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Review

COVID-19 and Myocarditis: Trends, Clinical Characteristics, and Future Directions

by
Mohammad Abumayyaleh
1,*,
Tobias Schupp
1,
Michael Behnes
1,
Ibrahim El-Battrawy
2,3,
Nazha Hamdani
3 and
Ibrahim Akin
1
1
Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany
2
Department of Cardiology and Angiology, Bergmannsheil University Hospitals, Ruhr University of Bochum, 44789 Bochum, Germany
3
Institut für Forschung und Lehre (IFL), Department of Molecular and Experimental Cardiology, Ruhr-University Bochum, 44789 Bochum, Germany
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2025, 14(13), 4560; https://doi.org/10.3390/jcm14134560 (registering DOI)
Submission received: 7 May 2025 / Revised: 22 June 2025 / Accepted: 23 June 2025 / Published: 27 June 2025
(This article belongs to the Section Cardiology)
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Abstract

Summary: COVID-19, caused by SARS-CoV-2, has been associated with a range of cardiovascular complications, including myocarditis. This review aims to systematically present the clinical manifestations, underlying pathophysiological mechanisms, diagnostic approaches, and management strategies for both COVID-19-associated myocarditis and myocarditis related to SARS-CoV-2 vaccination. We conducted a literature search using the PubMed database, covering studies published up to early 2024. Search terms included combinations of “COVID-19”, “Coronavirus”, “SARS-CoV-2”, and/or “vaccination” with “cardiac injury”, “cardiac inflammation”, “myocarditis”. The reported prevalence of COVID-19-associated myocarditis varies between 2.3% and 5.0%, though myocardial injury is more frequently observed than confirmed myocarditis. Pathophysiological mechanisms include direct viral damage, immune-mediated injury, and molecular mimicry. Clinically, patients may present with chest pain, dyspnea, and fever. Diagnostic workup includes electrocardiography (ECG), troponin measurement, echocardiography, cardiac magnetic resonance imaging (cMRI), and in selected cases, endomyocardial biopsy (EMB). The management and disposition of COVID-19-associated myocarditis varies according to severity, especially to allow targeted treatment of complications. Glucocorticoids are a mainstay of treatment in severe cases. Myocarditis following SARS-CoV-2 vaccination is rare, more frequently reported in males under 30 years, and is generally associated with a favorable prognosis. Despite this, the benefits of vaccination continue to outweigh the risks. COVID-19 is associated with an increased risk of heart failure and other cardiovascular complications, underlining the importance of long-term follow-up and preventive strategies. Further research is needed to better understand the pathogenesis and optimal management of myocarditis in the context of COVID-19, with the goal of developing evidence-based therapeutic algorithms.

1. Introduction

The outbreak of coronavirus disease 2019 (COVID-19), which was caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), developed into a global health crisis [1]. In the early stages of infection, patients with SARS-CoV-2 were either asymptomatic or presented with severe pneumonia, organ dysfunction, and even death [2]. The risk factors for severe COVID-19 were determined, including older age, male sex, ethnicity, and the presence of underlying conditions such as cardiovascular diseases, hypertension, and chronic pulmonary diseases [3]. As a multi-organ disease, COVID-19 primarily affected the lungs, with respiratory failure being the most common complication [4]. However, cardiac complications, including acute cardiac injury, new-onset systolic dysfunction, pericardial effusion and, in a minority of cases, acute myocarditis, were also observed [4,5,6,7]. It has been reported that cardiac injury may be caused by direct cardiomyocyte infection with cardiomyocyte apoptosis [8,9]. This hypothesis was not corroborated by subsequent data [10,11]. A more compelling hypothesis suggests that cardiac injury may result from indirect mechanisms such as ischemia, fever, and hyperinflammation that are secondary to the existing cytokine storm [9]. Furthermore, additional mechanisms, including stress cardiomyopathy and acute right ventricular failure resulting from pulmonary embolism, have also been proposed [12,13].
Acute myocarditis is generally defined as an inflammatory process involving the myocardium, which may affect the cardiac conduction system and/or the pericardium. The global incidence of acute myocarditis is estimated at approximately four to fourteen cases per 100,000 individuals annually [14,15,16]. It can result from exposure to infectious agents, including coronaviruses, influenza, and parvovirus, as well as from systemic autoimmune diseases such as systemic lupus erythematosus, certain pharmacological agents (e.g., immune checkpoint inhibitors), and toxic substances, including chemotherapeutic drugs and vaccines [17,18,19,20]. In young individuals, acute myocarditis is recognized as a significant cause of sudden cardiac death (SCD) [21]. Clinically, patients may present with acute chest pain, dyspnea, palpitations, or, less commonly, syncope [22]. Diagnostic findings can include the presence of myocardial inflammatory infiltrates with nonischemic cardiomyocyte necrosis on endomyocardial biopsy (EMB) or autopsy [17]. Myocardial edema is frequently observed using cardiac magnetic resonance imaging (cMRI) [23,24]. However, according to the European Society of Cardiology’s (ESC) position statement, the diagnosis is considered clinically suspected myocarditis of uncertain etiology in the absence of EMB [25].
Nevertheless, COVID-19-associated myocarditis has been linked to various complications, including the development of dilated cardiomyopathy (DCM) [26]. De novo heart failure (HF) has been observed in up to one-quarter of hospitalized patients and in approximately one-third of those requiring intensive care unit (ICU) admission [13]. In such cases, the management of HF resulting from DCM should follow the same principles as those applied in idiopathic DCM [27]. Hospitalized patients with COVID-19-associated acute myocarditis, often accompanied by respiratory insufficiency, have received a range of antiviral or immunosuppressive treatments, including hydroxychloroquine, tocilizumab, remdesivir, lopinavir/ritonavir, interferon beta, colchicine, intravenous steroids, and intravenous immunoglobulins [28,29,30,31,32,33]. Furthermore, myocarditis induced by SARS-CoV-2 vaccination has been recognized as a rare cause of hospitalization during the COVID-19 pandemic [34,35]. However, a more frequently encountered condition is myocardial injury, defined by elevated troponin levels exceeding the 99th percentile upper reference limit [36].
The purpose of this review is to provide a comprehensive and systematic overview of the current evidence on COVID-19-associated acute myocarditis. In this context, we will describe the current and future challenges in treating acute myocarditis, as well as the potential risk of an increased incidence of HF.

2. Materials and Methods

We conducted a structured literature review using the PubMed database to identify relevant studies on COVID-19-associated myocarditis and myocarditis related to SARS-CoV-2 vaccination. The search included articles published up to early 2024. For COVID-19-associated myocarditis, search terms included combinations of “COVID-19”, “SARS-CoV-2”, and “Coronavirus” with keywords such as “myocarditis”, “cardiac injury”, “cardiac inflammation”, “cardiac involvement”, and “pericarditis”. For vaccine-associated myocarditis, search terms included combinations of “vaccination”, “mRNA vaccine”, and “immunization” with keywords such as “myocarditis”, “cardiac injury”, “cardiac inflammation”, and “cardiac involvement”. In addition to the database search, we screened the reference lists of selected articles to identify further relevant studies.
We included peer-reviewed original research articles, observational studies, clinical trials, case reports, case series, and systematic reviews. Only articles published in English were considered. Preprints, commentaries, and conference abstracts were excluded. Articles focusing on non-cardiac complications of COVID-19 or vaccination were also excluded unless they provided significant discussion of myocarditis.
Titles and abstracts were screened to determine initial eligibility, followed by full-text review for articles deemed potentially relevant. From the selected studies, we extracted data on population characteristics, clinical manifestations, diagnostic findings, treatment approaches, and reported outcomes.

3. Epidemiology

The reported prevalence of COVID-19-associated acute myocarditis varies depending on the specific criteria employed. It is important to differentiate this condition from cardiac injury resulting from multiple organ failure, hypoxia, and activation of the hemostatic system [37]. A total of 1597 athletes across 13 centers with confirmed COVID-19 were evaluated using cMRI. Among them, 2.3% exhibited either clinical or subclinical acute myocarditis, while only 0.31% presented with cardiac symptoms, reflecting the detected prevalence [38]. In a retrospective cohort study using electronic medical records from 718,365 hospitalized patients with COVID-19, 35,820 (5.0%) developed acute myocarditis [39]. Among hospitalized patients at 23 centers in the United States (US) and Europe, the prevalence of COVID-19-associated acute myocarditis was 2.4 (confirmed/probable) and 4.1 (possible) cases per 1000 COVID-19 hospital admissions [40]. However, these cases were identified based on clinical presentation and included only patients who presented with symptoms at the time of their hospital admission. The prevalence did not include asymptomatic patients, and large-scale data on asymptomatic myocardial involvement are lacking. In a multicenter autopsy study, lymphocytic myocarditis was identified in 3 of 21 consecutive patients diagnosed with COVID-19. It should be noted that the definition of myocarditis included the presence of multiple foci of inflammation associated with myocyte injury. Immunohistochemistry was used to analyze the composition of inflammatory cells [41]. Among 277 patients in autopsy studies, the prevalence of myocarditis was less than 2% [42]. However, acute myocardial injury was more prevalent than myocarditis in hospitalized patients with COVID-19. The incidence of myocardial injury ranged from 19.7% to 28.7% in different studies [43,44,45]. Table 1 presents the prevalence of COVID-19-associated acute myocarditis.

4. Pathophysiology

SARS-CoV-2 is a large, enveloped RNA virus that shares significant nucleotide sequence homology with other coronaviruses, including SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) [46]. The virus utilizes ACE2 for cellular entry [47]. Transmembrane serine protease-2 (TMPRSS2), located on the plasma membrane, cleaves the viral spike protein, facilitating entry into the cytosol. Additionally, intracellular proteases such as the cathepsins in the endosomes contribute to this process [48]. ACE2 is predominantly expressed on cardiomyocytes, whereas TMPRSS2 is mainly found on endothelial cells, potentially enabling direct cardiac infection [49,50]. Cardiomyocytes can also express additional entry-related proteins, such as neuropilin-1 receptor (NRP1), integrin α5ß1, and cathepsins. These proteins may act as antigen-presenting cells (APCs), activating other immune cells, including dendritic cells and macrophages, and initiating specific T-helper cell responses [8,51,52,53]. The interaction between viral antigens and the resulting immune response can lead to cardiac injury, manifesting as myocarditis. In both COVID-19-related and autoimmune models of myocardial injury, myocardial infiltrates often consist of up to 80% macrophages, with fewer T and B lymphocytes, indicating a predominance of innate over adaptive immune response. Thus, referring to this process as “lymphocytic” myocarditis may be somewhat misleading. An additional potential mechanism of autoimmunity is molecular mimicry, wherein structural similarities between SARS-CoV-2 proteins and human peptides lead to cross-reactive immune responses. This mechanism may contribute to autoimmune-mediated myocardial damage, even in the absence of high viral load or direct viral invasion [54].
Two potential infection pathways in myocardial tissue are currently under investigation: direct infection and indirect injury via extracellular vesicles during a cytokine storm. Direct infection of cardiomyocytes is a plausible mechanism of myocarditis development [55]. Alternatively, the intense cytokine release associated with SARS-CoV-2 infection may also contribute. However, existing animal models have not shown that pro-inflammatory cytokines alone are sufficient to induce myocarditis [56]. Moreover, a high viral load does not appear necessary to trigger cardiac inflammation [57]. Figure 1 represents the proposed pathophysiological mechanisms of acute myocarditis.

5. Clinical Presentation and Diagnosis of COVID-19-Associated Acute Myocarditis

Patients with possible COVID-19-associated acute myocarditis may present with a range of symptoms, including those that are specific to the condition (e.g., chest pain, syncope, and palpitations) and those that are non-specific (e.g., respiratory symptoms such as dyspnea, cough, fever, and myalgias, or gastrointestinal symptoms like nausea and diarrhea) [40,58,59]. In this regard, dyspnea and cough were observed more in hospitalized patients with concomitant acute myocarditis and clinically diagnosed pneumonia than in those without pneumonia, respectively (78.3% vs. 35.5%) (69.6% vs. 29%) [40]. In previous studies on perimyocarditis, chest pain was the most frequently reported symptom, occurring in up to 95% of cases, followed by dyspnea (19–49%) and syncope in approximately 6% of cases [60,61,62]. Notably, fever was present in around 65% of patients [61]. An asymptomatic course was also reported in 5% of athletes with COVID-19-related cardiac involvement [63]. Additionally, flu-like symptoms may precede the onset of myocarditis. In this context, a large analysis with one-year follow-up showed a 7.9% risk of developing myocarditis following a respiratory tract infection with COVID-19 [64]. Other clinical presentations, including ventricular tachyarrhythmias, pericardial effusion, cardiogenic shock, and SCD, have also been described [29,31,65]. Cases of myositis and rhabdomyolysis have also been reported in patients with severe COVID-19 [66].
The electrocardiogram (ECG) has become an essential diagnostic tool in the emergency department. In general, our data showed that ECG abnormalities were present in hospitalized patients with COVID-19, including atrial fibrillation in approximately 7% of patients without diagnosed acute myocarditis, and prolonged QTc intervals as well as life-threatening arrhythmias with an incidence of 3.6% [67,68]. Nevertheless, ST-segment elevation was observed in patients with COVID-19 and perimyocarditis [65]. Based on our published and other available data, ECG remains an important diagnostic tool for the detection of arrhythmias or ST-segment deviations in patients with COVID-19-associated acute myocarditis. Patients exhibiting such ECG alterations should be classified as a high-risk group and subjected to monitoring due to the potential for malignant arrhythmias.
In terms of diagnostic utility, troponin testing is capable of detecting myocardial injury in the presence of necrosis [69,70]. It is important to note that myocarditis is not necessarily accompanied by necrosis. Consequently, the absence of elevated troponin does not necessarily rule out myocarditis but is more indicative of a severe form of myocarditis [71,72]. Troponin alone is an inadequate diagnostic tool for differentiating between myocardial injury and acute myocarditis, as it is typically elevated in both conditions. However, if troponin levels remain elevated after exclusion of myocardial ischemia for a patient with matching clinical symptoms for myocarditis, a diagnosis of myocarditis is highly probable and should be addressed by further diagnostic work-up [73]. Table 2 presents clinical presentation, ECG, troponin, and radiographic findings in COVID-19-associated acute myocarditis.
Transthoracic echocardiography can identify probable findings in patients with acute myocarditis, including reduced left ventricular ejection fraction (LVEF), segmental wall motion abnormalities, left ventricular thickening, and the presence of pericardial effusion when the pericardium is involved [59,81]. In patients with acute myocarditis, possible findings may include inferior and inferolateral wall hypokinesia, diastolic dysfunction, mild dysfunction in the right ventricle, and abnormal myocardial echogenicity [82]. LVEF serves as a prognostic indicator [61,82].
In patients with clinical suspicion of COVID-19-associated acute myocarditis, cMRI may be considered for diagnosis based on Lake-Louise criteria [83,84]. In this context, myocardial wall edema and T2 late gadolinium enhancement may occur in the setting of acute inflammation, whereas fibrotic remodeling may be more common in the later course of the disease [74]. Other potential causes can be excluded [24]. In addition, cMRI can be employed to monitor long-term outcomes or to monitor developing persistent inflammation [85,86]. However, the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases has stated that cMRI should not replace EMB in diagnosing myocarditis and also should not delay EMB in life-threatening cases [25]. EMB should be acknowledged as the gold standard for confirming the diagnosis of acute myocarditis based on the Dallas criteria [25,87]. However, in clinical practice, EMB is not routinely performed, and as a result, the diagnosis is typically based on clinical suspicion. In many cases, the underlying etiology remains unclear, and the condition is therefore referred to as clinically suspected myocarditis of unknown origin. Regarding that, cMRI is the most sensitive non-invasive diagnostic tool for detecting myocardial and pericardial involvement, and it should be considered in clinically stable patients with suspected myocarditis. Some case reports of COVID-19-associated acute myocarditis demonstrated the presence of lymphocytic infiltrates, myocardial edema, and necrosis, while others did not [78,88]. Given that the complication rate tends to decline with increasing expertise, it would be preferable for experienced centers to perform EMB [89,90].
The standard EMB, particularly the LV approach, is crucial for definitively diagnosing myocarditis and obtaining information on its pathophysiology, particularly when the right ventricle is structurally and functionally normal [91,92]. Furthermore, the sensitivity of the procedure can be enhanced by collecting more specimens than the minimum recommended number (from 4 to 6 specimens) [25]. Qualitative criteria to enhance the diagnostic yield of EMB in acute myocarditis include the Marburg criteria, which were delineated in a position statement drafted by the ESC experts [25]. However, EMB should be considered in patients with severe HF or cardiogenic shock suffering from fulminant myocarditis, ventricular arrhythmias, high-degree atrioventricular block or chronic inflammatory cardiomyopathy [17,93]. The necessity for an EMB may arise during either the acute or chronic phase of myocarditis, depending on the urgency of the matter. Furthermore, angiography may be considered to rule out myocardial infarction, especially in patients with acute myocardial injury [94].
Nevertheless, despite these findings in non-invasive diagnostic work-up, no single finding is pathognomonic for COVID-19 associated acute myocarditis. Rather, these finding should be interpreted in context with symptoms and patient history. Table 2 shows the prevalence of clinical presentations, ECG findings, laboratory parameters, radiographic and echocardiographic findings, cMRI, and EMB in patients with COVID-19-associated acute myocarditis.

6. Management of COVID-19-Associated Acute Myocarditis

To date, there are no evidence-based guidelines for the management of COVID-19-associated acute myocarditis. In terms of mortality risk, patients are typically categorized into three groups. In general, patients with clinically suspected myocarditis should avoid intense physical activity. Expert consensus recommends refraining from intense sports for a period of 3 to 6 months. For athletes, a repeat risk assessment is advised before returning to sports to evaluate their functional status and ensure safe reintegration [95]. Specific recommendations regarding driving restrictions and recovery timeline remain undefined and should be individualized. These decisions depend on the patient’s underlying comorbidities and the presence of complications, such as myocarditis-related LV dysfunction or arrhythmias causing syncope.
Low-risk patients with normal findings in echocardiography and mild symptoms and without arrhythmias were observed as outpatients [74]. Depending on the presence of symptoms, LVEF, and the occurrence of arrhythmias, patients may be classified intermediate- or high-risk [17]. However, both groups should be admitted to an advanced center as inpatients and monitored as needed. Furthermore, a number of factors influence the decision to hospitalize patients. If there are predictors of an unfavorable prognosis, such as fever, a subacute course, and evidence of a large pericardial effusion, it is recommended that the patient be admitted to the hospital [96]. If the desired outcomes of anti-inflammatory treatment do not occur within one week, hospitalization may need to be considered as the next step [97]. During the monitoring period, there is no evidence-based recommendation. Beta-blockers may be utilized for the prevention of arrhythmia. In the event that LVEF is impaired, ACE inhibitors or ARBs should be initiated according to the ESC HF guidelines [27]. In cases of severely impaired LVEF, guideline-based therapy for HF should be initiated in stable patients [24]. If patients exhibit ventricular arrhythmias, it may be advisable to provide them with a wearable cardioverter defibrillator (WCD) until a decision can be made regarding defibrillator implantation [98,99].
Patients with rapid disease progression should be managed at advanced centers with intensive care and mechanical circulatory support (MCS). If pneumonia is present, consider administering treatment with steroids [100]. For patients with pericardial involvement, it is recommended to consider the use of non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine therapy. In patients with hemodynamically relevant myocarditis or multisystem inflammatory syndrome in adults (MIS-A), intravenous steroids may be utilized. In addition, steroids may be employed in patients exhibiting biopsy-proven severe infiltrative changes or those presenting with fulminant myocarditis. Patients with HF should receive guideline-based therapy with follow-up [24]. In patients with suspected severe COVID-19-associated myocarditis, the use of intravenous corticosteroids may be considered [24,101]. In cases of recurrent or chronic inflammatory cardiomyopathy associated with autoimmune disorders, treatment should follow established guidelines for the underlying systemic condition [17]. Corticosteroids play a central role, often in combination with other immunosuppressive agents. Plasmapheresis may be employed in selected acute cases, such as myocarditis associated with antiphospholipid syndrome. In patients with refractory heart failure or cardiogenic shock, MCS, including left ventricular assist devices, or urgent heart transplantation may be necessary [17].
Myocardial injury in the context of COVID-19 has also been widely documented. This broad variability reflects the heterogeneous nature of its underlying causes, which may include acute coronary syndromes (type 1 myocardial infarction), demand ischemia (type 2 myocardial infarction), Takotsubo cardiomyopathy, sepsis, acute cor pulmonale due to macro- or microvascular pulmonary embolism, as well as injury related to chronic cardiovascular conditions such as preexisting HF. In some cases, acute viral infection may also unmask previously undiagnosed or subclinical heart disease. Given that multiple mechanisms may coexist in a single patient, determining the exact etiology of myocardial injury can be challenging, and establishing a targeted treatment strategy depends on accurate identification of the underlying cause [24]. In this review, due to the wide spectrum of myocardial injury mechanisms, we specifically focus on the management of myocarditis associated with SARS-CoV-2 infection and its vaccination.

7. Myocarditis After SARS-CoV-2-Vaccination; Should Vaccination Be Omitted?

Myocarditis following vaccination has been previously reported in the literature prior to the advent of SARS-CoV-2-vaccination [102]. However, vaccine-associated myocarditis in the context of SARS-CoV-2 vaccines has been relatively rare. Between December 2020 and June 2021, the United States Vaccine Adverse Event Reporting System (VAERS) reported 1226 possible cases of myocarditis after the administration of approximately 300 million mRNA vaccine doses. The majority of patients were male and under the age of 30 years old [103]. In a retrospective study conducted in Israel, it was observed that 5.1 million individuals who had received the full Pfizer-BioNTech mRNA vaccination, detecting 142 cases of acute myocarditis associated with SARS-CoV-2 vaccination [104]. However, individuals who had recovered from COVID-19 exhibited a fourfold higher risk of developing myocarditis compared to those who received SARS-CoV-2 vaccination [105]. As there is no systematic data regarding asymptomatic myocardial involvement after vaccination, it is possible that the data may be underestimated. Table 3 presents the incidence of vaccine-associated acute myocarditis.
Table 3. Incidence of vaccine-associated acute myocarditis.
Table 3. Incidence of vaccine-associated acute myocarditis.
Vaccine-Associated Acute Myocarditis
CountryVaccineTime PeriodIncidenceReferences
USBioNTech and ModernaDecember 2020–June 20211226/300 million doses[103]
Israel BioNTechDecember 2020–May 2021117/10.2 million doses[104]
DenmarkBioNTech and ModernaOctober 2020–October 2021269/4.1 million doses[106]
US and CanadaBioNTech and ModernaFebruary–May 202120/3.5 million doses[107]
Table 4. Clinical presentation, ECG, troponin, and radiographic findings in vaccine-associated acute myocarditis.
Table 4. Clinical presentation, ECG, troponin, and radiographic findings in vaccine-associated acute myocarditis.
Clinical PresentationVaccinePrevalenceReferences
Chest painPfizer-BioNTech/Moderna–P/M/J/AZD/C *90.1–100%[108,109,110]
SyncopeP/M/J/AZD/C *0.3%[110]
PalpitationsP/M/J/AZD/C *6.1%[110]
DyspneaPfizer-BioNTech/Moderna–P/M/J/AZD/C *25–25.7%[109,110]
CoughP/M/J/AZD/C *0.4%[110]
FeverPfizer-BioNTech/Moderna–P/M/J/AZD/C *11.9–32%[109,110]
MyalgiaPfizer-BioNTech/Moderna6%[109]
Gastrointestinal symptomsPfizer-BioNTech/Moderna–P/M/J/AZD/C *5.7–11%[109,110]
ECG
ST-segment elevationPfizer-BioNTech/Moderna–P/M/J/AZD/C *34.9–67.3%[109,110]
Other abnormal ST changesPfizer-BioNTech/Moderna9.6%[109]
Laboratory parameters
TroponinPfizer-BioNTech/Moderna–P/M/J/AZD/C *97.6–98.1%[109,110]
NT-proBNPPfizer-BioNTech/Moderna69.6%[109]
Echocardiographic findings
LV dysfunctionPfizer-BioNTech/Moderna–P/M/J/AZD/C *23.2–44%[109,110]
Wall motion abnormalitiesPfizer-BioNTech/Moderna34%[109]
Pericardial effusionPfizer-BioNTech/Moderna P/M/J/AZD/C *1.8–22%[109,110]
cMRI
T2 elevationPfizer-BioNTech/Moderna P/M/J/AZD/C *61.9–63.3%[109,110]
Late gadolinium enhancementPfizer-BioNTech/Moderna P/M/J/AZD/C *80.7–95.2%[109,110]
Pericardial effusionP/M/J/AZD/C *4.2%[110]
Behers et al. [109]: median of age 24 years (14–80 years old), time to symptom onset 3 days (1–90 days), vaccine: Pfizer 69.8% (first dose 13.2%, second dose 54.7%), Moderna 30.2% (first dose 5.7%, second dose 24.5%). Goyal et al. [110]: mean of age 25.5 ± 14.2 years old, time to symptom onset 4.01 ± 6.99 days, vaccine: mRNA-based vaccine (99.4%). *, Pfizer-BioNTech 73%, Moderna 26.4%, Janssen (J&J) 0.3%, AstraZeneca 0.2%, COVAXIN (Bharat Biotech) 0.04%, first dose 16.8%, second dose 83.2%. Abbreviation: ECG, electrocardiogram; ST-segment, ST segment is the flat, isoelectric section of the ECG between the end of the S wave (the J point) and the beginning of the T wave; NT-proBNP, N-terminal pro-brain natriuretic peptide; LV, left ventricular; cMRI, cardiac magnet resonance imaging.
The pathophysiology of COVID-19 vaccine-associated myocarditis is not understood at this time, but ongoing research may provide more information in the future. However, several hypotheses have been suggested. In the presence of predisposing factors such as age and male sex, the mRNA molecules themselves may be immunogenic, activating the innate immune system and leading to their destruction before they enter the host cells [111]. Yonker et al. reported that spike proteins may play a potentially important role in the development of COVID-19 vaccine-associated myocarditis [112]. In this context, a potential decrease or impairment in neutralizing antibodies has been discussed, resulting in higher levels of circulating spike proteins, with particular emphasis on the crucial role of anti-idiotype antibodies [113]. However, the mRNA molecules can also induce a systemic response resulting in myocardial damage. In this case, there should be evidence of involvement of other organs. Molecular mimicry between the spike proteins of SARS-CoV-2 and host self-antigens also seems theoretically possible [114]. Antibodies released in response to spike proteins may lead to cross-reactivity with other structures, such as a-myosin heavy chain, and result in myocardial damage as they attack it [115]. In addition, an increased dose of mRNA vaccine has been associated with the risk of myocarditis in groups at risk for vaccine-associated myocarditis [116,117]. Figure 1 represents the pathophysiology of vaccine-associated acute myocarditis. Regarding symptomatology, symptoms typically begin within the first few days after administration of the second dose of SARS-CoV-2 vaccine [118]. Almost all patients presenting with SARS-CoV-2-associated myocarditis present with chest pain (90.1–100%). This may reflect a selection bias to identify only symptomatic cases [108,109,110]. Troponin levels are elevated in most patients, peaking between 48 and 72 h after symptom onset [34]. In patients with suspected vaccine-associated myocarditis, cMRI is an invaluable diagnostic tool for establishing a diagnosis [119,120]. Table 4 illustrates the clinical presentation, ECG findings, troponin levels and radiographic findings of vaccine-associated acute myocarditis.
In accordance with current ESC guidelines, large population studies have demonstrated the safety of the SARS-CoV-2 vaccine, and anecdotal reports of vaccine-associated complications in patients with cardiomyopathy are available. It is recommended that all patients with cardiomyopathy receive the vaccine, especially those with signs or symptoms of HF, given the potential for worse outcomes in patients with cardiomyopathy who contract COVID-19 [121]. In general, patients exhibit a favorable prognosis, and the SARS-CoV-2 vaccine has a favorable benefit-to-risk ratio across all age and gender groups [30]. Data on evidence-based therapy is currently lacking. Nevertheless, some studies have utilized therapy with NSAIDs [122].

8. Outcomes and Long-Term Cardiac Complications Following COVID-19-Associated Myocarditis

An increased risk of cardiac arrhythmias and myocarditis was observed in COVID-19 patients compared to patients without COVID-19 with lower respiratory tract illnesses in 2019 [123]. Furthermore, in-hospital mortality rate for patients with myocarditis and concomitant SARS-CoV-2 infection was sixfold higher than that observed in patients with myocarditis alone [124]. Moreover, fatal myocarditis cases attributed to the SARS-CoV-2 vaccine have been documented [125]. The mortality rate in these groups remains high [126]. Nevertheless, the quality of the current evidence on the causal relationship and incidence of COVID-19 vaccine-associated myocarditis and HF remains low [127]. A cohort of 587,330 hospitalized patients in the US was divided into two groups; half had COVID-19, and the other half did not. During the 467-day follow-up period, HF developed in 10,979 previously unaffected patients. After adjusting for confounding factors, hospitalization due to COVID-19 was associated with an increased risk of HF (hazard ratio = 1.45, 95% confidence interval: 1.39–1.51). Age and race, specifically young age and white race, were identified as risk factors for HF after COVID-19 [128]. Furthermore, it has been demonstrated that acute decompensated HF in the context of a COVID-19 infection was associated with a higher mortality rate than acute decompensated HF without a COVID-19 infection [129]. Further analyses of COVID-19 patients in comparison to the control group revealed an elevated incidence of cardiovascular disease, including arrhythmia, ischemic and non-ischemic cardiomyopathy, as well as HF [130,131]. In the US, mortality rates due to HF increased in the early phases of the pandemic [132]. These data indicate that HF is a significant long-term effect of COVID-19 and may be prevented by adequate primary prevention measures against SARS-CoV-2 infection, as well as close follow-up care for COVID-19 patients [133]. It is noteworthy that the incidence of heart transplantation in 2020 exhibited a decline in many countries, although this trend was not universal [134]. However, there is still a lack of data regarding long-term epidemiology as well as treatment recommendations.

9. Current Evidence and Future Trends

In our international HOPE-COVID-19-registry, we conducted multiple subanalyses related to COVID-19 infection. However, the registry, similar to other registries, did not specifically examine COVID-19-associated acute myocarditis [135,136,137,138]. As evidenced by data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), the age-adjusted prevalence of myocarditis remained stable during the initial two years of the pandemic, when compared to the year prior to its onset [139]. The age-adjusted years lived with disability (YLDs) also remained unchanged. However, age-standardized mortality associated with myocarditis has been observed to decline over recent years [139]. One study indicated that at least half of the cases of myocarditis in the initial year of the pandemic were infected with SARS-CoV-2 [140]. In this context, it can be postulated that the prevalence of myocarditis has remained consistent, although there has been an increased prevalence of COVID-19-associated myocarditis. It remains to be seen how the trend will develop over the next few years. In addition, further investigation is necessary to understand the mechanisms and impact of acute myocarditis in COVID-19 patients on short-term as well as long-term follow-up. Similarly, close clinical as well as imaging follow-up should be undertaken to evaluate the vaccination associated myocarditis and SCD at long-term follow-up. Based on these data, treatment algorithms should be evaluated and underpinned by evidence.

Author Contributions

M.A., T.S., M.B., I.E.-B., N.H. and I.A. contributed to idea generation, writing, and revision; M.A.: Writing-original draft and drawing figure; I.A.: Supervision. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

This review is not financially supported.

Conflicts of Interest

The authors declare no competing interests. This encompassed all of the following: (1) the conception and design of the manuscript, the analysis and interpretation of data; (2) drafting the article or critically revising its important intellectual content; (3) final approval of the version submitted.

References

  1. Zhang, J.J.; Dong, X.; Liu, G.H.; Gao, Y.D. Risk and Protective Factors for COVID-19 Morbidity, Severity, and Mortality. Clin. Rev. Allergy Immunol. 2023, 64, 90–107. [Google Scholar] [CrossRef] [PubMed]
  2. Li, G.; Fan, Y.; Lai, Y.; Han, T.; Li, Z.; Zhou, P.; Pan, P.; Wang, W.; Hu, D.; Liu, X. Coronavirus infections and immune responses. J. Med. Virol. 2020, 92, 424–432. [Google Scholar] [CrossRef] [PubMed]
  3. Fauci, A.S.; Lane, H.C.; Redfield, R.R. COVID-19—Navigating the Uncharted. N. Engl. J. Med. 2020, 382, 1268–1269. [Google Scholar] [CrossRef]
  4. Berlin, D.A.; Gulick, R.M.; Martinez, F.J. Severe COVID-19. N. Engl. J. Med. 2020, 383, 2451–2460. [Google Scholar] [CrossRef] [PubMed]
  5. Li, C.; Jiang, J.; Wang, F.; Zhou, N.; Veronese, G.; Moslehi, J.J.; Ammirati, E.; Wang, D.W. Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients. J. Mol. Cell. Cardiol. 2020, 147, 74–87. [Google Scholar] [CrossRef]
  6. Alvarez-Garcia, J.; Jaladanki, S.; Rivas-Lasarte, M.; Cagliostro, M.; Gupta, A.; Joshi, A.; Ting, P.; Mitter, S.S.; Bagiella, E.; Mancini, D. New Heart Failure Diagnoses Among Patients Hospitalized for COVID-19. J. Am. Coll. Cardiol. 2021, 77, 2260–2262. [Google Scholar] [CrossRef]
  7. Castiello, T.; Georgiopoulos, G.; Finocchiaro, G.; Claudia, M.; Gianatti, A.; Delialis, D.; Aimo, A.; Prasad, S. COVID-19 and myocarditis: A systematic review and overview of current challenges. Heart Fail. Rev. 2022, 27, 251–261. [Google Scholar] [CrossRef]
  8. Chen, L.; Li, X.; Chen, M.; Feng, Y.; Xiong, C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc. Res. 2020, 116, 1097–1100. [Google Scholar] [CrossRef]
  9. Akhmerov, A.; Marban, E. COVID-19 and the Heart. Circ. Res. 2020, 126, 1443–1455. [Google Scholar] [CrossRef]
  10. Lindner, D.; Fitzek, A.; Brauninger, H.; Aleshcheva, G.; Edler, C.; Meissner, K.; Scherschel, K.; Kirchhof, P.; Escher, F.; Schultheiss, H.P. Association of Cardiac Infection with SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases. JAMA Cardiol. 2020, 5, 1281–1285. [Google Scholar] [CrossRef]
  11. Bearse, M.; Hung, Y.P.; Krauson, A.J.; Bonanno, L.; Boyraz, B.; Harris, C.K.; Helland, T.L.; Hilburn, C.F.; Hutchison, B.; Jobbagy, S.; et al. Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19. Mod. Pathol. 2021, 34, 1345–1357. [Google Scholar] [CrossRef] [PubMed]
  12. Scally, C.; Abbas, H.; Ahearn, T.; Srinivasan, J.; Mezincescu, A.; Rudd, A.; Spath, N.; Yucel-Finn, A.; Yuecel, R.; Oldroyd, K.; et al. Myocardial and Systemic Inflammation in Acute Stress-Induced (Takotsubo) Cardiomyopathy. Circulation 2019, 139, 1581–1592. [Google Scholar] [CrossRef]
  13. Bader, F.; Manla, Y.; Atallah, B.; Starling, R.C. Heart failure and COVID-19. Heart Fail. Rev. 2021, 26, 1–10. [Google Scholar] [CrossRef] [PubMed]
  14. Roth, G.A.; Mensah, G.A.; Johnson, C.O.; Addolorato, G.; Ammirati, E.; Baddour, L.M.; Barengo, N.C.; Beaton, A.Z.; Benjamin, E.J.; Benziger, C.P.; et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019: Update from the GBD 2019 Study. J. Am. Coll. Cardiol. 2020, 76, 2982–3021. [Google Scholar] [CrossRef] [PubMed]
  15. Fu, M.; Kontogeorgos, S.; Thunstrom, E.; Zverkova Sandstrom, T.; Kroon, C.; Bollano, E.; Schaufelberger, M.; Rosengren, A. Trends in myocarditis incidence, complications and mortality in Sweden from 2000 to 2014. Sci. Rep. 2022, 12, 1810. [Google Scholar] [CrossRef]
  16. Pahuja, M.; Adegbala, O.; Mishra, T.; Akintoye, E.; Chehab, O.; Mony, S.; Singh, M.; Ando, T.; Abubaker, H.; Yassin, A.; et al. Trends in the Incidence of In-Hospital Mortality, Cardiogenic Shock, and Utilization of Mechanical Circulatory Support Devices in Myocarditis (Analysis of National Inpatient Sample Data, 2005–2014). J. Card. Fail. 2019, 25, 457–467. [Google Scholar] [CrossRef]
  17. Ammirati, E.; Frigerio, M.; Adler, E.D.; Basso, C.; Birnie, D.H.; Brambatti, M.; Friedrich, M.G.; Klingel, K.; Lehtonen, J.; Moslehi, J.J.; et al. Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document. Circ. Heart Fail. 2020, 13, e007405. [Google Scholar] [CrossRef]
  18. Tschope, C.; Ammirati, E.; Bozkurt, B.; Caforio, A.L.P.; Cooper, L.T.; Felix, S.B.; Hare, J.M.; Heidecker, B.; Heymans, S.; Hübner, N.; et al. Myocarditis and inflammatory cardiomyopathy: Current evidence and future directions. Nat. Rev. Cardiol. 2021, 18, 169–193. [Google Scholar] [CrossRef]
  19. Nguyen, L.S.; Cooper, L.T.; Kerneis, M.; Funck-Brentano, C.; Silvain, J.; Brechot, N.; Hekimian, G.; Ammirati, E.; Ben M’barek, B.; Redheuil, A.; et al. Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database. Nat. Commun. 2022, 13, 25. [Google Scholar] [CrossRef]
  20. Khan, A.A.; Ashraf, A.; Baker, D.; Al-Omary, M.S.; Savage, L.; Ekmejian, A.; Singh, R.S.H.; Brienesse, S.; Majeed, T.; Gordon, T.; et al. Clozapine and incidence of myocarditis and sudden death—Long term Australian experience. Int. J. Cardiol. 2017, 238, 136–139. [Google Scholar] [CrossRef]
  21. Harmon, K.G.; Drezner, J.A.; Maleszewski, J.J.; Lopez-Anderson, M.; Owens, D.; Prutkin, J.M.; Asif, I.M.; Klossner, D.; Ackerman, M.J. Pathogeneses of sudden cardiac death in national collegiate athletic association athletes. Circ. Arrhythm. Electrophysiol. 2014, 7, 198–204. [Google Scholar] [CrossRef] [PubMed]
  22. Lieberman, E.B.; Hutchins, G.M.; Herskowitz, A.; Rose, N.R.; Baughman, K.L. Clinicopathologic description of myocarditis. J. Am. Coll. Cardiol. 1991, 18, 1617–1626. [Google Scholar] [CrossRef] [PubMed]
  23. Ferreira, V.M.; Schulz-Menger, J.; Holmvang, G.; Kramer, C.M.; Carbone, I.; Sechtem, U.; Kindermann, I.; Gutberlet, M.; Cooper, L.T.; Liu, P.; et al. Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations. J. Am. Coll. Cardiol. 2018, 72, 3158–3176. [Google Scholar] [CrossRef] [PubMed]
  24. Writing Committee; Gluckman, T.J.; Bhave, N.M.; Allen, L.A.; Chung, E.H.; Spatz, E.S.; Ammirati, E.; Baggish, A.L.; Bozkurt, B.; Cornwell, W.K.; et al. 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee. J. Am. Coll. Cardiol. 2022, 79, 1717–1756. [Google Scholar]
  25. Caforio, A.L.; Pankuweit, S.; Arbustini, E.; Basso, C.; Gimeno-Blanes, J.; Felix, S.B.; Fu, M.; Heliö, T.; Heymans, S.; Jahns, R.; et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur. Heart J. 2013, 34, 2636–2648. [Google Scholar] [CrossRef]
  26. Caceres-Acosta, M.F.; Idrobo, B.D.; Urbano Alban, D.C. SARS-CoV-2 dilated cardiomyopathy. Br. J. Cardiol. 2022, 29, 30. [Google Scholar]
  27. McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Bohm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. Corrigendum to: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 2021, 42, 4901. [Google Scholar]
  28. Ho, J.S.; Sia, C.H.; Chan, M.Y.; Lin, W.; Wong, R.C. Coronavirus-induced myocarditis: A meta-summary of cases. Heart Lung 2020, 49, 681–685. [Google Scholar] [CrossRef]
  29. Hu, H.; Ma, F.; Wei, X.; Fang, Y. Corrigendum to: Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. Eur. Heart J. 2021, 42, 191. [Google Scholar] [CrossRef]
  30. Huyut, M.A. Novel Coronavirus Pneumonia and Cardiomyopathy: A Case Report. Arq. Bras. Cardiol. 2020, 114, 843–845. [Google Scholar] [CrossRef]
  31. Zeng, J.H.; Liu, Y.X.; Yuan, J.; Wang, F.X.; Wu, W.B.; Li, J.X.; Wang, L.F.; Gao, H.; Wang, Y.; Dong, C.F.; et al. First case of COVID-19 complicated with fulminant myocarditis: A case report and insights. Infection 2020, 48, 773–777. [Google Scholar] [CrossRef] [PubMed]
  32. Yan, L.; Mir, M.; Sanchez, P.; Beg, M.; Peters, J.; Enriquez, O.; Gilbert, A. COVID-19 in a Hispanic Woman. Arch. Pathol. Lab. Med. 2020, 144, 1041–1047. [Google Scholar] [CrossRef] [PubMed]
  33. Newton-Cheh, C.; Zlotoff, D.A.; Hung, J.; Rupasov, A.; Crowley, J.C.; Funamoto, M. Case 24-2020: A 44-Year-Old Woman with Chest Pain, Dyspnea, and Shock. N. Engl. J. Med. 2020, 383, 475–484. [Google Scholar] [CrossRef] [PubMed]
  34. Montgomery, J.; Ryan, M.; Engler, R.; Hoffman, D.; McClenathan, B.; Collins, L.; Loran, D.; Hrncir, D.; Herring, K.; Platzer, M.; et al. Myocarditis Following Immunization with mRNA COVID-19 Vaccines in Members of the US Military. JAMA Cardiol. 2021, 6, 1202–1206. [Google Scholar] [CrossRef]
  35. Kim, H.W.; Jenista, E.R.; Wendell, D.C.; Azevedo, C.F.; Campbell, M.J.; Darty, S.N.; Parker, M.A.; Kim, R.J. Patients with Acute Myocarditis Following mRNA COVID-19 Vaccination. JAMA Cardiol. 2021, 6, 1196–1201. [Google Scholar] [CrossRef]
  36. Thygesen, K.; Alpert, J.S.; Jaffe, A.S.; Chaitman, B.R.; Bax, J.J.; Morrow, D.A.; White, H.D.; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). J. Am. Coll. Cardiol. 2018, 72, 2231–2264. [Google Scholar] [CrossRef]
  37. Siripanthong, B.; Nazarian, S.; Muser, D.; Deo, R.; Santangeli, P.; Khanji, M.Y.; Cooper, L.T.; Chahal, C.A.A. Recognizing COVID-19-related myocarditis: The possible pathophysiology and proposed guideline for diagnosis and management. Heart Rhythm 2020, 17, 1463–1471. [Google Scholar] [CrossRef]
  38. Daniels, C.J.; Rajpal, S.; Greenshields, J.T.; Rosenthal, G.L.; Chung, E.H.; Terrin, M.; Jeudy, J.; Mattson, S.E.; Law, I.H.; Borchers, J.; et al. Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes with Recent SARS-CoV-2 Infection: Results From the Big Ten COVID-19 Cardiac Registry. JAMA Cardiol. 2021, 6, 1078–1087. [Google Scholar] [CrossRef]
  39. Buckley, B.J.R.; Harrison, S.L.; Fazio-Eynullayeva, E.; Underhill, P.; Lane, D.A.; Lip, G.Y.H. Prevalence and clinical outcomes of myocarditis and pericarditis in 718,365 COVID-19 patients. Eur. J. Clin. Investig. 2021, 51, e13679. [Google Scholar] [CrossRef]
  40. Ammirati, E.; Lupi, L.; Palazzini, M.; Hendren, N.S.; Grodin, J.L.; Cannistraci, C.V.; Schmidt, M.; Hekimian, G.; Peretto, G.; Bochaton, T.; et al. Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis. Circulation 2022, 145, 1123–1139. [Google Scholar] [CrossRef]
  41. Basso, C.; Leone, O.; Rizzo, S.; De Gaspari, M.; van der Wal, A.C.; Aubry, M.C.; Bois, M.C.; Lin, P.T.; Maleszewski, J.J.; Stone, J.R. Pathological features of COVID-19-associated myocardial injury: A multicentre cardiovascular pathology study. Eur. Heart J. 2020, 41, 3827–3835. [Google Scholar] [CrossRef] [PubMed]
  42. Halushka, M.K.; Vander Heide, R.S. Myocarditis is rare in COVID-19 autopsies: Cardiovascular findings across 277 postmortem examinations. Cardiovasc. Pathol. 2021, 50, 107300. [Google Scholar] [CrossRef]
  43. Shi, S.; Qin, M.; Shen, B.; Cai, Y.; Liu, T.; Yang, F.; Gong, W.; Liu, X.; Liang, J.; Zhao, Q.; et al. Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020, 5, 802–810. [Google Scholar] [CrossRef]
  44. Guo, T.; Fan, Y.; Chen, M.; Wu, X.; Zhang, L.; He, T.; Wang, H.; Wan, J.; Wang, X.; Lu, Z. Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020, 5, 811–818. [Google Scholar] [CrossRef] [PubMed]
  45. Heberto, A.B.; Carlos, P.C.J.; Antonio, C.R.J.; Patricia, P.P.; Enrique, T.R.; Danira, M.P.J.; Benito, G.Á.E.; Alfredo, M.R.J. Implications of myocardial injury in Mexican hospitalized patients with coronavirus disease 2019 (COVID-19). Int. J. Cardiol. Heart Vasc. 2020, 30, 100638. [Google Scholar] [CrossRef] [PubMed]
  46. Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579, 270–273. [Google Scholar] [CrossRef]
  47. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Kruger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280 e8. [Google Scholar] [CrossRef]
  48. Bailey, A.L.; Dmytrenko, O.; Greenberg, L.; Bredemeyer, A.L.; Ma, P.; Liu, J.; Penna, V.; Winkler, E.S.; Sviben, S.; Brooks, E.; et al. SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis. JACC Basic Transl. Sci. 2021, 6, 331–345. [Google Scholar] [CrossRef]
  49. Theoharides, T.C. Potential association of mast cells with coronavirus disease 2019. Ann. Allergy Asthma Immunol. 2021, 126, 217–218. [Google Scholar] [CrossRef]
  50. Hikmet, F.; Mear, L.; Edvinsson, A.; Micke, P.; Uhlen, M.; Lindskog, C. The protein expression profile of ACE2 in human tissues. Mol. Syst. Biol. 2020, 16, e9610. [Google Scholar] [CrossRef]
  51. Bojkova, D.; Wagner, J.U.G.; Shumliakivska, M.; Aslan, G.S.; Saleem, U.; Hansen, A.; Luxán, G.; Günther, S.; Pham, M.D.; Krishnan, J.; et al. SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes. Cardiovasc. Res. 2020, 116, 2207–2215. [Google Scholar] [CrossRef]
  52. Robinson, E.L.; Alkass, K.; Bergmann, O.; Maguire, J.J.; Roderick, H.L.; Davenport, A.P. Genes encoding ACE2, TMPRSS2 and related proteins mediating SARS-CoV-2 viral entry are upregulated with age in human cardiomyocytes. J. Mol. Cell. Cardiol. 2020, 147, 88–91. [Google Scholar] [CrossRef] [PubMed]
  53. Song, X.; Hu, W.; Yu, H.; Zhao, L.; Zhao, Y.; Zhao, X.; Xue, H.; Zhao, Y. Little to no expression of angiotensin-converting enzyme-2 on most human peripheral blood immune cells but highly expressed on tissue macrophages. Cytom. Part A 2023, 103, 136–145. [Google Scholar] [CrossRef] [PubMed]
  54. Angileri, F.; Legare, S.; Gammazza, A.M.; de Macario, E.C.; Macario, A.J.; Cappello, F. Molecular mimicry may explain multi-organ damage in COVID-19. Autoimmun. Rev. 2020, 19, 102591. [Google Scholar] [CrossRef]
  55. Fairweather, D.; Beetler, D.J.; Di Florio, D.N.; Musigk, N.; Heidecker, B.; Cooper, L.T., Jr. COVID-19, Myocarditis and Pericarditis. Circ. Res. 2023, 132, 1302–1319. [Google Scholar] [CrossRef] [PubMed]
  56. Ryabkova, V.A.; Churilov, L.P.; Shoenfeld, Y. Influenza infection, SARS, MERS and COVID-19: Cytokine storm-The common denominator and the lessons to be learned. Clin. Immunol. 2021, 223, 108652. [Google Scholar] [CrossRef]
  57. Fairweather, D.; Kaya, Z.; Shellam, G.R.; Lawson, C.M.; Rose, N.R. From infection to autoimmunity. J. Autoimmun. 2001, 16, 175–186. [Google Scholar] [CrossRef]
  58. Kim, I.C.; Kim, J.Y.; Kim, H.A.; Han, S. COVID-19-related myocarditis in a 21-year-old female patient. Eur. Heart J. 2020, 41, 1859. [Google Scholar] [CrossRef]
  59. Sala, S.; Peretto, G.; Gramegna, M.; Palmisano, A.; Villatore, A.; Vignale, D.; De Cobelli, F.; Tresoldi, M.; Cappelletti, A.M.; Basso, C.; et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur. Heart J. 2020, 41, 1861–1862. [Google Scholar] [CrossRef]
  60. Younis, A.; Matetzky, S.; Mulla, W.; Masalha, E.; Afel, Y.; Chernomordik, F.; Fardman, A.; Goitein, O.; Ben-Zekry, S.; Peled, Y.; et al. Epidemiology Characteristics and Outcome of Patients with Clinically Diagnosed Acute Myocarditis. Am. J. Med. 2020, 133, 492–499. [Google Scholar] [CrossRef]
  61. Ammirati, E.; Cipriani, M.; Moro, C.; Raineri, C.; Pini, D.; Sormani, P.; Mantovani, R.; Varrenti, M.; Pedrotti, P.; Conca, C.; et al. Clinical Presentation and Outcome in a Contemporary Cohort of Patients with Acute Myocarditis: Multicenter Lombardy Registry. Circulation 2018, 138, 1088–1099. [Google Scholar] [CrossRef]
  62. White, J.A.; Hansen, R.; Abdelhaleem, A.; Mikami, Y.; Peng, M.; Rivest, S.; Satriano, A.; Dykstra, S.; Flewitt, J.; Heydari, B.; et al. Natural History of Myocardial Injury and Chamber Remodeling in Acute Myocarditis. Circ. Cardiovasc. Imaging. 2019, 12, e008614. [Google Scholar] [CrossRef] [PubMed]
  63. Moulson, N.; Petek, B.J.; Drezner, J.A.; Harmon, K.G.; Kliethermes, S.A.; Patel, M.R.; Baggish, A.L. SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes. Circulation 2021, 144, 256–266. [Google Scholar] [CrossRef] [PubMed]
  64. Zuin, M.; Rigatelli, G.; Bilato, C.; Porcari, A.; Merlo, M.; Roncon, L.; Sinagra, G. One-Year Risk of Myocarditis After COVID-19 Infection: A Systematic Review and Meta-analysis. Can. J. Cardiol. 2023, 39, 839–844. [Google Scholar] [CrossRef] [PubMed]
  65. Inciardi, R.M.; Lupi, L.; Zaccone, G.; Italia, L.; Raffo, M.; Tomasoni, D.; Cani, D.S.; Cerini, M.; Farina, D.; Gavazzi, E.; et al. Cardiac Involvement in a Patient with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020, 5, 819–824. [Google Scholar] [CrossRef]
  66. Freund, O.; Eviatar, T.; Bornstein, G. Concurrent myopathy and inflammatory cardiac disease in COVID-19 patients: A case series and literature review. Rheumatol. Int. 2022, 42, 905–912. [Google Scholar] [CrossRef]
  67. Susca, N.; Solimando, A.G.; Borrelli, P.; Marziliano, D.; Monitillo, F.; Raimondo, P.; Vestito, D.; Lopizzo, A.; Brindicci, G.; Abumayyaleh, M.; et al. Electrocardiographic Pathological Findings Caused by the SARS-CoV-2 Virus Infection: Evidence from a Retrospective Multicenter International Cohort Longitudinal Pilot Study of 548 Subjects. J. Cardiovasc. Dev. Dis. 2023, 10, 58. [Google Scholar] [CrossRef]
  68. Santoro, F.; Monitillo, F.; Raimondo, P.; Lopizzo, A.; Brindicci, G.; Gilio, M.; Musaico, F.; Mazzola, M.; Vestito, D.; Di Benedetto, R.; et al. QTc Interval Prolongation and Life-Threatening Arrhythmias During Hospitalization in Patients with Coronavirus Disease 2019 (COVID-19): Results From a Multicenter Prospective Registry. Clin. Infect. Dis. 2021, 73, e4031–e4038. [Google Scholar] [CrossRef]
  69. Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020, 395, 1054–1062. [Google Scholar] [CrossRef]
  70. Lovell, J.P.; Cihakova, D.; Gilotra, N.A. COVID-19 and Myocarditis: Review of Clinical Presentations, Pathogenesis and Management. Heart Int. 2022, 16, 20–27. [Google Scholar] [CrossRef]
  71. Berg, J.; Kottwitz, J.; Baltensperger, N.; Kissel, C.K.; Lovrinovic, M.; Mehra, T.; Scherff, F.; Schmied, C.; Templin, C.; Lüscher, T.F.; et al. Cardiac Magnetic Resonance Imaging in Myocarditis Reveals Persistent Disease Activity Despite Normalization of Cardiac Enzymes and Inflammatory Parameters at 3-Month Follow-Up. Circ. Heart Fail. 2017, 10, e004262. [Google Scholar] [CrossRef] [PubMed]
  72. Gilotra, N.A.; Minkove, N.; Bennett, M.K.; Tedford, R.J.; Steenbergen, C.; Judge, D.P.; Halushka, M.K.; Russell, S.D. Lack of Relationship Between Serum Cardiac Troponin I Level and Giant Cell Myocarditis Diagnosis and Outcomes. J. Card. Fail. 2016, 22, 583–585. [Google Scholar] [CrossRef]
  73. Peretto, G.; Sala, S.; Caforio, A.L.P. Acute myocardial injury, MINOCA, or myocarditis? Improving characterization of coronavirus-associated myocardial involvement. Eur. Heart J. 2020, 41, 2124–2125. [Google Scholar] [CrossRef]
  74. Rout, A.; Suri, S.; Vorla, M.; Kalra, D.K. Myocarditis associated with COVID-19 and its vaccines—A systematic review. Prog. Cardiovasc. Dis. 2022, 74, 111–121. [Google Scholar] [CrossRef]
  75. Sawalha, K.; Abozenah, M.; Kadado, A.J.; Battisha, A.; Al-Akchar, M.; Salerno, C.; Hernandez-Montfort, J.; Islam, A.M. Systematic Review of COVID-19 Related Myocarditis: Insights on Management and Outcome. Cardiovasc. Revasc. Med. 2021, 23, 107–113. [Google Scholar] [CrossRef] [PubMed]
  76. Theetha Kariyanna, P.; Sabih, A.; Sutarjono, B.; Shah, K.; Vargas Pelaez, A.; Lewis, J.; Yu, R.; Grewal, E.S.; Jayarangaiah, A.; Das, S.; et al. A Systematic Review of COVID-19 and Pericarditis. Cureus 2022, 14, e27948. [Google Scholar] [CrossRef] [PubMed]
  77. Yan, X.; Wang, S.; Ma, P.; Yang, B.; Si, D.; Liu, G.; Liu, L.; Ding, M.; Yang, W.; Li, J.; et al. Cardiac injury is associated with inflammation in geriatric COVID-19 patients. J. Clin. Lab. Anal. 2021, 35, e23654. [Google Scholar] [CrossRef]
  78. Rathore, S.S.; Rojas, G.A.; Sondhi, M.; Pothuru, S.; Pydi, R.; Kancherla, N.; Singh, R.; Ahmed, N.K.; Shah, J.; Tousif, S.; et al. Myocarditis associated with COVID-19 disease: A systematic review of published case reports and case series. Int. J. Clin. Pract. 2021, 75, e14470. [Google Scholar] [CrossRef]
  79. Starekova, J.; Bluemke, D.A.; Bradham, W.S.; Eckhardt, L.L.; Grist, T.M.; Kusmirek, J.E.; Purtell, C.S.; Schiebler, M.L.; Reeder, S.B. Evaluation for Myocarditis in Competitive Student Athletes Recovering From Coronavirus Disease 2019 with Cardiac Magnetic Resonance Imaging. JAMA Cardiol. 2021, 6, 945–950. [Google Scholar] [CrossRef]
  80. Lagana, N.; Cei, M.; Evangelista, I.; Cerutti, S.; Colombo, A.; Conte, L.; Mormina, E.; Rotiroti, G.; Versace, A.G.; Porta, C.; et al. Suspected myocarditis in patients with COVID-19: A multicenter case series. Medicine 2021, 100, e24552. [Google Scholar] [CrossRef]
  81. Dweck, M.R.; Bularga, A.; Hahn, R.T.; Bing, R.; Lee, K.K.; Chapman, A.R.; White, A.; Di Salvo, G.; Sade, L.E.; Pearce, K.; et al. Global evaluation of echocardiography in patients with COVID-19. Eur. Heart J. Cardiovasc. Imaging 2020, 21, 949–958. [Google Scholar] [CrossRef]
  82. Ammirati, E.; Veronese, G.; Brambatti, M.; Merlo, M.; Cipriani, M.; Potena, L.; Sormani, P.; Aoki, T.; Sugimura, K.; Sawamura, A.; et al. Fulminant Versus Acute Nonfulminant Myocarditis in Patients with Left Ventricular Systolic Dysfunction. J. Am. Coll. Cardiol. 2019, 74, 299–311. [Google Scholar] [CrossRef] [PubMed]
  83. Kelle, S.; Bucciarelli-Ducci, C.; Judd, R.M.; Kwong, R.Y.; Simonetti, O.; Plein, S.; Raimondi, F.; Weinsaft, J.W.; Wong, T.C.; Carr, J. Society for Cardiovascular Magnetic Resonance (SCMR) recommended CMR protocols for scanning patients with active or convalescent phase COVID-19 infection. J. Cardiovasc. Magn. Reson. 2020, 22, 61. [Google Scholar] [CrossRef]
  84. Clark, D.E.; Aggarwal, S.K.; Phillips, N.J.; Soslow, J.H.; Dendy, J.M.; Hughes, S.G. Cardiac Magnetic Resonance in the Evaluation of COVID-19. Card. Fail. Rev. 2022, 8, e09. [Google Scholar] [CrossRef] [PubMed]
  85. Puntmann, V.O.; Carerj, M.L.; Wieters, I.; Fahim, M.; Arendt, C.; Hoffmann, J.; Shchendrygina, A.; Escher, F.; Vasa-Nicotera, M.; Zeiher, A.M.; et al. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered from Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020, 5, 1265–1273. [Google Scholar] [CrossRef] [PubMed]
  86. Puntmann, V.O.; Martin, S.; Shchendrygina, A.; Hoffmann, J.; Ka, M.M.; Giokoglu, E.; Vanchin, B.; Holm, N.; Karyou, A.; Laux, G.S.; et al. Long-term cardiac pathology in individuals with mild initial COVID-19 illness. Nat. Med. 2022, 28, 2117–2123. [Google Scholar] [CrossRef]
  87. Aretz, H.T. Myocarditis: The Dallas criteria. Hum. Pathol. 1987, 18, 619–624. [Google Scholar] [CrossRef]
  88. Haussner, W.; DeRosa, A.P.; Haussner, D.; Tran, J.; Torres-Lavoro, J.; Kamler, J.; Shah, K. COVID-19 associated myocarditis: A systematic review. Am. J. Emerg. Med. 2022, 51, 150–155. [Google Scholar] [CrossRef]
  89. Bennett, M.K.; Gilotra, N.A.; Harrington, C.; Rao, S.; Dunn, J.M.; Freitag, T.B.; Halushka, M.K.; Russell, S.D. Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from 2000-2009. Circ. Heart Fail. 2013, 6, 676–684. [Google Scholar] [CrossRef]
  90. Singh, V.; Mendirichaga, R.; Savani, G.T.; Rodriguez, A.; Blumer, V.; Elmariah, S.; Inglessis-Azuaje, I.; Palacios, I. Comparison of Utilization Trends, Indications, and Complications of Endomyocardial Biopsy in Native Versus Donor Hearts (from the Nationwide Inpatient Sample 2002 to 2014). Am. J. Cardiol. 2018, 121, 356–363. [Google Scholar] [CrossRef]
  91. Cooper, L.T.; Baughman, K.L.; Feldman, A.M.; Frustaci, A.; Jessup, M.; Kuhl, U.; Levine, G.N.; Narula, J.; Starling, R.C.; Towbin, J.; et al. The role of endomyocardial biopsy in the management of cardiovascular disease: A scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J. Am. Coll. Cardiol. 2007, 50, 1914–1931. [Google Scholar]
  92. Chimenti, C.; Frustaci, A. Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: A retrospective study over a 28-year period. Circulation 2013, 128, 1531–1541. [Google Scholar] [CrossRef] [PubMed]
  93. Kociol, R.D.; Cooper, L.T.; Fang, J.C.; Moslehi, J.J.; Pang, P.S.; Sabe, M.A.; Shah, R.V.; Sims, D.B.; Thiene, G.; Vardeny, O.; et al. Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association. Circulation 2020, 141, e69–e92. [Google Scholar] [CrossRef] [PubMed]
  94. Sarda, L.; Colin, P.; Boccara, F.; Daou, D.; Lebtahi, R.; Faraggi, M.; Nguyen, C.; Cohen, A.; Slama, M.S.; Steg, P.G.; et al. Myocarditis in patients with clinical presentation of myocardial infarction and normal coronary angiograms. J. Am. Coll. Cardiol. 2001, 37, 786–792. [Google Scholar] [CrossRef]
  95. Phelan, D.; Kim, J.H.; Chung, E.H. A game plan for the resumption of sport and exercise after coronavirus disease 2019 (COVID-19) Infection. JAMA Cardiol. 2020, 5, 1085–1086. [Google Scholar] [CrossRef] [PubMed]
  96. Imazio, M.; Cecchi, E.; Demichelis, B.; Ierna, S.; Demarie, D.; Ghisio, A.; Pomari, F.; Coda, L.; Belli, R.; Trinchero, R. Indicators of poor prognosis of acute pericarditis. Circulation 2007, 115, 2739–2744. [Google Scholar] [CrossRef]
  97. Adler, Y.; Charron, P.; Imazio, M.; Badano, L.; Baron-Esquivias, G.; Bogaert, J.; Brucato, A.; Gueret, P.; Klingel, K.; Lionis, C.; et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 2015, 36, 2921–2964. [Google Scholar]
  98. Tscholl, V.; Wielander, D.; Kelch, F.; Stroux, A.; Attanasio, P.; Tschope, C.; Landmesser, U.; Roser, M.; Huemer, M.; Heidecker, B.; et al. Benefit of a wearable cardioverter defibrillator for detection and therapy of arrhythmias in patients with myocarditis. ESC Heart Fail. 2021, 8, 2428–2437. [Google Scholar] [CrossRef]
  99. El-Battrawy, I.; Koepsel, K.; Tenbrink, D.; Kovacs, B.; Dreher, T.C.; Blockhaus, C.; Gotzmann, M.; Klein, N.; Kuntz, T.; Shin, D.; et al. Use of the Wearable Cardioverter-Defibrillator Among Patients with Myocarditis and Reduced Ejection Fraction or Ventricular Tachyarrhythmia: Data From a Multicenter Registry. J. Am. Heart Assoc. 2023, 12, e030615. [Google Scholar] [CrossRef]
  100. RECOVERY Collaborative Group; Horby, P.; Lim, W.S.; Emberson, J.R.; Mafham, M.; Bell, J.L.; Linsell, L.; Staplin, N.; Brightling, C.; Ustianowski, A.; et al. Dexamethasone in Hospitalized Patients with COVID-19. N. Engl. J. Med. 2021, 384, 693–704. [Google Scholar]
  101. Chau, V.Q.; Giustino, G.; Mahmood, K.; Oliveros, E.; Neibart, E.; Oloomi, M.; Moss, N.; Mitter, S.S.; Contreras, J.P.; Croft, L.; et al. Cardiogenic Shock and Hyperinflammatory Syndrome in Young Males with COVID-19. Circ. Heart Fail. 2020, 13, e007485. [Google Scholar] [CrossRef] [PubMed]
  102. Su, J.R.; McNeil, M.M.; Welsh, K.J.; Marquez, P.L.; Ng, C.; Yan, M.; Cano, M.V. Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990–2018. Vaccine 2021, 39, 839–845. [Google Scholar] [CrossRef] [PubMed]
  103. Gargano, J.W.; Wallace, M.; Hadler, S.C.; Langley, G.; Su, J.R.; Oster, M.E.; Broder, K.R.; Gee, J.; Weintraub, E.; Shimabukuro, T.; 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. [Google Scholar] [CrossRef]
  104. Mevorach, D.; Anis, E.; Cedar, N.; Bromberg, M.; Haas, E.J.; Nadir, E.; Olsha-Castell, S.; Arad, D.; Hasin, T.; Levi, N.; et al. Myocarditis after BNT162b2 mRNA Vaccine against COVID-19 in Israel. N. Engl. J. Med. 2021, 385, 2140–2149. [Google Scholar] [CrossRef] [PubMed]
  105. Barda, N.; Dagan, N.; Ben-Shlomo, Y.; Kepten, E.; Waxman, J.; Ohana, R.; Hernán, M.A.; Lipsitch, M.; Kohane, I.; Netzer, D.; et al. Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. N. Engl. J. Med. 2021, 385, 1078–1090. [Google Scholar] [CrossRef]
  106. Husby, A.; Hansen, J.V.; Fosbol, E.; Thiesson, E.M.; Madsen, M.; Thomsen, R.W.; Sørensen, H.T.; Andersen, M.; Wohlfahrt, J.; Gislason, G.; et al. SARS-CoV-2 vaccination and myocarditis or myopericarditis: Population based cohort study. BMJ 2021, 375, 068665. [Google Scholar] [CrossRef]
  107. Diaz, G.A.; Parsons, G.T.; Gering, S.K.; Meier, A.R.; Hutchinson, I.V.; Robicsek, A. Myocarditis and Pericarditis After Vaccination for COVID-19. JAMA 2021, 326, 1210–1212. [Google Scholar] [CrossRef]
  108. Bozkurt, B.; Kamat, I.; Hotez, P.J. Myocarditis with COVID-19 mRNA Vaccines. Circulation 2021, 144, 471–484. [Google Scholar] [CrossRef]
  109. Behers, B.J.; Patrick, G.A.; Jones, J.M.; Carr, R.A.; Behers, B.M.; Melchor, J.; Rahl, D.E.; Guerriero, T.D.; Zhang, H.; Ozkardes, C.; et al. Myocarditis Following COVID-19 Vaccination: A Systematic Review of Case Reports. Yale J. Biol. Med. 2022, 95, 237–247. [Google Scholar]
  110. Goyal, M.; Ray, I.; Mascarenhas, D.; Kunal, S.; Sachdeva, R.A.; Ish, P. Myocarditis post-SARS-CoV-2 vaccination: A systematic review. QJM 2023, 116, 7–25. [Google Scholar] [CrossRef]
  111. Kariko, K.; Buckstein, M.; Ni, H.; Weissman, D. Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005, 23, 165–175. [Google Scholar] [CrossRef] [PubMed]
  112. Yonker, L.M.; Swank, Z.; Bartsch, Y.C.; Burns, M.D.; Kane, A.; Boribong, B.P.; Davis, J.P.; Loiselle, M.; Novak, T.; Senussi, Y.; et al. Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis. Circulation 2023, 147, 867–876. [Google Scholar] [CrossRef] [PubMed]
  113. Murphy, W.J.; Longo, D.L. A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination. N. Engl. J. Med. 2022, 386, 394–396. [Google Scholar] [CrossRef]
  114. Vojdani, A.; Kharrazian, D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin. Immunol. 2020, 217, 108480. [Google Scholar] [CrossRef] [PubMed]
  115. Kanduc, D.; Shoenfeld, Y. Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: Implications for the vaccine. Immunol. Res. 2020, 68, 310–313. [Google Scholar] [CrossRef]
  116. Patone, M.; Mei, X.W.; Handunnetthi, L.; Dixon, S.; Zaccardi, F.; Shankar-Hari, M.; Watkinson, P.; Khunti, K.; Harnden, A.; Coupland, C.A.C.; et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat. Med. 2022, 28, 410–422. [Google Scholar] [CrossRef]
  117. Patone, M.; Mei, X.W.; Handunnetthi, L.; Dixon, S.; Zaccardi, F.; Shankar-Hari, M.; Watkinson, P.; Khunti, K.; Harnden, A.; Coupland, C.A.; et al. Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex. Circulation 2022, 146, 743–754. [Google Scholar] [CrossRef]
  118. Woo, W.; Kim, A.Y.; Yon, D.K.; Lee, S.W.; Hwang, J.; Jacob, L.; Koyanagi, A.; Kim, M.S.; Moon, D.H.; Jung, J.W.; et al. Clinical characteristics and prognostic factors of myocarditis associated with the mRNA COVID-19 vaccine. J. Med. Virol. 2022, 94, 1566–1580. [Google Scholar] [CrossRef]
  119. Shiyovich, A.; Witberg, G.; Aviv, Y.; Eisen, A.; Orvin, K.; Wiessman, M.; Grinberg, T.; Porter, A.; Kornowski, R.; Hamdan, A. Myocarditis following COVID-19 vaccination: Magnetic resonance imaging study. Eur. Heart J. Cardiovasc. Imaging 2022, 23, 1075–1082. [Google Scholar] [CrossRef]
  120. Kim, S.G.; Lee, J.Y.; Jeong, W.G.; Lee, J.E.; Kim, Y.H. Cardiac Magnetic Resonance Imaging Findings and Clinical Features of COVID-19 Vaccine-Associated Myocarditis, Compared with Those of Other Types of Myocarditis. J. Korean Med. Sci. 2024, 39, e42. [Google Scholar] [CrossRef]
  121. Arbelo, E.; Protonotarios, A.; Gimeno, J.R.; Arbustini, E.; Barriales-Villa, R.; Basso, C.; Bezzina, C.R.; Biagini, E.; A Blom, N.; A de Boer, R.; et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur. Heart J. 2023, 44, 3503–3626. [Google Scholar]
  122. Oster, M.E.; Shay, D.K.; Su, J.R.; Gee, J.; Creech, C.B.; Broder, K.R.; Edwards, K.; Soslow, J.H.; Dendy, J.M.; Schlaudecker, E.; 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. [Google Scholar] [CrossRef] [PubMed]
  123. Daugherty, S.E.; Guo, Y.; Heath, K.; Dasmarinas, M.C.; Jubilo, K.G.; Samranvedhya, J.; Lipsitch, M.; Cohen, K. Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: Retrospective cohort study. BMJ 2021, 373, 1098. [Google Scholar] [CrossRef]
  124. Bemtgen, X.; Kaier, K.; Rilinger, J.; Rottmann, F.; Supady, A.; von Zur Muhlen, C.; Westermann, D.; Wengenmayer, T.; Staudacher, D.L. Myocarditis mortality with and without COVID-19: Insights from a national registry. Clin. Res. Cardiol. 2024, 113, 216–222. [Google Scholar] [CrossRef]
  125. Hulscher, N.; Hodkinson, R.; Makis, W.; McCullough, P.A. Autopsy findings in cases of fatal COVID-19 vaccine-induced myocarditis. ESC Heart Fail. 2024, 11, 2467–2468. [Google Scholar] [CrossRef] [PubMed]
  126. Ammirati, E.; Conti, N.; Palazzini, M.; Rocchetti, M.; Spangaro, A.; Garascia, A.; Lupi, L.; Cereda, A. Fulminant Myocarditis Temporally Associated with COVID-19 Vaccination. Curr. Cardiol. Rep. 2024, 26, 97–112. [Google Scholar] [CrossRef]
  127. Bouchlarhem, A.; Boulouiz, S.; Bazid, Z.; Ismaili, N.; El Ouafi, N. Is There a Causal Link Between Acute Myocarditis and COVID-19 Vaccination: An Umbrella Review of Published Systematic Reviews and Meta-Analyses. Clin. Med. Insights Cardiol. 2024, 18, 11795468231221406. [Google Scholar] [CrossRef] [PubMed]
  128. Salah, H.M.; Fudim, M.; O’Neil, S.T.; Manna, A.; Chute, C.G.; Caughey, M.C. Post-recovery COVID-19 and incident heart failure in the National COVID Cohort Collaborative (N3C) study. Nat. Commun. 2022, 13, 4117. [Google Scholar] [CrossRef] [PubMed]
  129. Fatuyi, M.; Amoah, J.; Egbuchiem, H.; Antia, A.; Akinti, S.; Mararenko, A.; Alzamara, M.; Bhatia, A. Impact of COVID-19 Infection on Clinical Outcomes Among Patients with Acute Decompensated Heart Failure: A Nationwide Analysis. Curr. Probl. Cardiol. 2023, 48, 101908. [Google Scholar] [CrossRef]
  130. Xie, Y.; Xu, E.; Bowe, B.; Al-Aly, Z. Long-term cardiovascular outcomes of COVID-19. Nat. Med. 2022, 28, 583–590. [Google Scholar] [CrossRef]
  131. Wang, W.; Wang, C.Y.; Wang, S.I.; Wei, J.C. Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks. eClinicalMedicine 2022, 53, 101619. [Google Scholar] [CrossRef]
  132. Minhas, A.M.K.; Fudim, M.; Abramov, D. The Pandemic That Never Left. J. Card. Fail. 2024, 30, 1179–1180. [Google Scholar] [CrossRef]
  133. Zuin, M.; Rigatelli, G.; Roncon, L.; Pasquetto, G.; Bilato, C. Risk of incident heart failure after COVID-19 recovery: A systematic review and meta-analysis. Heart Fail. Rev. 2023, 28, 859–864. [Google Scholar] [CrossRef] [PubMed]
  134. Manla, Y.; Badarin, F.A.; Bader, N.; Lee-St John, T.; Mehra, M.R.; Bader, F. Worldwide and Country-Specific Impact of the COVID-19 Pandemic on Heart Transplantation Volumes: A Longitudinal Analysis of 2020 and 2021. Curr. Probl. Cardiol. 2023, 48, 101870. [Google Scholar] [CrossRef]
  135. Nunez-Gil, I.J.; Fernandez-Perez, C.; Estrada, V.; Becerra-Munoz, V.M.; El-Battrawy, I.; Uribarri, A.; Fernández-Rozas, I.; Feltes, G.; Viana-Llamas, M.C.; Trabattoni, D.; et al. Mortality risk assessment in Spain and Italy, insights of the HOPE COVID-19 registry. Intern. Emerg. Med. 2021, 16, 957–966. [Google Scholar] [CrossRef] [PubMed]
  136. El-Battrawy, I.; Nunez-Gil, I.J.; Abumayyaleh, M.; Estrada, V.; Manuel Becerra-Munoz, V.; Uribarri, A.; Fernández-Rozas, I.; Feltes, G.; Arroyo-Espliguero, R.; Trabattoni, D.; et al. COVID-19 and the impact of arterial hypertension-An analysis of the international HOPE COVID-19 Registry (Italy-Spain-Germany). Eur. J. Clin. Investig. 2021, 51, e13582. [Google Scholar] [CrossRef] [PubMed]
  137. Abumayyaleh, M.; Nunez-Gil, I.J.; El-Battrawy, I.; Estrada, V.; Becerra-Munoz, V.M.; Uribarri, A.; Fernández-Rozas, I.; Feltes, G.; Arroyo-Espliguero, R.; Trabattoni, D.; et al. Sepsis of Patients Infected by SARS-CoV-2: Real-World Experience from the International HOPE-COVID-19-Registry and Validation of HOPE Sepsis Score. Front Med. 2021, 8, 728102. [Google Scholar] [CrossRef]
  138. Abumayyaleh, M.; Nunez Gil, I.J.; El-Battrawy, I.; Estrada, V.; Becerra-Munoz, V.M.; Aparisi, A.; Fernández-Rozas, I.; Feltes, G.; Arroyo-Espliguero, R.; Trabattoni, D.; et al. Does there exist an obesity paradox in COVID-19? Insights of the international HOPE-COVID-19-registry. Obes. Res. Clin. Pract. 2021, 15, 275–280. [Google Scholar] [CrossRef]
  139. Mensah, G.A.; Fuster, V.; Murray, C.J.L.; Roth, G.A. Global Burden of Cardiovascular D, Risks C. Global Burden of Cardiovascular Diseases and Risks, 1990–2022. J. Am. Coll. Cardiol. 2023, 82, 2350–2473. [Google Scholar] [CrossRef]
  140. Petersen, M.; Mehrad, B.; Keeley, E.C. Acute myocarditis during the COVID-19 pandemic: A single center experience. Am. Heart J. Plus 2021, 5, 100030. [Google Scholar] [CrossRef]
Jcm 14 04560 g001
Figure 1. Pathophysiology of acute myocarditis in COVID-19-associated and its vaccine-associated acute myocarditis.
Figure 1. Pathophysiology of acute myocarditis in COVID-19-associated and its vaccine-associated acute myocarditis.
Jcm 14 04560 g001
Table 1. Prevalence of COVID-19-associated acute myocarditis.
Table 1. Prevalence of COVID-19-associated acute myocarditis.
COVID-19-Associated Acute Myocarditis
CountryTime PeriodSex MalePrevalenceReferences
USMarch 2020–December 202060.4%2.3% *[38]
USJanuary 2021–June 202043.5%5% Ω[39]
US and EuropeFebruary 2020–April 202161.1%2.4–4.1 per 1000 h.Ω[40]
Internationaluntil September 202062%2% π[42]
* Myocarditis prevalence: 2.3% in COVID-19-positive screened athletes; symptomatic cases: 0.31%. Ω Myocarditis prevalence in hospitalized patients. π Myocarditis prevalence in autopsy studies. Abbreviation: US, United States; h, hospitalization.
Table 2. Clinical presentation, ECG, troponin, and radiographic findings in COVID-19-associated acute myocarditis.
Table 2. Clinical presentation, ECG, troponin, and radiographic findings in COVID-19-associated acute myocarditis.
Clinical PresentationPrevalenceReferences
Chest pain55.5–60%[40,74,75,76]
Syncope6%[40]
Palpitations11.1%[40]
Dyspnea53.7–80%[40,74,75,76]
Cough39–67%[40,75,76]
Fever57–82.4%[77,78]
Myalgia12%[76]
Gastrointestinal symptoms33–44.4%[40,75]
Asymptomatic1.5–5%[63,79]
ECG
ST-segment elevation25.9–28%[40,75]
Other abnormal ST changes13–24%[40,76]
QTc prolongation25%[80]
Laboratory parameters
Troponin86–90%[75,78]
NT-proBNP50–87%[75,78]
Radiographic findings
Cardiomegaly in x-ray31%[76]
Bilateral infiltrates in x-ray31%[76]
Ground-glass opacities in CT50%[76]
Echocardiographic findings
LV dysfunction20%[76]
Wall motion abnormalities20%[76]
Pericardial effusion46–67%[40]
cMRI
T2 elevation100%[38]
Late gadolinium enhancement40.7–50%[38,76]
EMB
Positive results for myocarditis82.3%[40]
Abbreviation: ECG, electrocardiogram; ST-segment, ST segment is the flat, isoelectric section of the ECG between the end of the S wave (the J point) and the beginning of the T wave. QTc, heart-rate corrected QT interval; NT-proBNP, N-terminal pro-brain natriuretic peptide; CT, computer tomography; LV, left ventricular; cMRI, cardiac magnet resonance imaging; EMB, endomyocardial biopsy.
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Abumayyaleh, M.; Schupp, T.; Behnes, M.; El-Battrawy, I.; Hamdani, N.; Akin, I. COVID-19 and Myocarditis: Trends, Clinical Characteristics, and Future Directions. J. Clin. Med. 2025, 14, 4560. https://doi.org/10.3390/jcm14134560

AMA Style

Abumayyaleh M, Schupp T, Behnes M, El-Battrawy I, Hamdani N, Akin I. COVID-19 and Myocarditis: Trends, Clinical Characteristics, and Future Directions. Journal of Clinical Medicine. 2025; 14(13):4560. https://doi.org/10.3390/jcm14134560

Chicago/Turabian Style

Abumayyaleh, Mohammad, Tobias Schupp, Michael Behnes, Ibrahim El-Battrawy, Nazha Hamdani, and Ibrahim Akin. 2025. "COVID-19 and Myocarditis: Trends, Clinical Characteristics, and Future Directions" Journal of Clinical Medicine 14, no. 13: 4560. https://doi.org/10.3390/jcm14134560

APA Style

Abumayyaleh, M., Schupp, T., Behnes, M., El-Battrawy, I., Hamdani, N., & Akin, I. (2025). COVID-19 and Myocarditis: Trends, Clinical Characteristics, and Future Directions. Journal of Clinical Medicine, 14(13), 4560. https://doi.org/10.3390/jcm14134560

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