Abstract:
Aim: Vaccines have been mainly described to provide
cardioprotective effects with rare reports showing rare association with
myopericarditis. However, vaccines have not been well studied regarding
its effects on heart rhythm disorders.
Methods: we used vaccine adverse event reporting system (VAERS)
between 1990-2021 to search for atrial fibrillation and other less
prevalent arrhythmia. Disproportionality signal analysis was conducted
by measuring reporting odds ratio (ROR) with 95% confidence interval
(CI).
Results: Over 1,300,000 adverse events were reported between
1990-2021. Among these events, atrial fibrillation was reported 2149
times in association with various vaccines. 90% of atrial fibrillation
was associated with COVID-19 vaccines with ROR of 13.18 (CI 95%: 11.3
to 15.4) (P<0.0001). Interestingly, influenza vaccines,
polyvalent polysaccharide pneumococcal (PPSV23) vaccine, pneumococcal
13-valent (PCV13) vaccine, zoster vaccine, and tetanus-containing
vaccines were significantly associated with reduced atrial fibrillation.
Finally, our analysis showed that COVID-19 vaccines were associated with
much higher incidence of other cardiac arrhythmias compared with other
vaccines.
Conclusions: While vaccines have not been linked to heart
rhythm disorders, the introduction of COVID-19 vaccines in 2020 showed
significant association with atrial fibrillation. This study showed
unprecedent detrimental effect of COVID-19 vaccines on atrial
fibrillation and warrants the need to take that into consideration when
prescribing COVID-19 vaccines.
Introduction:
Over the last few decades, Atrial Fibrillation (AF) has been a rapidly
growing global health problem becoming the most common sustained cardiac
arrhythmia(1). Consequences include
decreased cardiac output and thrombus
formation(2,
3). On electrocardiogram, it is
characterized by the presence of rapid, irregular, fibrillatory waves
varying in size, shape, and duration. AF is associated with a plethora
of cardiac and non-cardiac conditions including hypertension, ischemic
heart disease, congestive heart failure, valvular heart disease,
inflammatory states, hyperthyroidism, obesity, alcohol use disorder,
infections, and sepsis(4).
Influenza and Herpes Zoster (HZ) infections were shown to increase the
rate of development of AF(5-7). The
relationship between atrial fibrillation with Helicobacter pylori and
Chlamydia pneumoniae infections remains
debatable(8-11). Particularly interesting,
sepsis has been implicated in the increasing number of hospitalizations
of patients with new-onset AF(12-14).
Pathophysiologically, AF likely originates from the underlying
inflammatory process that occurs with infections and sepsis leading to
the release of a wide-range of inflammatory mediators including
high-sensitivity C-reactive protein (CRP), Interleukin-6 (IL-6),
Interleukin-8 (IL-8), and Tumor Necrosis Factor-a (TNF-a). These in turn
act directly or through exerting oxidative stress to trigger atrial
electrical remodeling with decreased atrial refractory period,
conduction heterogeneity, abnormal calcium and ionic handling, as well
as atrial ectopy. Far less understood is the variation in AF incidence
between types of infections being highest in pneumonia, while more
recurrence and a long-term prognosis being observed with
gastrointestinal infections. This might be related to different cytokine
profiles involved with each type of
infection(15).
The novel coronavirus disease-2019 (COVID-19) seems to be the culprit in
a significant proportion of reported atrial fibrillation cases over the
last one and a half years. Atrial fibrillation is the most commonly
encountered cardiac arrythmia in the disease. This could be explained by
the associated inflammatory/cytokine storm, hypoxemia, direct
cardiotoxic effects, sympathetic nervous system overactivity, or
secondary to therapeutic agents and drug-drug
interactions(16).
While the correlation with infections and sepsis has been
well-established, the relationship between atrial fibrillation and
vaccinations is yet to be fully elucidated. Influenza vaccine has been
noted to decrease the risk of development of AF while the anthrax
vaccine adsorbed (AVA) and the smallpox vaccines showed no increased
risk(5, 7,
17, 18).
Our aim in this study is to shed the light on the reported incidence of
atrial fibrillation with different widely-used vaccines.
Methods:
The Vaccine Adverse Event Reporting System (VAERS) is a well-established
and publicly accessible database used for monitoring adverse events
associated with vaccinations. This system has data starting from 1990
and is updated regularly. It accumulates reports from around the globe
on vaccine quality complaints as reported by health care professionals,
producers, and from those having received the vaccine. In particular, it
identifies name of the vaccine, the adverse reaction seen, the severity
of the reaction and other related information. Ethics committee approval
was not needed for the use of this system since it is anonymous. In the
present study we comprehensively evaluated the incidence of cardiac
arrhythmias in association with all vaccines (COVID, Zoster, Influenza,
Pneumococcal, Hepatitis B, TDAP, TD, TTOX, Smallpox, Anthrax, Typhoid,
Meningococcal, Hepatitis A, Lyme, MMR, Yellow Fever, HPV, Japanese
Encephalitis virus, Poliovirus, Varicella).
We looked for arrhythmia adverse events (AEs) using standardized medical
terms according to the Medical Dictionary for Regulatory Activities, the
list of terms included “atrial fibrillation”, “long QT”, “atrial
flutter”, “ventricular tachycardia”; “ventricular fibrillation”,
“supraventricular tachycardia”, “sick sinus syndrome”, “bundle
branch block” and “heart block”.
The association between the use of vaccines with arrhythmia adverse
events was assessed by disproportionality signal detection analysis
using the reporting odds ratio (ROR). ROR is a measure of the magnitude
of association between an exposure to a given vaccine and the odds of
patients experiencing a specific adverse event, compared to the odds of
the same event occurring with all other vaccines in the database. ROR
was considered significant when the lower limit of the 95% confidence
interval (CI) was >1.0.
Results:
The patient characteristics of reported cases are shown in table 1.
Overall, no significant sex differences existed with a nearly equal
proportion of reported adverse events in males and females. Patients at
the age of 50 years and above constituted about 85% of cases with the
remainder falling in the 19-49 age group. Serious adverse events
occurred in 823 cases compared to 739 non-serious events, while 81 cases
(4.9 %) had an outcome of death. In the majority of cases (913
patients), onset of adverse events was within the first seven days
following vaccine administration. This was followed by 243 patients
developing adverse events later than one month following administration.
Onset within 8-14 and 15-30 days occurred in 101 and 161 patients,
respectively. Table 2 further characterizes vaccine-associated AF and
showing that COVID-19 vaccines reported the most frequent reported AF
(84%) among all other vaccines.
As shown in figure 1 and table 3, individuals who received the COVID-19
vaccine had a significantly higher risk of developing atrial
fibrillation with a ROR (CI 95%) of 13.18 (11.3 to 15.4) with
P<0.0001. Interestingly, the risk of atrial fibrillation was
significantly decreased in those receiving the zoster with ROR (CI 95%)
of 0.6, (0.5-0.75, P < 0.0001), Flu (0.43, 0.36-0.5, P
< 0.0001), PPV13 (0.4, 0.26-0.65, P=0.0001), and PPSV23 (0.4,
0.28-0.53, P < 0.0001) vaccines. Those who were administered
the tetanus vaccines had the least likelihood of developing atrial
fibrillation with an ROR of 0.3 (0.2-0.6, P<0.0001). Further
analysis revealed that Pfizer and Moderna COVID-19 vaccines were
responsible for more than 90% of COVID-19 vaccine-associated AF likely
due to widespread use of these types of vaccines in the united states
(table 4).
A wide array of arrhythmias other than atrial fibrillation was reported
following vaccine administration. Supraventricular Tachycardia (SVT) was
the most common with 438 cases followed by atrio-ventricular blocks
(262), bundle-branch blocks (238), ventricular tachycardias (220), among
others. In about two thirds of these cases, patients had received the
COVID-19 vaccine. COVID-19 was the suspected culprit in 50.5% of Long
QT and 80.3% of atrial flutter cases. Sick Sinus Syndrome (SSS) was the
least reported with only 14 cases. Notably however, 92.8% of patients
with SSS had received the COVID-19 vaccine (table 5).
Discussion:
While the link between infection and atrial fibrillation is still poorly
characterized, the impact of vaccine on this disease is largely unknown.
Our study comprehensively analyzed all reported vaccine-related atrial
fibrillation and demonstrated for the first time an unknown association
between vaccines and atrial fibrillation. Particularly, we show that,
among all vaccine, COVID-19 vaccines are significantly associated with
the risk of atrial fibrillation with reported odds ratio of almost 10
compared to patients who didn’t take any of the COVID-19 vaccines.
Additionally, almost all cardiac rhythm disorders that reported in VAERS
were primarily shown to be associated with COVID-19 vaccines compared to
other vaccines.
The role of inflammation in atrial fibrillation is an emerging field.
Inflammation contributes to pathogenesis of AF via structural and
electrophysiological alterations of the atrium that enhances the
susceptibly for AF development(19,
20). Myocarditis and pericarditis have
been linked to increase risk of AF(21).
Several proinflammatory signaling are described to mediate atrial
fibrillation. For example, the NLRP3 inflammasome, a classic pathway
mediating IL-18 and IL-1β production, has been shown to be increased on
AF patients(22). Systematically, AF
incidence is known to be elevated critically ill and septic
patients(12). Additionally, upregulation
of inflammatory markers has been correlated with
AF(23).
Since several studies have supported the role of inflammation in AF,
different groups have demonstrated that certain infections may
participate in atrial fibrillation development. Beside the posing risk
of sepsis as mentioned above, pneumococcal pneumonia has been shown to
increase the risk of new onset AF(24). H.
pylori was shown to be associated with high incidence of
AF(25). Viral infections such as
influenza, hepatitis C, and Zika viruses were correlated with elevated
risk of atrial fibrillation(5,
26, 27).
While COVID-19 vaccines-associated arrhythmia is a novel finding in this
study, the underlying mechanism are unknown. COVID-19 vaccines have been
reported to increase the risk of myocarditis and pericarditis which may
explain the enhanced risk of AF after COVID-19 vaccines, however,
further studies are warranted to delineate the underlying the mechanisms
that drive this process.
Although our study uncovered a novel association between vaccines and
arrhythmias, certain limitations are notable. While VAERS provides
important data, multiple reservations arise such as under-reporting,
inaccuracy and incomprehensiveness. Additionally, the population
characteristics regarding cardiac history and other cardio-metabolic
profile are unknown.
In conclusions, our findings showed that COVID-19 vaccines are strongly
associated with AF and other arrhythmias. We recommend obtaining
electrocardiogram for certain population who are at high risk for AF
before receiving the vaccine. Further studies are required to study
rhythm disorders with COVID-19 vaccines regarding which population are
at higher risk for AF.
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Acknowledgment: None.
Funding: The authors declare that this work was not supported
by any funds or grants.
Competing Interests: The authors have no relevant financial or
non-financial interests to disclose
Data Availability: The datasets from the current study are
available from the corresponding author upon request