Vaccines for coronavirus disease 2019 (COVID-19) include ChAdOx1-SARS-COV-2 (AstraZeneca), Ad26.COV2.S (Janssen), mRNA-1273 (Moderna), BNT162b2 (Pfizer), BBIBP-CorV (Sinopharm), CoronaVac (Sinovac), and Bharat Biotech BBV152 (Covaxin).

To find the association between COVID-19 vaccines and myocardial infarction (MI).

This is a systematic review that involved searching databases such as MEDLINE, EMBASE, and PakMediNet after making a search strategy using MeSH and Emtree terms. Eligibility criteria were set, and studies having no mention of MI as a complication of COVID-19 vaccination, protocols, genetic studies, and animal studies were excluded. Data was extracted using a predesigned extraction table, and 29 studies were selected after screening and applying the eligibility criteria.

The majority of studies mentioned AstraZeneca (18 studies) followed by Pfizer (14 studies) and Moderna (9 studies) in subjects reporting MI after vaccination. Out of all the studies, 69% reported MI cases after the first COVID-19 vaccination dose and 14% after the second, 44% reported ST-segment elevation MI, and 26% reported non-ST-segment elevation MI. The mortality rate was 29% after MI.

In conclusion, many studies linked MI to COVID-19 vaccinations, but no definitive association could be found.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2. The first case of COVID-19 was reported in Wuhan, China and rapidly spread to the rest of the world[1]. The COVID-19 outbreak was declared a pandemic on March 11, 2020[2]. Although severe acute respiratory syndrome coronavirus 2 primarily affects the respiratory tract, it frequently causes cardiac, gastrointestinal, hepatic, nephrological, and central nervous system distress[3]. It mainly causes nonspecific symptoms like fever, cough, and myalgia; however, in severe cases, it can lead to respiratory failure, septic shock, multiorgan dysfunction, and even death[4].

COVID-19 treatment is most often general supportive care and nutritional support in addition to respiratory care. However, due to the lack of clinically approved interventions for COVID-19 treatment, attempts have been made for vaccine development to prevent the disease[3]. As a result, the safety and efficacy of several vaccines have been approved by the World Health Organization. Among these are AstraZeneca/Oxford, Johnson and Johnson/Janssen, Moderna, Pfizer/BioNTech, Sinopharm, Sinovac, and the Bharat Biotech BBV152 Covaxin vaccine[5]. Vaccines for severe acute respiratory syndrome coronavirus 2 have several different mechanisms of action, including: (1) RNA and DNA vaccines that are genetically engineered to produce a protein that warrants an immune response; (2) Vector vaccines that introduce a type of virus that cannot produce disease but can effectively generate an immune response; (3) Vaccines that use genetically modified viruses to become weaker or inactivated in order not to cause virulence but retain their antigenicity; and (4) Harmless fragments of proteins or protein shells with similar antigenicity to the COVID-19 virus that are used in protein-based vaccines to produce immunity[5].

It is not uncommon to experience side effects following a COVID-19 vaccine. Fatigue, headache, muscle pain, joint pain, chills, fever, generalized body pain, and local reaction at the injection site are some of the side effects that have been reported after COVID-19 vaccination[6]. Several cardiovascular adverse effects have also been reported after COVID-19 vaccination, including myocarditis, pericarditis, and thrombotic events. Additionally, rare cardiovascular events such as hypertension, acute coronary syndrome, stress cardiomyopathy, arrhythmias, and cardiac arrest have also been reported. Although the relationship between these rare events and the vaccination is doubtful, the incidence of these rare side effects post vaccination in the absence of any other obvious cause in otherwise healthy individuals may suggest a causal relationship between the two[7].

When only focusing on myocardial infarction (MI), it is observed that after a person experiences an MI, there is a 20% chance of mortality in the 1^st year and 10% thereafter[8]. According to Johansson et al[9], the relative risk of cardiovascular morbidity and mortality was 30% higher in those who suffered from MI compared to the general population. The aims of this review were to identify the pathophysiological links between MI and COVID-19 vaccination and investigate the doses and frequencies of COVID-19 vaccines, the types of MI, and mortality statistics linked with the vaccine administration in the available literature.

A total of 56 studies were identified, but only 29 were selected after applying the eligibility criteria (Table 2)[5-7,10-35]. The majority of these were case reports that reported the incidence of MI after COVID-19 vaccination but could not prove any causative relationship between the two. They also could not prove whether MI was due to vaccination-related changes in the body. The majority of side effects reported were from AstraZeneca followed by Pfizer and Moderna vaccines (Figure 2).

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Figure 2 Frequency of vaccines given to subjects in each study.

Based on the studies included in this report, patients usually suffered from MI after the first dose of the vaccine (69%). Of these studies, 53.3% of case reports reported MI within a few hours of vaccine administration and the rest within 10 d. Out of these patients, 44% of cases reported were of ST-segment elevation MI (STEMI), and 26% were non-ST-segment elevation MI (NSTEMI). The mortality rate was 29% (Figure 3). The most studies reported were from the United States, the United Kingdom, and India (Figure 4).

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Figure 3 Characteristics of research studies analyzed. A: Doses of vaccines given to subjects/participants in studies analyzed; B: Percentage/frequencies of types of myocardial infarction reported in studies analyzed; C: Type of studies analyzed; D: Mortality status of subjects/participants in various studies after suffering from myocardial infarction post-vaccination. MI: Myocardial infarction; STEMI: ST-segment elevated myocardial infarction; NSTEMI: Non-ST-segment elevated myocardial infarction.

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Figure 4 Frequency of studies reporting myocardial infarction after coronavirus disease 2019 vaccination in different countries.

Possible mechanisms behind MI that have been identified after the literature review are as follows: (1) Kounis syndrome, which can cause MI through different mechanisms like allergic vasospasm and stent occlusion with a thrombus infiltrated by eosinophils or mast cells; (2) Vaccine-induced thrombotic thrombocytopenia; (3) Acute coronary syndrome after influenza vaccine administration as both influenza and COVID-19 vaccines share a common excipient (polysorbate 80); (4) Demand–supply mismatch ischemia, which can be caused by the stress of getting the vaccine in elderly people with other associated comorbidities; and (5) Myocarditis.

Globally, 65.8% of people have received at least one dose of a COVID-19 vaccine, and 11.79 billion doses have been administered globally[36]. The doses of various vaccines administered through May 25, 2022 are as follows: Pfizer, 613 million; Moderna, 147 million; AstraZeneca, 67 million; Janssen, 19 million; Sputnik V, 1.85 million; Sinopharm, 2.31 million; Sinovac, 3737; and Covaxin, 44. Pakistan has administered at least 248672457 doses of COVID-19 vaccines so far. Assuming that every person needs two doses, that is enough to have vaccinated about 57.4% of the country’s population[37].

MI remains one of the rare complications of a COVID-19 vaccination[7]. In this review, nearly 69% of the studies reported MI occurrence after the first dose, and 14% reported it after the second. It is a known fact that a subsequent or a booster dose of a vaccine is given to increase the antibody titer. This is especially crucial in those with a weakened immune response due to comorbidities[38]. A theory based on this finding is that since MI occurrence is higher after the first vaccine dose, immune response probably plays no role or only a minimal role in MI pathophysiology. If MI was due to overstimulation of the immune system, then the frequency of MI after the second dose would be higher.

A study showed that COVID-19 vaccination produces an optimum immune response in chronic inflammatory disease patients on immunosuppressive therapy, and the risk of adverse consequences is not higher than in the normal population[39]. No single inflammatory biomarker of systemic manifestations of vaccines has been identified but rather a battery of biomarkers, specifically, interleukin-6, C-reactive protein, and the interferon signaling pathway. A vaccine starts its action within minutes, starting from the injection site and spreading throughout the body. The factors known to affect the reactogenicity of various COVID-19 vaccines are age, gender, psychological/physical stressors, obesity, pre-existing immunity, vaccine characteristics (route, site, and method of vaccine administration), vaccine composition, antigen type, combination, and dose[40].

According to McManus et al[41], the incidence of STEMI compared to NSTEMI has reduced over the past few years. In the present research, patients with STEMI were present in 44% of the studies compared to 26% with NSTEMI after COVID-19 vaccination[41]. A recent case reported STEMI in a post-COVID-19-vaccinated patient in April 2022, and the patient also had a history of myocarditis. A possible explanation was the transient atrial fibrillation or plaque rupture after the myocarditis[42]. Therefore, myocarditis on the one hand is a primary complication of COVID-19 vaccination and on the other hand is a secondary cause of MI development after COVID-19 vaccination.

In his blog, Labos wrote a critique in which he pointed out that in order to state the link between inflammation and MI after COVID-19 vaccination, the inflammatory biomarkers need to be measured before, soon after, and a month after vaccination[43]. Jabagi et al[10] proved that there was no association between increased risk of MI post Pfizer vaccination for COVID-19. He did a serial analysis 1 d, 1 wk, and 2 wk post vaccination[10].

Kounis syndrome is one of the mechanisms identified for the occurrence of MI post COVID-19 vaccination as it has been observed in various patients who received a COVID-19 vaccination (Pfizer, AstraZeneca, and Sinovac vaccines)[5,15]. It manifests as an acute coronary syndrome accompanied by mast cell activation due to hypersensitivity or an allergic or anaphylactic reaction[44]. It is more commonly linked with STEMI, which probably explains the higher percentage of STEMI cases after COVID-19 vaccination compared to NSTEMI in the present research.

Vaccine-induced thrombotic thrombocytopenia is another mechanism linking MI with COVID-19 vaccines. In vaccine-induced thrombotic thrombocytopenia, tetramers of platelet factor 4 crosslink with vaccine proteins to form multimolecular aggregates. The ethylenediamine tetraacetic acid in the vaccine possibly causes capillary leakage and dissemination of components in the blood. The multimolecular aggregates are recognized by immunoglobulin G antibodies, which activate platelets, neutrophils, and the complement system, resulting in massive coagulation system activation[45]. This can lead to MI and eventually mortality or long-term morbidity.

Polysorbate 80, an excipient in the AstraZeneca vaccine, is seen to trigger allergic reactions in those allergic to the compound. Similarly, polyethylene glycol is the excipient found in Pfizer and is a cause of severe anaphylaxis in those allergic to polyethylene glycol. However, polyethylene glycol allergy is very rare compared to polysorbate 80 allergy[46], which probably explains the increased number of MI cases reported in patients vaccinated with AstraZeneca compared to other vaccines.

The literature searched and analyzed in this study was quite diverse. Therefore, one of the challenges faced while compiling this review was to bring the results under one umbrella. It was observed that robust original research needs to be conducted to probe the mechanisms of and the association between MI and COVID-19 vaccination. Considering the amount of clinical evidence available linking MI with COVID-19 vaccination, it is a bit early to make definitive deductions regarding their link.

It can be concluded that there is a link between COVID-19 vaccinations and MI in temporal terms of occurrence. However, there is also a possibility that the link was found purely by chance as a majority of cases were reported within 1 d, which is too short a time for a build-up of definitive causative mechanisms for MI. This is due to the diversity of risk factors for MI, such as age, gender, body mass index, ethnicity, and physical/mental stressors. This link can be definitively proven by conducting research while considering the confounders. AstraZeneca was seen to induce the greatest amount of coronary artery disease, with STEMI as the leading type, and this primarily followed the first vaccination dose.