Review of the current literature regarding cardiac adverse events following COVID-19 vaccination

INTRODUCTION The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), which was responsible for coronavirus disease 2019 (COVID-19) infection, was discovered in Wuhan, China, in December 20191. Since then, the disease has spread globally, resulting in a pandemic. Because there is no specific antiviral treatment for COVID-19 disease, vaccination seems to appear the most effective vehicle for controlling the infection. Until now, many vaccines have been developed and approved for immediate use by the health authorities. Two types of messenger RNA (mRNA)based COVID-19 vaccines, namely, BNT162b2 mRNA (PfizerBioNTech, NY) and mRNA-1273 (Moderna, Cambridge, MA), have been administered in hundreds of millions of doses since they have received provisional Food and Drug Administration (FDA) approval in the United States in December 20201. Janssen Ad26.COV2.S (Johnson and Johnson, New Brunswick, NJ) and The ChAdOx1 [Oxford/AstraZeneca (AZD1222)] were recombinant types of vaccines, in which replication-deficient human adenovirus type 26 vector was used to transfer the virus1. Although side effects from these vaccines are generally mild and transient, there has been an upsurge of cases with cardiac adverse events reported after COVID-19 vaccination. As a result, the objective of this review was to assess all cardiovascular adverse events reported following COVID-19 immunization, as well as the likely mechanisms behind them.


INTRODUCTION
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was responsible for coronavirus disease 2019  infection, was discovered in Wuhan, China, in December 2019 1 . Since then, the disease has spread globally, resulting in a pandemic. Because there is no specific antiviral treatment for COVID-19 disease, vaccination seems to appear the most effective vehicle for controlling the infection. Until now, many vaccines have been developed and approved for immediate use by the health authorities. Two types of messenger RNA (mRNA)based COVID-19 vaccines, namely, BNT162b2 mRNA (Pfizer-BioNTech, NY) and mRNA-1273 (Moderna, Cambridge, MA), have been administered in hundreds of millions of doses since they have received provisional Food and Drug Administration (FDA) approval in the United States in December 2020 1 . Janssen Ad26.COV2.S (Johnson and Johnson, New Brunswick, NJ) and The ChAdOx1 [Oxford/AstraZeneca (AZD1222)] were recombinant types of vaccines, in which replication-deficient human adenovirus type 26 vector was used to transfer the virus 1 . Although side effects from these vaccines are generally mild and transient, there has been an upsurge of cases with cardiac adverse events reported after COVID-19 vaccination. As a result, the objective of this review was to assess all cardiovascular adverse events reported following COVID-19 immunization, as well as the likely mechanisms behind them.

Vaccination types
Baseline clinical characteristics, electrocardiographic findings, and laboratory findings Table 2 summarizes the baseline characteristics, presenting symptoms, electrocardiography, and laboratory results in all published cases. Patients who were diagnosed with AM were relatively younger and almost all of them were male. By contrast, AMI cases were older. The common complaint in all patients was chest pain. Electrocardiography findings in AM cases ranged from no ischemic changes to ST elevation, PR depression, and nonspecific ST changes [2][3][4][5][6][7][8][9][10][11][12][13][14][15] . Remarkably, patients who presented with AMI following immunization had ST elevation only in inferior leads [16][17][18][19][20] . Troponin levels were measured in all patients who developed a cardiac event after vaccination. In all of them, it was reported above the reference range. The data on brain natriuretic peptide (BNP) levels were shared in very few cases 2,5,10-12,13-15 . On the other hand, C-reactive protein (CRP) levels were elevated in all reported cases. Contrary to COVID-19 infection, lymphopenia was not detected in most patients with post-vaccine cardiac events.

DISCUSSION
AM is generally regarded as an uncommon adverse effect following vaccination. According to reports, the majority of previously documented post-vaccine AM cases were subclinical and were discovered by routine pre-and post-vaccine troponin level assessments 21 . However, in our review, all the cases documented following COVID-19 immunization were symptomatic. This implies that asymptomatic individuals might not be identified, and as a result, cardiac events following immunization might be significantly greater than predicted. Although the causes of AM due to COVID-19 vaccinations are not well understood, several potential pathophysiological explanations have been proposed. It has been considered that in some people with genetic vulnerability, the immunological response to mRNA-based COVID-19 vaccines may be uncontrollable, resulting in the activation of an abnormal innate and acquired immune response 22 . Also, both dendritic cells and Toll-like receptor-expressing cells subjected to mRNA may still be able to produce cytokines in certain people, albeit this may be significantly decreased when exposed to mRNA with nucleoside alterations as opposed to unmodified RNA 22 . As a result, the immune system may recognize the mRNA as an antigen, leading to hyperactivation of the inflammatory and immunologic pathways, which may have a role in the occurrence of AM in certain people as part of a systemic response 22 .
During vaccination, an allergic reaction may develop, which can be classified as a vaccine-related adverse effect. It is always difficult to determine whether a response is caused by the vaccination or by other causes. Adjuvants are usually included in the vaccines to enhance stability, solubility, and absorption, which can result in IgE-mediated anaphylactic responses following immunization. This might be one explanation for AMI following the COVID-19 vaccination. The fact that all published AMI cases had their complaints started within a short time after the initial dosage of vaccination supports this hypothesis. Another potential AMI cause, as proposed by Warkentin et al., is vaccine-induced prothrombotic immune thrombocytopenia, which is similar to heparin-induced thrombocytopenia and leads to thrombotic manifestation 23 .

Future perspective
The number of documented cases supports the "very uncommon" interpretation of vaccine-related cardiac side effects despite the fact that hundreds of millions of COVID-19 vaccinations have been administered globally. It was also clearly demonstrated that the majority of the patients with cardiac adverse events demonstrated full recovery in terms of both symptoms and imaging. Moreover, it must be highlighted that since there has been no causative link between COVID-19 vaccinations and cardiac events, the effectiveness of the COVID-19 vaccination far exceeds some possible drawbacks. Consequently, more research on AM, AMI, and other cardiac events before and after COVID-19 vaccination will enrich the literature about the long-term effects of the vaccination and determining the incidence rate.