Immunization-associated myocarditis post mRNA COVID-19 vaccination: a review article

mínima fracción de toda la población vacunada. Los beneficios que ofrece la vacuna del COVID-19 son mucho mayores a los efectos que una infección por COVID-19 podría causar. Se recomienda seguir administrando la vacuna del COVID-19 para hacer frente a la pandemia del coronavirus. Abstract Introduction: Vaccination-related myocarditis has been reported as a major side effect of the mRNA COVID-19 vaccine. In this review article, a series of 15 global case reports of laboratory-confirmed myocarditis post COVID-19 vaccination were summarized. Objectives: The main objective of this article is to critically analyze and summarize published case reports on vaccination-associated myocarditis. Methodology: Google Scholar was used to search for confirmed cases of vaccination-associated myocarditis from 2021 to 2022. Results: It was found that there is a higher prevalence of immunization-related myocarditis in young adults, especially in male patients (94%). Genetic defects, environmental aspects and dietary habits were discovered as other factors that could have stimulated the development of myocarditis. Troponin and C-reactive protein levels were elevated in most cases (93%). Conclusions: vaccination-associated myocarditis case reports are very rare and only represent a minimal fraction of the total population that has been vaccinated. The benefits offered by the COVID-19 vaccine far outweigh the effects a COVID-19 infection. It is recommended to continue administering the mRNA vaccine to manage the COVID-19 pandemic.


Introduction
The novel coronavirus disease (COVID-19) originated in Wuhan, China in 2019. The World Health Organization (WHO) declared the COVID-19 disease a pandemic in 2020. The SARS-CoV-2 virus is highly transmissible and spreads through respiratory droplets, including saliva, sneezing, and coughing (1). At the time of writing, there has been a total of 532,545,504 COVID-19 confirmed cases in the world according to the Johns Hopkins Coronavirus Research Center (2). Vaccination is often acknowledged as the most efficient approach to tackle infectious diseases caused by viruses. Nowadays, mRNA vaccines have become a powerful tool to fight the COVID-19 pandemic. In addition, mRNA vaccines offer more advantages than conventional vaccines such as rapid development and higher immune response (3). However, some medical reports suggest that COVID-19 mRNA vaccines may cause some rare side effects; it has been revealed that some patients may develop myocarditis after COVID-19 immunization. Myocarditis is a heterogeneous cardiac disease that is defined as the inflammation of the muscular layer of the heart, the myocardium, principally due to a viral infection (4). Moreover, the diagnosis of myocarditis is usually assessed under the Lake Louis criteria (CLL). Positron emission tomography/computed tomography (PET/CT), electrocardiography (ECG), echocardiography, plasma tests, endomyocardial biopsy (EMB) and cardiac magnetic resonance imaging (CMR) are among the modalities for diagnosis of myocarditis, the latter being the most preferred technique (4,5,6). Furthermore, viral myocarditis can be asymptomatic, mild, or severe (5). In cases where myocarditis is asymptomatic, this disease can remain undiagnosed. Whilst, mild symptoms of myocarditis may include chest pain, chest tightness, tachycardia, and fatigue (4,5). Whereas, the most severe cases of myocarditis may lead to dilated cardiomyopathy, cardiac arrest, arrythmias, acute heart failure and even death (4,5). Acute myocarditis is a subclassification of the disease which can occur during a period of less than a month after diagnosis; acute myocarditis symptoms are mild. While fulminant myocarditis is more severe and can cause cardiogenic shock (4). Besides the viral pathogenesis of myocarditis, some other aetiologias also include bacterial infections, myocardial toxins, certain drugs, and autoimmune diseases (4). However, the pathogenic mechanism of vaccination-associated ´ I n m u n i d a d P á g i n a 29 | 17 myocarditis is yet to be discovered. Some researchers believe that the mRNA vaccine exposure might have caused this adverse response. Nevertheless, genetic defects, environmental aspects and dietary habits may be underlying factors responsible for the development of myocarditis. Additionally, evidence of direct myocardial involvement has not been found until now and some authors emphasize the importance to regularly monitor any adverse event that the mRNA vaccine could cause (7,8,9). The main goal of this review was to critically summaries published literature to clarify the association between myocarditis and COVID-19 vaccination, to provide a more in-depth insight of factors that could have influenced this adverse response and evaluate the risks between the mRNA vaccine and a COVID-19 infection.

Materials and Method
In this review article, I used Google Scholar search engine to find published literature about patients diagnosed with myocarditis after COVID-19 immunization. I selected case reports from different countries. However, my main preferences were articles written in English. All mRNA vaccine brands included in this review were Pfizer-BioNTech, Moderna and AstraZeneca. I used "COVID-19"," myocarditis", "vaccination", "case report" keywords to select articles from 2021 to 2022. To obtain the results for this review, I only chose primary sources and excluded books, secondary papers, and other review articles. My results were narrowed down by gathering case reports of laboratoryconfirmed myocarditis cases. I ended up selecting 15 articles that met the searching criteria. Some of the information that I gathered were demographics, ECG, CMR, ECHO, EMB, troponin and CRP laboratory results and all this data was collected into Microsoft Excel spreadsheets.

Discussion
In the literature data, many case reports rely on serological tests to evaluate biomarkers levels. Biomarkers have been particularly useful for research, management, diagnosis, and treatment of diseases. For this reason, this review article is focused on two biomarkers in particular; it appears that troponin I and C-reactive protein (CRP) levels are good inflammatory markers for the diagnosis of myocarditis. The rise in troponin I levels may suggest myocardial injury or damage which in turn can lead to myocarditis (5 www.anatomiadigital.org other case reports that took part of this review where troponin and CRP levels were all elevated, except of only one case report where troponin and CRP levels were normal (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). For this reason, these two biomarkers could be extremely helpful for diagnosis of myocarditis. Even though myocarditis was accredited to the mRNA vaccine in this case, the research responsible for this study failed to evaluate other underlying factors. For instance: genetic and environmental factors were not taken into consideration. No information on dietary habits, physical activity, or other comorbidities were provided.
Some evidence suggests that genetic and environmental factors may induce the development of myocarditis in some clinical studies (23). It has been revealed that individuals with family history of heart disease will be more prone to suffer from a cardiac disease throughout their life span. In addition, defects in genes (such as TTN, DSP, and Dystrophin) that encode for structural proteins are strongly associated with cardiac diseases. These genetic mutations make individuals more susceptible to myocarditis. Moreover, environmental factors such as chemotherapy, pregnancy, physical activity, and alcohol consumption are linked to the development of myocarditis and cardiomyopathy (23). There is one case which was included in this review of a 27-year-old professional athlete who died suddenly of fulminant myocarditis after COVID-19 vaccination. This death was attributed to athlete's heart and fatal arrythmia with myocarditis happening afterwards (19). Therefore, physical activity is a major factor for this adverse outcome. Besides, numerous studies using animal models have implied the key role of genetics in cardiac diseases. For instance: in a study by Wei et al., some mice were treated with immune checkpoint inhibitors (ICI), which is frequently used as a cancer treatment, as a result mice developed ICI-induced myocarditis as an adverse immune response to this treatment. From these results, it was discovered that the Pdcd1 (which encodes for PD-1 protein) and Ctla4 (which encodes for CTLA4 protein) alleles play a significant role in the development of fatal myocarditis due to interactions between CTL4 and PD-1 proteins (24). Furthermore, another animal model-based study points out that the M2 gene, which encodes for capsid protein, is another causal factor of fatal myocarditis in mice (25). In addition, human DSP variants have been associated with inherited acute myocarditis (4). Another important finding from this review was the gender inclination to vaccinationrelated myocarditis; most case reports suggests that side effects might appear to be more predominantly in young males. Thus, there might be a possibility that exhibiting the XY chromosome could be a predisposition to suffer from myocarditis. Since genetic testing is not a routine procedure for diagnosis of myocarditis, we will not know for certain if some of the case reports presented in this review may have had a genetic aetiologia. Thus, vaccination-induced myocarditis may not be caused directly by the mRNA vaccine but could be indirectly caused by genetic predisposition.
The benefits of a certain type of diet might be effective for the treatment of myocarditis.
Since gluten is one of the main components of processed foods and it has been associated ´ I n m u n i d a d P á g i n a 34 | 17 with autoimmune and chronic diseases due to its proinflammatory, cytotoxic and immunogenic properties. Following a gluten-free diet might be favorable to successfully treat patients with autoimmune-myocarditis (26). In a study by Marcolongo et al., three pediatric patients with autoimmune-induced myocarditis were treated with immunosuppressive therapy (IT) accompanied by a gluten-free diet. After following this treatment, patients showed some considerable improvement in their health (27). Moreover, another author also highlights the importance of diet in a case report where a patient was hospitalized after showing symptoms of myocarditis. As Myrmel et al. argues, a CD-associated myocarditis case was managed by making the patient follow a glute-free diet regimen and a heart failure treatment; after a 4-month follow-up, the patient stopped having chest pain and dyspneal was less frequent (28). On the other hand, some dietary deficiencies might be detrimental, and they could exacerbate the severity of the disease in some individuals. As discussed by Favere et al., a vitamin E and selenium-deficient diet might aggravate the severity of viral myocarditis in mice models; it was further revealed that diet may affect both the virus and the host by altering the virus genetic makeup (29). Furthermore, deficiency of vitamin D may influence the inflammation of the myocardium. Enayati et al., details the findings of a laboratory experiment using vitamin D in mice models with autoimmune-induced myocarditis. Consequently, vitamin D repressed cardiac inflammation while ameliorating cardiac function. These results could have been attributed to the vitamin D's anti-inflammatory properties (30). In addition, taking certain drugs may have a negative impact in certain cases. For example: non-steroidal medications were prescribed in two of the case reports that took part of this review. Non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended for treatment of myocarditis because these drugs may have the potential to cause renal impairment that could aggravate the condition of the patients. Furthermore, anti-viral agents such as remdesivir and lopinavir have not shown any significant effect in reducing duration of hospital stay and mortality rates (7). Thus, dietary habits have an important impact in the prevention and treatment of myocarditis.
The results of this review also indicate that 26 individuals took the Pfizer-BioNTech vaccine (52%), whereas 23 patients were immunized with the Moderna vaccine (46%) and there is only one patient who received only one dose of the AstraZeneca vaccine (2%) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). The BNT162b2-mRNA (Pfizer-BioNTech) vaccine proved to be highly effective in some medical reports. Polack et al, argues that the BNT162b2-mRNA vaccine is 95% effective in successfully providing protection against COVID-19 for everyone 16 years of age and older. Furthermore, clinical trials revealed that the vaccine is safe after a 2month of postvaccination follow-up (31). These results were consistent with another study by Thomas et al, which emphasizes that the vaccine is safe, but it gradually loses its efficacy over time. On the other hand, there were a few cases where the vaccine showed some adverse effects, an equivalent ratio of deaths was found between the vaccinated group and the placebo group in a clinical study, and these adverse effects were not ´ I n m u n i d a d P á g i n a 35 | 17  (9). Hence, myocarditis cases are rare among vaccinated recipients and these few cases may not even be related to vaccine exposure.
The pathogenesis of vaccination-related myocarditis is not well known. However, some mechanisms were proposed by some researchers. For instance, Hassanzadeh et al., suggests that inflammation of the myocardium may have been caused by abnormal apoptosis and cross-reactive anti-idiotype antibodies. It also has been theorized that the COVID-19 vaccine produces an immune response that could cause autoimmunemyocarditis (21). Moreover, Mengesha et al., argues the possibility of molecular mimicry between the SARS-CoV-2 virus spike protein and a cardiac protein that could have triggered an acquired or innate immune response (17). In addition, using animal models to design a study that could help us understand the pathogenic mechanism of vaccinationassociated myocarditis might be extremely useful. Therefore, to better understand the pathogenesis of vaccination-induced myocarditis, more research must be done.
Finally, it is also important to compare and evaluate the possible risks between a COVID-19 infection and the risks of suffering from myocarditis as a side effect of vaccination. The risks of suffering from a COVID-19 infection are still very appalling; some patients with increased disease severity after being infected with COVID-19 are more likely to be hospitalized with mechanical ventilation support for several days, many others are left with some sequelae and some patients might have a higher risk of death. Furthermore, Nunn et al., argues that vaccination may increase the risk of developing myocarditis (12) On the contrary, as Wallace et al. discussed the vaccine significantly lowers the risk of COVID-19-related hospitalization by 95.9% and the probability of adverse effects is extremely low compared to a COVID-19 infection (33). Some of the most common adverse events after vaccination include muscle pain, headache, chills, fatigue, and fever. Myocarditis being far less common among vaccine recipients; according to a British study, there is an approximate incidence of 1 to 10 per 1,000,000 people who can develop myocarditis after vaccination, compared to an incidence of 40 per 1,000,000 cases with myocarditis after a COVID-19 infection which is a much higher ratio. Another study reveals that 136 individuals developed myocarditis out of 1.5 million people who were vaccinated against COVID-19 in Israel; this study also points out that the symptoms that people had were mostly mild (12). Therefore, the risks of a COVID-19 infection are by ´ I n m u n i d a d P á g i n a 36 | 17 On the other hand, the clinical trials that monitored the efficacy of the COVID-19 vaccine were all blinded and selected their participants randomly. Hence, these results are reliable and excluded the possibility of bias. Furthermore, it could have been more advantageous to collaborate with other specialized researchers in the field to have a more in-dept analysis and evaluation of results. Therefore, a collaboration with other researchers, it is highly recommended.

Conclusion
 In conclusion, the benefits of vaccination against COVID-19 outweighs the adverse effects of a possible SARS-CoV-2 infection. Myocarditis is a rare complication which has a low incidence among vaccine recipients and this adverse event might not be directly associated with the mRNA vaccine. Several studies have shown that there are genetic, environmental, and dietary factors that we must take into consideration before deducting this disease aetiologia. Moreover, it is suggested that we keep monitoring the vaccine efficacy and any side effects. Further research needs to be done to investigate the possible pathogenesis of vaccination-related myocarditis. The administration of the mRNA COVID-19 vaccine is still recommended to fight the COVID-19 pandemic.