Myocarditis Following COVID-19 Vaccine: What Did We Learn?

Authors: Joseph Abourjeili, Christelle Lattouf, Anthony Abou Mrad, Elio Salameh, Rana Zareef, Fadi Bitar, Mariam Arabi

Abstract

The COVID-19 pandemic has had a profound global impact, with vaccination emerging as a key strategy for controlling the virus. However, concerns have arisen regarding potential cardiovascular side effects, particularly myocarditis following mRNA COVID-19 vaccination. This review examines the risk of post-vaccination myocarditis by analyzing over 40 studies. Findings indicate that myocarditis occurs most commonly within 2 to 4 days after the second dose, particularly in males aged 12 to 39 years. Proposed mechanisms include molecular mimicry and hypersensitivity reactions. Despite these concerns, most cases present with mild symptoms such as chest pain and dyspnea, resolving with supportive care. Importantly, the overall safety profile of COVID-19 vaccines remains high, with benefits significantly outweighing risks. Further multi-center studies are needed to fully understand the pathophysiology and mitigate potential adverse effects. No clinical trials were conducted for this review.

Introduction

At the end of 2019, the globe witnessed a lifechanging the spread of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), also known as the COVID-19 pandemic. The novel virus has spread at an unpreceded pace. This crisis has brought exceptional changes to everyday life. Up until December 2024 and according to World Health Organization (WHO), 776 973 432 people have been infected and 7 077 725 have died secondary to COVID-19 infection.^ 1 ^ Even now, the virus remains an active contributor to global mortality and morbidity.

The novel SARS-CoV-2 is a positive sense single-stranded RNA enveloped virus that belongs to the β-coronavirus subfamily.^ 2 ^ This family predominantly affects the respiratory system. For instance, the notorious virus causes viral pneumonia that can progress to precipitate acute respiratory distress syndrome.^ 3 ^ In addition to the overwhelming respiratory complications, it is important to note that COVID-19 is a multi-system disease, inducing serious end organ damage in the brain, kidney, liver, and the heart.^4,5^ For instance, strokes, paralysis, seizures, heart failure and more have been documented as fatal complications of COVID-19.^ 5 ^

Several therapeutic drugs were employed to treat the pandemic; however, drug repurposing was ultimately not the solution.^6,7^ Rather, the major method that facilitated the reduction in mortality and hospitalization rates was global vaccination against the notorious virus.^8,9^ Fortunately, vaccines against COVID-19 had developed in a speedy fashion and are now widely distributed worldwide.

Up until early 2023, the Food and Drug Administration (FDA) had authorized the use of several vaccines in the battle against COVID-19. Among these, 2 vaccines stand Pfizer-BioNTech (mRNA-BNT162b2) and Moderna (mRNA-1273), both of which employ the mRNA technology.^ 10 ^ The mechanism of action for this technique involves injecting a mRNA fragment of the virus into the host, where it is delivered to the host’s translational machinery and ultimately translated into the viral antigen against which the host will induce an appropriate immune response and gain immunity.^ 10 ^

Current research studies and clinical trials suggest that COVID-19 vaccines have an acceptable safety profile. However like many other vaccines before them, they have several side effects. Some of the most commonly reported side effects include headaches, myalgia, and fever.^11,12^ These side effects are usually mild to moderate, self-limiting, and resolve within days of vaccination. However, despite their infrequent occurrence, serious complications following COVID-19 vaccines have been reported, among which thrombosis, glomerular damage, and most notably cardiovascular disorders such as heart failure, heart block, and myocarditis^ 11 ^ stand out.

Myocarditis is defined as the inflammation of the myocardial cells. It can be further classified into acute, subacute, or chronic with the area of inflammation of the myocardium being focal or diffuse.^ 13 ^ Typical myocarditis symptoms include new onset of persistent chest pain, dyspnea, fever, arrythmias, and palpitations.^14,15^ Diagnosis entails abnormal lab findings (such as elevated levels of cardiac biomarker troponin), frequent abnormal cardiac MRI findings, myocardial edema, and electrocardiographic alterations (such as ST elevations).^ 14 ^ Importantly, myocarditis can further progress to heart block, heart failure, dilated cardiomyopathy, arrhythmias, and sudden death.^ 14 ^ Thus, it is important to try and manage this condition before further complications arise.

Moreover, myocarditis post COVID-19 vaccination can be defined as the occurrence of a myocarditis event following the administration of the vaccine. Diagnostic criteria for myocarditis post vaccination does not differentiate from other forms of myocarditis. It also includes physical examination, assessment of symptoms, ECG, troponin, cardiac MRI, and others.^16,17^ The median onset of occurrence is around 3 days post vaccination.^ 17 ^

In this review, we investigate the risk of myocarditis in patients vaccinated with COVID-19. We discuss the incidence of myocarditis following COVID-19 vaccine administration in the general population as well as the younger population (≤19). In addition, we indwell into the pathophysiology of myocarditis secondary to COVID-19 vaccine and its risk factors.

Methodology

A comprehensive narrative literature review was conducted using PubMed, Medline, and Google Scholar. The search strategy incorporated predefined keywords and MeSH terms, including “COVID-19 vaccines” and “myocarditis,” to ensure a focused and systematic selection of relevant studies. Articles published after 2020 were considered, with inclusion criteria encompassing retrospective cohort studies, case series, and systematic reviews that examined post-vaccination myocarditis in both the general population and individuals aged ≤19 years. Studies were screened based on relevance, methodological rigor, and quality of evidence, with preference given to peer-reviewed publications. Data extraction focused on incidence rates, clinical presentation, risk factors, and proposed pathophysiological mechanisms. To enhance objectivity, study selection and data interpretation were conducted independently by multiple reviewers, with discrepancies resolved through discussion.

Ethical Approval and Informed Consent

Ethics approval was not required for this study as it is a literature review based on previously published research and does not involve human participants or animal subjects.

Results

According to a systematic review and meta-analysis conducted by Rahmani et al^ 9 ^ encompassing 54 studies, the clinical efficacy of the FDA-approved mRNA vaccines was discovered to be superior to other vaccination methods for combating COVID-19,^ 9 ^ specifically by reducing the incidence of COVID-19 induced symptoms, disease development, hospitalization, and progression following these mRNA vaccines compared to others.^ 9 ^

A study conducted by Singh et al^ 12 ^ in 2022 on the safety profile of COVID-19 vaccinations in the United Stated of America demonstrated that out of 239.97 million doses of COVID-19 vaccines administered, a total of 141 208 individuals suffered from at least 1 side effect.^ 12 ^ The incidence of at least 1 side effect from the mRNA vaccines Pfizer-BioNTech and Moderna, were 0.04% and 0.06% respectively. Fortunately, the effects were most commonly mild, mostly restricted to fever and headaches that resolved rapidly.

However, some serious side effects may still arise post-vaccination. Of these serious adverse effects are cardiovascular complications, such as myocarditis. The first reported case of myocarditis post mRNA vaccine was in May 2021,^ 18 ^ with CDC data the following month (June 2021) indicating an incidence of 40.6 males aged 12 to 29 years old per million second doses of the COVID-19 mRNA vaccines. As of January 2022, 1175 confirmed cases of COVID-vaccine mediated myocarditis were reported in individuals aged 30 and younger.^ 18 ^ Since then, many other articles were published that documented the incidence of myocarditis following COVID-19 vaccination, summarized in Table 1.

Interestingly, most of the studies demonstrate that myocarditis occurs predominantly post the second dosage of the mRNA COVID-19 vaccines, and preferentially affects males (Table 1). For instance, a retrospective study conducted by Truong et al^ 24 ^ in 2022 collected data from 26 centers across the United States of America on adolescents and young adults that had suspected myocarditis within a span of 30 days of COVID-19 mRNA vaccination. Out of the 139 suspected myocarditis cases, 97.8% (n = 136) occurred post vaccination, and 91.4%(n = 128) of all cases occurred after the second dose.^ 24 ^ These results were further solidified by a systematic review conducted by Ilonze and Guglin published in 2022.^ 23 ^ The systematic review reported data from 238 patients who presented with myocarditis post COVID-19 vaccination, 87.1% (n = 201) being males, and interestingly, myocarditis occurred after the second dosage in 80% (n = 182) of cases.

Likewise, in the younger population, a case series of myocarditis reported by Marshall et al^ 25 ^ demonstrated that all of the 7 documented adolescents (ages 14-19) were males and acquired myocarditis post the second dose of the Pfizer-BioNTech COVID-19 vaccine.^ 25 ^

It is important to note that in all the studies discussed above, there were abnormal cardiac findings indicative of myocarditis such as increased troponin levels, elevated ST on EKG, myocardial edema, and late gadolinium enhancement on cardiac MRI, as one would expect with non-vaccine induced myocarditis.

On the other hand, multiple reports indicate an increased incidence of myocarditis and pericarditis in adolescents and young adults following mRNA COVID-19 vaccinations worldwide as compared to the adult population,^19,20^ with results summarized in Table 2. Additionally, myocarditis rates post-vaccination among children aged 12 to 15 was significantly higher than those resulting from COVID-19 infection, while adults showed opposite results, with post-vaccination and baseline rates being similar and much lower than those related to the infection with the virus.^21,22^ Remarkably, no significant data concerning the smaller age group (<9 years old) was found in our search, emphasizing the essential requirement for future research to address this noteworthy gap in knowledge.

The most common symptoms that were present in the younger population included chest pain, dyspnea, shortness of breath, palpitation, syncope, and general weakness with febrile and non-febrile presentations.^19-25,28^ These symptoms occurred 2 to 3 days after a second dose of mRNA vaccine and were associated with elevated cardiac troponin levels.^ 29 ^ In addition, electrocardiograms showed ST segment elevation and cardiac magnetic imaging findings were suggestive of myocarditis.^29,30^ These findings were similar to the adult presentation. Many studies showed that the median hospital length was 2 to 4 days.^21,24^ Notably, the risk factors for myocarditis post vaccination for the pediatric population include male sex and taking the second dose of the vaccine.^24,31,32^ Thankfully, the vast majority of adolescents and young adults presenting with suspected myocarditis following COVID-19 vaccination experience rapid recovery of symptoms and end up having a mild clinical course.^21,24^

Although different mechanisms have been proposed, almost all instances resolved whether treatment was provided or not.^19-23^ Besides providing supportive care, a study by Luxi et al^ 29 ^ showed that patients were administered nonsteroidal anti-inflammatory drugs, steroids, and colchicine. In some cases, intravenous immunoglobulin and acetylsalicylic acid were used as treatments, while others were prescribed β-blockers and angiotensin-converting enzyme inhibitors to address left ventricular systolic dysfunction.^ 29 ^

Despite its presence and well documented incidence in the literature, the risk of myocarditis post-mRNA COVID-19 vaccination in the pediatric population remains nearly negligible at a mere 0.006% in the 12- to 17-year age group,^ 33 ^ and the potentially disastrous long-term negative effects of COVID-19 outweigh it by far. As such, current CDC guidelines suggest a COVID-19 vaccination should be given to everyone 12 years and older,^26,27,33,34^ as the benefits have proven to outweigh the risks.^ 35 ^

Discussion

The COVID-19 pandemic has been an unprecedent global health crisis that prompted the rapid development of vaccines to fight its spread. These vaccines have a major role in controlling and mitigating the impact of the pandemic; however, many side effects and negative outcomes following vaccination have been reported.^8,9^ Among these adverse effects, myocarditis has emerged as a notable outcome.^10,13^ In most of the papers included in this review, the diagnostic criteria for myocarditis was similar and included abnormal ECG findings such as ST segment elevation,^ 20 ^ increased troponin levels,^24,25^ and abnormal cardiac MRI findings including dilated cardiomyopathy.^ 13 ^ Most of the studies showed that myocarditis predominantly occurs after the administration of the second dose of mRNA vaccine^ 24 ^ with a higher incidence in males.^ 28 ^ Most of the patients across the different studies received supportive care, while some also received NSAIDs, colchicine, intravenous immunoglobulins, and ACE inhibitors in order to alleviate symptoms like dyspnea, fever, and angina.^19,21,23^ Remarkably, the majority of cases, whether treated or not, exhibited a self-resolving pattern.^ 22 ^

Moreover, there are several suggested hypotheses that attempt to explain the link between myocarditis and the mRNA vaccinations. One hypothesis suggests that myocarditis presents after COVID vaccination due to an autoimmune reaction triggered by “molecular mimicry,” depicted in Figure 1. To further clarify, when the viral antigen is injected in the body in the form of a vaccine, the immune system undergoes sensitization and produces a reactive response against it, priming the body to fight the same antigen on future encounters. However, in this case the viral antigens resemble host proteins, specifically myocardial proteins. Consequently, autoreactive sensitization occurs, prompting the body to mount an immune response against its own self myocardial proteins, leading to inflammation in the heart chambers and therefore myocarditis.^ 36 ^ This hypothesis was demonstrated in an experimental study conducted by Vojdani and Kharrazian,^ 37 ^ where antibodies targeted against COVID-19 spike protein were able to cross react to α-myosin, a molecule that is normally present in the heart.^ 37 ^

Another potential underlying mechanism includes hypersensitivity. To clarify, myocarditis may be an event that occurs due to a hypersensitive reaction of the body to the vaccine.^ 38 ^ However, since myocarditis predominantly appears around 3 days post-vaccination, then this can be a case of delayed hypersensitivity.

The underlying reason for the preferential occurrence of this condition in males compared to females remains unclear. However, hormonal differences between the 2 sexes may play an important role. Females produce more estrogen than males, and this hormone has an inhibitory role on pro-inflammatory T-cells. Thus, it is suggested that the lower grade cell-mediated immune response reduces the extent of inflammation around the heart chambers, and consequently reduces the risk of myocarditis.^ 30 ^

It is important to note that myocarditis can also be a complication of COVID-19 infection itself. While it may occur as a long-term consequence of the virus, it is most commonly observed during the early stages of the disease, typically within the first few weeks after symptom onset. Patone et al.,^ 39 ^ in a self-controlled case series study, found that approximately 40 per 1 million COVID-19 patients develop myocarditis within 28 days of infection—a rate significantly higher than that reported following vaccination. Furthermore, a large study in England^ 40 ^ demonstrated that the overall risk of myocarditis is substantially greater immediately after a COVID-19 infection compared to the weeks following coronavirus vaccination. Although some cases of overlapping viral infection and vaccination may obscure the precise cause of myocardial inflammation, such instances are rare. The majority of vaccinated individuals would have either fully recovered from a prior infection or not been infected before receiving the vaccine.

Conclusion

In conclusion, the available data discussed in this paper demonstrate global vaccination against COVID-19 as the most successful method to battle the virus. However, several cardiovascular complications have been reported following vaccination, among which is the inflammation of myocardial cells, better known as myocarditis. As discussed in this review paper, myocarditis is an important cardiac complication that can be fatal as it can further progress to heart block, heart failure, and even sudden death. However, most of the cases that occurred following the vaccine administration resolved completely whether with or without treatment. The information discussed in this paper demonstrated that myocarditis post COVID-19 infection was diagnosed through clinical presentation associated with abnormal ECG findings, such as ST elevation, and abnormal cardiac marker levels. Interestingly, in the majority of the cited articles, myocarditis exhibited a pattern of occurrence 2 to 4 days post the second dosage of COVID vaccine administration, particularly the Pfizer-BioNTech and Moderna vaccines. However, despite the concerns, the vaccination’s safety profile is high, and the benefits outweigh the cons especially after studies indicating the lower risk of myocarditis following vaccines compared to the infection itself. Importantly, as we enter the fifth year of the coronavirus, it is important to continuously monitor any adverse effect that might arise from COVID-19 booster vaccinations. Moreover, despite its low occurrence, it is important to employ multicentral studies with proper testing, in an attempt to understand the exact mechanism for post-vaccination induced myocarditis eventually preventing its recurrence and the complications that may arise with it.