group) and COVID-19 cases. However, the infiltration degree in each condition is different, and in both cases, these findings do not represent clinically relevant myocarditis. In addition, in SARS-CoV-2 patients, myocardial tissue cells exhibit significant macrophage inflammatory infiltration, which is related to the viral lymphoid effect [39]. Kawakami performed an autopsy of the myocardium in 16 patients who died of SARS-CoV-2 infection. In one case, myocarditis with macrophage and T cell infiltration was found [39]. Bae et al. [24] reported that a 38-year-old female was diagnosed with myocarditis 4 days after receiving the mrna-1273 vaccine (Moderna). After ventricular septal tissue sections were harvested, hematoxylin-eosin staining and immunohistochemical staining for leukocyte common antigen (LCA) were performed. Lymphocytic infiltration was found in muscle fibers and stroma [24]. A 50-year-old man was diagnosed with myocarditis after vaccination, presenting with chest pain with tachycardia and ST-segment elevation observed on the ECG. Laboratory examination showed that cardiac troponin I was significantly increased, the left ventricular ejection fraction (LVEF) on cardiac ultrasound was 35%, and gadolinium enhancement was observed in late left ventricular imaging. The right ventricular septal endocardial myocardium was biopsied, and hematoxylin-eosin staining and immunostaining were performed. A small number of eosinophils, T lymphocytes and macrophages were found in some tissues, indicating that myocardial cells sustained inflammation and damage [40]. Nunn et al. [23] reported that a 31-year-old female patient with myocarditis was inoculated with the BioNTech/Pfizer vaccine 17 days ago. The hs-TnT and N-terminal pro b-type natriuretic peptide (NT-proBNP) were increased. The patient underwent a myocardial biopsy and eosin methylene blue staining. Finally, the patient was diagnosed with non-giant cell myocarditis [23]. Three patients with myocarditis caused by BNT162b2 vaccination were reported by the University of La Pienza in Rome, Italy. Compared with the control group (6.1 $\pm$ 1 u/mL) of vaccinated patients without myocarditis, the serum cationic protein level of all patients increased (23.4 $\pm$ 17 u/mL) (p = 0.079). The myocardial tissue was harvested for pathological section and stained with human eosinophil major basic protein (EMBP), showing the crystal degranulation of eosinophils, indicating myocardial injury and strong infiltration of eosinophils. It was found that a large number of myocardial cells died and were surrounded by eosinophils in the myocardial tissue (IHC antibody) [25]. A 22-year-old Korean male suffered from chest pain, ECG and related examinations: ventricular fibrillation, myocarditis, and finally sudden death 5 days after receiving BNT162b2 mRNA vaccine. Myocardial tissue sections were harvested and stained with hematoxylin and eosin, showing a large number of inflammatory infiltrates (mainly neutrophils) in myocardial cells. Inflammatory cells were mainly distributed in the atrium and sinoatrial node, and ventricular contraction zone cells were necrotic [26]. COVID-19-induced myocarditis is also considered to be a relatively rare disease. It has been found that macrophage and T cell infiltration can be seen in dead patients with myocarditis. Although myocarditis involving macrophage and T cell infiltration can also be seen in the non-infectious death (control group) and COVID-19 cases, the degree for each condition is different, and in both cases, these findings do not represent clinically relevant myocarditis. In addition, in SARS-CoV-2 patients, myocardial tissue cells exhibit high macrophage inflammatory infiltration, which is related to the viral lymphoid effect [39]. Kawakami et al. [39] performed an autopsy of the myocardium in 16 patients who died of SARS-CoV-2 infection. Myocarditis with macrophage and T cell infiltration was found in one case diagnosed with myocarditis [39]. The above findings suggest significant eosinophil infiltration in cases of myocarditis tissue caused by the COVID-19 vaccine, while macrophages are mainly present in the myocarditis associated with COVID-19 disease [26, 39, 41]. The reasons and mechanisms for the above differences remain unclear, warranting further research.

The 2018 Lake Louise criteria (LLC) upgraded version requires that the diagnosis of Acute myocarditis (AM) must meet at least one sequence sensitive to edema (T2 weighted imaging or T2 mapping) and at least one T1 sequence (T1 mapping, ECV, myocardial delayed enhancement imaging) and be positive at the same time. T1 weighted images can reflect the difference in longitudinal relaxation of myocardial tissue and reduce the influence of transverse relaxation of other tissues. In cases of acute myocarditis, gadolinium injection can enhance the early development of the myocardium. In contrast, T2 weighted images can highlight the difference in transverse relaxation. When myocardial edema occurs, the tissue shows a strong signal, and T2 time is prolonged [42, 43, 44, 45, 46, 47]. Giulia et al. [48] compared the diagnostic performance of the new and old LLC in different clinical manifestations: myocardial infarction, cardiomyopathy, and arrhythmia. Using T2-weighted short-tau inversion recovery (T2w-STIR), T2 mapping, T1 weighted images, and late gadolinium enhancement (LGE), the positive rate of the new standard LLC was 58.3%, while the positive rate of the old standard LLC was 37.9% when patients had clinical manifestations of myocardial infarct, cardiomyopathy and arrhythmia. The new LLC standard significantly improves the accuracy of CMR in diagnosing acute myocarditis, especially in patients with myocarditis whose clinical manifestations are not obvious [48]. Kravchenko et al. [27] found that the CMR results of 20 patients with myocarditis suspected to be caused by COVID-19 mRNA vaccine immunization exhibited similar manifestations to viral myocarditis, and LLC met the diagnostic criteria. Shiyovich et al. [18] reported that the CMR imaging results of myocarditis patients inoculated with Pfizer BNT162b2 vaccine were inconsistent with those of the latest early diagnosis standard of LLC, but selective bias could not be ruled out. In addition, in patients clinically diagnosed with myocarditis after vaccination, the CMR imaging results were relatively mild and consistent with the performance of “classic myocarditis”. Pan et al. [49] reported that natural T1 has a significant advantage over LLC in evaluating the sensitivity of myocarditis. Emanuele et al. [19] reported the diagnosis and manifestations of nonischemic epicardial LGE and myocarditis in 23 cases of CMR. The CMR features of acute myocarditis include a high signal (nonischemic epicardium) on the short axis of T2 weighted STIR, and the results are consistent with LGE. At the same time, acute myocarditis can be confirmed on surface images T1 and T2 [19]. It has been established that cardiac magnetic resonance tissue feature tracking is more effective than traditional LLC in diagnosing myocarditis, especially in patients with good ejection function. Therefore, CMR plays a positive role in diagnosing and evaluating myocarditis caused by immunization with the 2019 coronavirus disease vaccine [18, 50].

The CMR manifestations of myocarditis caused by COVID-19 mRNA vaccine treatment are mainly abnormalities in the inferior epicardial wall, the inferior lateral segment of the myocardium, and the inferior wall of the myocardium [51, 52]. The following cases can support this view. Dedda et al. [19] reported 27 cases of myocarditis caused by the 2019 coronavirus vaccine, exhibiting chest pain (n = 25), palpitations (n = 10), myalgia (n = 9) and dyspnea (n = 7), of which 77.8% (n = 21/27) exhibited increased cardiac troponin T, 85.1% (n = 23/27) displayed non-ischemic late gadolinium enhancement under epicardium matched with CMR T2 images, and 25.9% (n = 7/27) showed pericarditis. Meyer-Szary et al. [28] reported three patients with myocarditis immunized with the COVID-19 RNA vaccine. CMR showed that myocardial damage mainly occurred in the lower and lower lateral segments of the myocardium, and T2 weighted stir epicardial edema signal [28]. Consistent with findings reported by Chelala et al. [29]. In 5 patients with acute myocarditis after immunization with the COVID-19 mRNA vaccine, CMR showed that all patients had LGE with simple epicardial enhancement (n = 4), involvement of the inferior wall or anterolateral wall (n = 5), epicardial enhancement (n = 1), and increased myocardial T2 signal intensity (n = 5) [29]. Patel et al. [30] reported the acute myocardium of 5 young men after receiving the COVID-19 mRNA vaccine. CMR showed that myocardial edema and LGE were mainly distributed in the bottom and middle lateral of the left ventricle, and the prognosis was good [30]. Amir et al. [20] retrospectively analyzed 15 patients with myocarditis induced by the BNT162b2 vaccine that were predominantly young (average age of 17 $\pm$ 1 years) and male. CMR showed edema on T2 in 90% (n = 12) of patients and pathological LGE in 90% (4/5) of patients. CMR reexamination six months after discharge found myocardial scarring in 7 out of 9 patients [20]. Christophe et al. [31] reported 3 patients with severe myocarditis caused by the COVID-19 RNA vaccine. During CMR, all patients exhibited LGE in the inferior epicardial or inferior wall and edema in the T2 weighted sequence [31]. Das reported a male patient with myocarditis with LVEF 50% and RVEF 46%. COVID-19 RNA vaccine, epicardial and mesangial LGE were shown in the lower and lateral segments of the left ventricle [32]. Oka et al. [33] reported a case in a male patient where CMR showed LGE in the lower septum. T2 weighted imaging showed left ventricular (LV) myocardial wall edema. LGE disappeared after 5 weeks, but the hyperintensity of LV whole wall persisted [33]. In conclusion, CMR of myocarditis caused by COVID-19 mRNA vaccine immunization exhibits LGE in the inferior epicardial wall, the inferior lateral segment and inferior wall of the myocardium, and most cases display edema on T2.

Most of the symptoms of myocarditis after COVID-19 mRNA vaccination were mild and the prognosis was good, but some patients had severe concurrent symptoms and sequelae. For example, Choi et al. [26] reported that a 22-year-old man in Korea developed chest pain 5 days after the first dose of BNT162b2 mRNA vaccine and died 7 hours later, autopsy showed that the cause of death was myocarditis [26]. Amir et al. [20] reported that a patient diagnosed with myocarditis after COVID-19 mRNA vaccine had pericardial effusion 6 months later. Oka et al. [33] reported that a Korean myocarditis patient developed syncope, heart failure and atrioventricular block 2 weeks after discharge. To sum up, myocarditis after COVID-19 mRNA vaccination needs to be paid great attention. However, it is difficult to diagnose by laboratory tests and other diagnostic methods in the early stage of the disease. CMR is sensitive and effective to discriminate early myocarditis [50].