key: cord-0882792-on6bs84d
authors: Hana, David; Patel, Kevin; Roman, Sherif; Gattas, Boula; Sofka, Sarah
title: Clinical Cardiovascular Adverse Events Reported Post COVID-19 Vaccination: Are they a real risk?
date: 2021-12-10
journal: Curr Probl Cardiol
DOI: 10.1016/j.cpcardiol.2021.101077
sha: f843ce8fbd55ac63068cc83c19e85e9aaa1a1afe
doc_id: 882792
cord_uid: on6bs84d

Given the urgent need to control the spread of the novel COVID-19 virus, thirteen vaccines have been approved for emergency use before completing all three phases of the clinical trials. Thereby a careful monitor of the adverse effects postvaccination is essential. We searched through PubMed and other reporting systems like VAERS for the reported cardiovascular adverse events post-COVID-19 vaccination. Through our review, we determined that the incidence of all the reported cardiovascular events is very rare. Additionally, the vaccine was initially given to the elderly and high-risk populations in which cardiovascular events such as myocardial infarction and arrhythmias are already more prevalent, while other cardiovascular events such as myocarditis or vaccine-induced thrombotic thrombocytopenia were more common in younger populations. Moreover, a direct causal relationship, if any, between vaccination and adverse events is yet to be fully elucidated. Thus, at this time point, the benefits of vaccination far outweigh the risk.

Adverse effects such as fatigue, headaches, and local injection site reaction have been reported after receiving COVID-19 vaccines; however, rare serious adverse events were also recorded [2, 3] . Multiple studies reported cardiovascular complications in hospitalized patients with COVID-19 infection [4, 5] . Recently few reports described rare cardiovascular adverse events post-COVID-19 vaccination [6] . Although some of these reported adverse events are serious, the benefits of vaccination outweighed the risks [7, 8] . There are also reports of similar rare complications following vaccination with other vaccines such as smallpox and influenza [9] .

The relation between vaccination and these rare complications is still ambiguous. However, the occurrence of these rare events postvaccination with the absence of any other obvious cause may suggest that the vaccine can be a precipitant factor. It is essential to report these adverse events along with long-term follow-up of patients with these complications. In this review, we describe the cardiovascular complications that were reported post-COVID-19 vaccination, such as myocarditis, pericarditis, thrombotic events in addition to other rare, reported cases of hypertension, acute coronary syndrome, stress cardiomyopathy, arrhythmias and cardiac arrest.

COVID-19 mRNA vaccinations set a precedent in the field of virology with their rapid development and demonstration of safety and effectiveness [10, 11] . The two mRNA vaccines (CDC) Advisory Committee on Immunization Practices (ACIP) convened to examine the risks and benefits. On June 23, 2021, the committee determined that there was likely an association between COVID-19 vaccines and myocarditis and pericarditis though the benefits still far outweighed the risks [12] . When viewed historically, myocarditis and pericarditis after vaccination is not a new phenomenon. There are reported cases as early as 1957 following vaccinations for smallpox, hepatitis B, and even influenza [9] . However, the incidence of these cases is rare with only smallpox vaccination having a strong correlation with myocarditis and pericarditis [13] .

Myocarditis is idiopathic in about 50% of cases [14] . In patients with an identifiable cause, the most common cause is viral. Other causes can include granulomatous inflammatory Clinical Cardiovascular Adverse Events Reported after COVID-19 Vaccine 6 diseases, polymyositis and dermatomyositis, and collagen vascular diseases [15] . Myocarditis is more common in younger adults and appears to affect both genders equally [16] . The pathophysiology is believed to be largely immune-mediated. It is proposed that the microbial agent gains entry through either the gastrointestinal or respiratory tracts and binds to specific receptors in the myocardium leading to cell lysis and subsequent immune dysfunction with molecular mimicry playing a large role. The variable clinical presentation of myocarditis makes it difficult to estimate the incidence, though it is thought to be 10 to 20 per 100,000 cases per year with 1. 5 In reports of post-COVID-19 vaccination myocarditis, there have been 2 cases that included cardiac biopsies, which lacked the expected myocardial infiltration [35, 37] . PCR testing of cardiac tissue for SARS-CoV-19 virus was also negative [35, 37] . Though caution should be taken when hypothesizing based on only two cases, this may suggest there is a different mechanism leading to myocardial injury than the usual microbial and lymphocyte infiltration of myocardial tissue.

In a case report, it was shown that the IgG and IgM antibody levels against SARS-CoV-2 spike protein were not different in a patient with myocarditis than in individuals without myocarditis post-COVID-19 vaccination [28] . This argues against a hyperimmune response.

Molecular mimicry has also been hypothesized as a potential mechanism. Antibodies against SARS-CoV-2 spike proteins have been shown to cross react with similar human protein sequences including -myosin [38] . However, reports typically lack severe autoimmune reactions. COVID-19 infection has been associated with an increased incidence of myocarditis and pericarditis [5] , which would raise the question of whether breakthrough infections could explain post-vaccination myocarditis and pericarditis. However, in most reports, patients tested negative for COVID-19 [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] . Innate response to mRNA vaccine products such as the lipid nanoparticles or other adjuvants is also unlikely as these have been shown to not result in an inflammatory or immune response [10, 11] . In addition, cases of myocarditis and pericarditis have also been reported in the Janssen vaccine as well, which is not an mRNA-based vaccine

In patients presenting with chest pain after COVID-19 vaccination, management should include ECG, troponins, and inflammatory markers [12] . Hospitalization may be required for patients with signs of myocardial injury, arrhythmia, or hemodynamic instability. Supportive care along with non-steroidal anti-inflammatory drugs should be given, though published cases have used steroids and colchicine as well [29, 32] . Strenuous physical activity should also be limited until resolution. The CDC currently recommends delaying the second dose when Clinical Cardiovascular Adverse Events Reported after COVID-19 Vaccine 9 applicable if myocarditis or pericarditis occurs following the first dose, though the CDC still recommends considering obtaining the second dose following resolution [39] .

Although there has been a considerable amount of attention and media discussions on post-COVID vaccination myocarditis and pericarditis, the number of cases is relatively very small considering the number of vaccine doses administered. COVID-19 infection itself yields a considerable risk of hospitalization, death, myocarditis, and pericarditis, which is much greater than that related to COVID-19 vaccination [12] . Thus, the risk-benefit discussion overwhelmingly favors vaccination. COVID-19 vaccination not only decreases hospitalization due to COVID-19 complications and death, but it also decreases COVID-19 complications including myocarditis and pericarditis [40, 41] 

Within a few weeks of initiating public vaccination efforts, several rare cases of vaccineinduced thrombotic thrombocytopenia (VITT) have been reported after receiving COVID-19 vaccines, especially following the adenoviral vector AstraZeneca and Janssen vaccines. These rare cases of VITT have a significant impact on stumbling the global vaccination program progression [42, 43] . Such reports led to a temporary pause of Janssen vaccine use from April 

Over the past few months, vascular thrombosis, myocarditis and pericarditis occupied the top discussions among the medical community for the major cardiovascular (CV) complications that might be related to covid vaccines. However, there are other possible post-COVID vaccination CV complications that need to be highlighted and taken into consideration. [69, 70] . In addition, Boivin and his colleagues suggested that the stress of getting the vaccine in elder people with other associated comorbidities can lead to demand-supply mismatch ischemia [66] . and 5.9%, respectively [75, 76] . The prevalence is much lower after COVID-19 vaccine.

According to VAERS, the prevalence of palpitations and atrial fibrillation are 0.006% and 0.0009%, respectively [21] .

The initial data from the clinical trial by Pfizer for its vaccine demonstrated 1 event of cardiac arrest and 2 deaths. Reports indicated that death occurred at the same rate as in the general population [64] . As of April 2021, Edler and his colleagues in Germany reported 3 cases of death after covid vaccine administration within 15 days. All of them had a history of severe cardiovascular diseases and other comorbidities. Two patients (one tested negative for COVID) were found on the postmortem forensic exam to have a pulmonary embolism (PE) and recurrent MI as the cause of death. The third patient died from covid infection within 10 days after vaccine administration. The authors did not report what type of vaccine was administered [77] . Kaur [78] . No more case reports about post-vaccination deaths and cardiac arrests could be found in the literature. No evidence of direct correlation with the vaccine has been found.

It is crucial to understand a few points. First, the purpose of this review article is to increase awareness among health care workers about the possible cardiovascular events postvaccination. Second, the vaccine was initially given to the elderly and high-risk populations, so it is expected that this age group will have cardiovascular events. Such vulnerable populations are more amenable to develop adverse effects from medication in general. Though our review did not show this correlation for all CV adverse effects, some adverse effects such as MI and arrhythmias were more commonly seen in these already vulnerable population. While other cardiovascular events such as myocarditis or vaccine-induced thrombotic thrombocytopenia were more common in younger populations. Third, compared with the total number of vaccine doses given, the incidence of all reported cardiovascular adverse events remains very rare.

Finally, a direct causal relationship, if any, between vaccination and the adverse events is yet to be fully elucidated. All presented data are from case reports and the reporting systems. Thus, based on our review, we conclude that the benefits of vaccination far outweigh the risk at this time.

The development of this manuscript was not supported by grant funding.

Marcucci 

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