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\begin{document}

\title{Vaccines and Heart Failure: Analysis of Vaccine Adverse Events Reporting
System between 1990-2021}



\author[1]{Zaki Al-yafeai}%
\author[2]{David Aziz}%
\author[2]{Mohamed Ghoweba}%
\author[2]{Akhilesh Babbili}%
\affil[1]{LSU Health Shreveport}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\begin{abstract}
Introduction: the role of vaccines in preventing diseases is
well-established. However, the evolving techniques and types of vaccine
necessitate the search for its safety more than ever. While cases of
takotsubo cardiomyopathy and COVID-19 vaccine have been described, a
comprehensive study to investigate the role of vaccination with
cardiomyopathy and heart failure is lacking. The aim of this study is to
investigate the link between the current vaccines and heart failure.
Method: we utilized vaccine adverse event reporting system (VAERS) to
search for cardiomyopathy, cardiac failure or ventricular dysfunction.
Disproportionality signal analysis was conducted by measuring reporting
odds ratio (ROR) with 95\% confidence interval (CI). Results: VAERS
reported over 1,300,000 adverse events between 1990-2021. Heart failure
was reported over 2000 times in association with multiple vaccines. 56\%
of vaccine-related heart failure reported in males; 88\% were serious;
19\% mortality rate. The majority of reported heart failure was related
to COVID-19 vaccines with ROR of 21.6 (CI: 18.3 to 25.4,
P\textless{}0.0001). Smallpox was also significant with ROR 7.2 (CI
5.5-9.6, P\textless{}0.0001) On the other hand, heart failure was
minimally described to be associated with other vaccines (influenza,
zoster, tetanus, human papillomavirus (PPV)). Conclusions: Our study
showed for the first time that vaccines maybe associated with heart
failure. In particular, we show that covid-19 and smallpox vaccines are
associated with increased risk of heart failure. Vaccines against
Influenza, zoster, tetanus and (PPV) are associated with reduced heart
failure. These data warrant longitudinal studies to delineate the
association between heart failure and vaccines.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Heart failure (HF) is a clinical syndrome caused by malfunction of the
heart's ability to pump blood to the rest of the body due to impaired
ventricular filling or ejection. Clinical manifestations encompass a
large constellation of signs and symptoms of volume overload. HF affects
over 6 million Americans\textsuperscript{(1)} and costing the healthcare
system up to 32 billion dollars annually(2). When unmanaged, it can be
debilitating, rapidly progressive and ultimately fatal.

Throughout decades of research, the scientific community has identified
various etiologies of HF that range from common conditions such as
coronary artery disease and valvular diseases, to less common conditions
such as infections(3, 4). Several studies have repeatedly shown that
influenza infection represent a significant hazard for patients with
heart failure. Sepsis was shown to increase hospitalization of heart
failure and mortality. More recently amidst the COVID-19 pandemic, there
have been reports of increased incidence of heart failure in patients
with acute COVID-19 infection(5).

Based on the role of infections on heart failure, it was reasonable to
hypothesize that vaccines may curb the deleterious effects of infections
on heart failure. Indeed, several studies have demonstrated a
cardioprotective of annual influenza vaccine(6, 7). Influenza
vaccination reduced all-cause mortality in patients enrolled on
PARADIGM-HF(8). Additionally, pneumococcal vaccination was associated
with lower heart failure incidence and all-cause mortality(9). Based on
these studies, the 2022 American College of Cardiology/American Heart
Association/ Heart Failure Society of America HF guidelines encouraged
vaccination for heart failure patients(10).

Whereas the previous strongly showed a positive impact of vaccination on
heart failure, a comprehensive evaluation of the role of vaccination in
heart failure is lacking especially with the evolving techniques and
types of vaccines, such as mRNA vaccines. For example, previous case
reports described an association between Takotsubo (stress)
cardiomyopathy and COVID-19 vaccine(11). Therefore, we decided to
analyze VAERS database to provide the first comprehensive evaluation of
the association between vaccines and cardiomyopathy/heart failure.

\textbf{Methods}

Vaccine Adverse Event Reporting System (VAERS) is a national warning
system established in 1990 to detect the possible safety problems of the
US- Licensed vaccines. It is co-managed by the CDC and FDA. VAERS is a
passive reporting system where Healthcare professionals, Vaccine
manufacturers, and vaccine receivers anonymously report the adverse
events that come under their attention. It is a freely and easily
accessible platform that collects data from all over the globe and is
updated regularly. The primary objectives of VAERS are to detect new,
unusual, and rare adverse events of newly licensed vaccines,
administration errors, increased monitoring of the known adverse events.
The data is limited to vaccine adverse event reports between 1990 to the
most recent date for which the data is available. The current study is
compendious and exclusive to assess the incidence of Heart failure
associated with all the US-licensed vaccines (COVID, Zoster, Influenza,
HPV, Tetanus, Meningococcal, Hepatitis-A, Hepatitis-B, MMR)

We obtained information using the standardized medical terms according
to the Medical Dictionary of Health Terms like ``Cardiac dysfunction,
Cardiomyopathy, Ventricular dysfunction, Diastolic dysfunction, Heart
failure, Congestive heart failure, Systolic dysfunction, Systolic heart
failure, Diastolic heart failure.''

The adverse events associated with the vaccines were assessed by
disproportionality signal analysis was conducted by measuring Reporting
Odds Ratio (ROR). ROR represents the odds of a certain event (Heart
failure) occurring with the exposure to vaccine compared to the odds of
the same event occurring with all other vaccines in the database. ROR
was considered significant with the lower limit of the 95\% Confidence
Interval (CI) was \textgreater{}1.

\textbf{Results}

Table 1 shows the patient characteristics of reported heart failure
cases with all vaccines. Overall, no significant sex differences existed
with about 53.8\% of cases reported in males compared to 44.4\% in
females. The age group of 65 years and above constituted about 49.6\% of
cases while 37.7\% and 6.9\% lied within the 18-64- and 0-17-years age
groups, respectively. Serious adverse events were reported in 86.8\% of
cases compared to 13.2\% of non-serious events.

As shown in Table 2, the highest incidence of reported adverse events
was associated with the COVID-19 vaccine (93.9\%) with a remarkable
significance. A distant second was the incidence associated with the
Influenza vaccine (6.9\%). Other reported vaccines included in
descending order: zoster (3.1\%), pneumococcal (2.9\%), hepatitis B
(2.3\%), and smallpox (2.1\%) vaccines. Next, we analyzed different
types of heart failure associated with vaccines. While 60\% of the
reported heart failure are poorly defined, left ventricular failure was
the most common type (10\%) followed by right ventricular failure
(5.5\%). Acute exacerbation of heart failure reported among 8\%.
Interestingly, diastolic heart failure was twice more frequently
reported (3\%) compared to systolic dysfunction (1.5\%) as shown in
Table 3.

The patient characteristics of COVID-19 associated reported heart
failure cases are shown in Table 4. About 55.5\% of cases were reported
in males compared to 43.5\% in females. As with other vaccines, most
reported adverse events were serious in about 88.8\% of cases compared
to 11.5\% of non-serious cases. The highest number of reported cases was
associated with the use of the Pfizer/Biontech vaccine with 1212 cases
(61.93\%). The Moderna vaccine was associated with 910 cases (46.5\%)
while the Jensen vaccine was associated with 169 cases (8.64\%). Other
manufacturers accounted for 0.36\% of cases (Table 5).

Finally, we analyzed the reported odds ratio (ROR) of the most common
vaccines compared the entire database. Individuals who received the
COVID-19 vaccine had a significantly higher risk of developing heart
failure with a ROR (CI 95\%) of 21.6 (18.3 to 25.4) with
P\textless{}0.0001. The second highest incidence was reported in
association with the smallpox vaccine (7.2, 5.5-9.6, P \textless{}
0.0001). Interestingly, the risk of heart failure was significantly
decreased in those receiving the hepatitis B (0.73, 0.6-9.22, P=0.0242),
Influenza (0.71,0.6-0.8, P \textless{} 0.0001), and Zoster (0.6,
0.5-0.77, P \textless{} 0.0001) vaccines denoting possible
cardioprotective properties. PPV vaccine recipients had the least
likelihood of developing heart failure with an ROR of 0.1 (0.08-0.13,
P\textless{}0.0001). Notably, the results of the influenza vaccine
conform with research studies showing decreased morbidity and mortality
among heart failure patients receiving the annual flu vaccine (12, 13).

\textbf{Discussion}

The role of immune based process in heart failure development and
progression has shown considerable attention lately. In this paper, we
analyzed VAERS database to identify the role of vaccines in heart
failure. Our results showed that COVID-19 vaccines were associated the
most with heart failure (acute or chronic) with ROR of 21, followed by
smallpox vaccine (ROR 7.2). Vaccines for Influenza, zoster, hepatitis,
and PPV were associated with reduced incidence of heart failure.

The relationship between infection and heart failure is not very well
characterized. While a direct cause of infection in heart failure
pathogenesis is ill defined, infection is known to precipitates
decompensation and mortality in heart failure patients(14). COVID-19
infection has been implicated in heart failure occurrence. For example,
in Wahun, China, heart failure was among the most common outcomes after
COVID-19 infection(15). Possible mechanisms have been postulated such as
infiltration of inflammatory cells, release of cytokines and endothelial
injury(16). Influenza infection is associated with enhanced mortality
and morbidity in hospitalized heart failure patients(17). Other types of
infections are much less studied in the context of heart failure.

Most of the existing vaccine literature focused on the impact of
influenza vaccination on cardiovascular health. For instance, influenza
vaccination has been shown to be associated with reduced all-cause
mortality and from acute myocardial infarction and stroke in
hypertension patients(18). Additionally, the same research group and
others elegantly showed that annual influenza vaccination was associated
with significant decrease of death among heart failure patients(12, 13).
Influenza vaccines reduced death and hospitalization from stroke, acute
coronary disease and heart failure and in patients with acute coronary
disease(19). Despite the protective effect of influenza vaccines in
heart failure, much less is known about the effect of other vaccines on
heart failure. Our data corroborated with the current literature by
showing significant reduction of heart failure exacerbation or incidence
in patients who received influenza vaccines compared to other vaccine.
Surprisingly, our results showed a significant increase of heart failure
incidence or exacerbation in patients who received COVID-19 or smallpox
vaccines. While an explanation for this association is not clear,
COVID-19 and smallpox vaccines have been shown to increase the risk of
myopericarditis, coronary artery disease and arrhythmia (20-23) which
may potentially contribute to heart failure development and progression.

While this study showed a novel association between vaccines and heart
failure, further studies are warranted to delineate the molecular
mechanisms underlying this association. Additionally, using passive
surveillance systems such as VAERS suffer from important limitations
including reporting bias and inaccuracy of adverse events reports. Due
to the publicity of COVID-19 vaccination adverse events, it is possible
that many complications have been reported more frequently. It is also
important to mention that studies based on VAERS generally conclude
association, however, do not prove causality. Due to these limitations,
our results should be interpreted with caution until clinical trials
have been conducted.

In conclusion, our results here showed that vaccines against Influenza,
zoster, hepatitis, and PPV are associated with reduced heart failure
incidence and exacerbation. However, heart failure is associated with
COVID-19 and smallpox vaccines. This study serves as a good start to
investigate further the association between vaccines and heart failure
in longitudinal studies.

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\textbf{Acknowledgment}

None.

\textbf{Funding:}

The authors declare that this work was not supported by any funds or
grants.

\textbf{Competing Interests}

The authors have no relevant financial or non-financial interests to
disclose.

\textbf{Author Contributions}

All the authors contributed to the study design, writing and analysis.
Data collection and analysis {[}Zaki Al-Yafeai David Aziz, and Akhilesh
Babbili{]}, design {[} Zaki Al-Yafeai, David Aziz, Mohamed Ghoweba{]}.
The first draft was written by {[}Zaki Al-Yafeai, David Aziz, Mohamed
Ghoweba{]} with edits and revision from all the authors. All authors
read and approved the manuscript.

\textbf{Data Availability}

The datasets from the current study are available from the corresponding
author upon request.

\textbf{Hosted file}

\verb`Data.pptx`  available at \url{https://authorea.com/users/472173/articles/566164-vaccines-and-heart-failure-analysis-of-vaccine-adverse-events-reporting-system-between-1990-2021}

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