Journal of

Cardiovascular
Development and Disease

Systematic Review
Blood Pressure Increase following COVID-19 Vaccination:
A Systematic Overview and Meta-Analysis
Fabio Angeli 1,2, * , Gianpaolo Reboldi 3 , Monica Trapasso 4 , Gabriella Santilli 3 , Martina Zappa 1
and Paolo Verdecchia 5

1 Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; [email protected]
2 Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri IRCCS,
21049 Tradate, Italy
3 Department of Medicine, and Centro di Ricerca Clinica e Traslazionale (CERICLET), University of Perugia,
06100 Perugia, Italy; [email protected] (G.R.); [email protected] (G.S.)
4 Dipartimento di Igiene e Prevenzione Sanitaria, PSAL, Sede Territoriale di Varese, ATS Insubria,
21100 Varese, Italy; [email protected]
5 Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia,
06100 Perugia, Italy; [email protected]
* Correspondence: [email protected]

Abstract: Coronavirus disease 2019 (COVID-19) vaccines proved a strong clinical efficacy against
symptomatic or moderate/severe COVID-19 and are considered the most promising approach for
curbing the pandemic. However, some questions regarding the safety of COVID-19 vaccines have
been recently raised. Among adverse events to vaccines and despite a lack of signal during phase III
clinical trials, an increase in blood pressure (BP) after COVID-19 vaccination has been reported as a
potential adverse reaction. We systematically analyze this topic and undertook a meta-analysis of
available data to estimate the proportion of patients with abnormal BP or raise in BP after vaccination.
Six studies entered the final analysis. Overall, studies accrued 357,387 subjects with 13,444 events
Citation: Angeli, F.; Reboldi, G.; of abnormal or increased BP. After exclusion of outlier studies, the pooled estimated proportion of
Trapasso, M.; Santilli, G.; Zappa, M.; abnormal/increased BP after vaccination was 3.20% (95% CI: 1.62–6.21). Proportions of cases of stage
Verdecchia, P. Blood Pressure III hypertension or hypertensive urgencies and emergencies was 0.6% (95% CI: 0.1% to 5.1%). In
Increase following COVID-19 conclusion, abnormal BP is not rare after COVID-19 vaccination, but the basic mechanisms of this
Vaccination: A Systematic Overview phenomenon are still unclear and require further research.
and Meta-Analysis. J. Cardiovasc. Dev.
Dis. 2022, 9, 150. https://doi.org/
Keywords: COVID-19; vaccine; blood pressure; hypertension; adverse drug reaction; BNT162b2;
10.3390/jcdd9050150
mRNA-1273; Ad26.COV2.S; CVnCoV; ChAdOx1nCoV-19; NVX-CoV2373; Gam-COVID-Vac
Academic Editor: Jörg Männer

Received: 30 March 2022

Accepted: 7 May 2022
1. Introduction
Published: 9 May 2022
Different therapeutic strategies are under scrutiny to block the transition from infection
Publisher’s Note: MDPI stays neutral
to severe forms of coronavirus disease 2019 (COVID-19) [1,2]. They include prevention of
with regard to jurisdictional claims in
the viral RNA synthesis and replication, blockade of SARS-CoV-2 from binding to human
published maps and institutional affil-
cell receptors, the restoration of the host’s innate immunity, and the modulation of the
iations.
host’s specific receptors or enzymes [1–6].
However, vaccines to prevent SARS-CoV-2 infection are considered the most promising
approach, offering the opportunity to come out of the current phase of the pandemic [2,7].
Copyright: © 2022 by the authors.
COVID-19 vaccines have been developed using different advanced technologies
Licensee MDPI, Basel, Switzerland. and several platforms [7–9], including live attenuated vaccines, inactivated vaccines, re-
This article is an open access article combinant protein vaccines, vector vaccines (replication-incompetent vector vaccines,
distributed under the terms and replication-competent vector vaccines, and inactivated virus vector vaccines), DNA vac-
conditions of the Creative Commons cines, and RNA vaccines (Table 1). By 18 March 2022 a total of 10,925,055,390 vaccine
Attribution (CC BY) license (https:// doses have been administered globally (5,007,662,851 persons vaccinated with at least one
creativecommons.org/licenses/by/ dose, and 4,446,884,806 persons fully vaccinated; (https://covid19.who.int/ accessed on
4.0/). 18 March 2022).

J. Cardiovasc. Dev. Dis. 2022, 9, 150. https://doi.org/10.3390/jcdd9050150 https://www.mdpi.com/journal/jcdd

J. Cardiovasc. Dev. Dis. 2022, 9, 150 2 of 9

Table 1. Main features of COVID-19 vaccines.

Vaccine Developer Platform Doses

BNT162b2 * Pfizer/BioNTech mRNA 2
mRNA-1273 * Moderna mRNA 2
Ad26.COV2.S * Janssen/Johnson & Johnson DNA Adenovirus vector 1
CVnCoV CureVAC mRNA 2
ChAdOx1nCoV-19 * AstraZeneca/University of Oxford/Serum Institute of India DNA Adenovirus vector 2
NVX-CoV2373 * Novavax Recombinant protein 2
Gam-COVID-Vac (Sputnik V) Gamaleya Institute DNA Adenovirus vectors 2
* vaccines authorized for use in the European Union (https://www.ema.europa.eu/en/human-regulatory/
overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/covid-19-vaccines accessed
on 18 March 2022).

Despite the clinical efficacy against symptomatic or moderate/severe COVID-19

ranged from 67% to 95% in several clinical trial [10–15], some questions regarding the
safety of COVID-19 vaccines have been recently raised and mainly based on reports of
thromboembolic events [16–22]. An extremely carefully monitoring of safety issues showed
other rare adverse events occurring after COVID-19 vaccination, including anaphylaxis, my-
ocarditis/pericarditis, and Guillain-Barré Syndrome (https://www.cdc.gov/coronavirus/
2019-ncov/vaccines/safety/adverse-events.html accessed on 18 March 2022) [2].
Just recently and despite a lack of signal during the main phase III clinical trials, an
increase in blood pressure (BP) after COVID-19 vaccination has been reported [2,23–25].
The main aim of this review was to systematically analyze data on this topic, offering
an overview of the clinical implications and potential mechanisms of this phenomenon.
Specifically, we undertook a meta-analysis of available data to estimate the proportion of
patients with abnormal or raised BP after vaccination.

2. Materials and Methods

2.1. Study Selection and Outcome Measures
We addressed analyses and clinical studies (both retrospective and prospective) meet-
ing all the following inclusion criteria: (a) data on incidence of abnormal or increased BP
regardless of the specific vaccination strategy; (b) publication in a peer-reviewed journal
before 28 February 2022; (c) no age or language restriction, in order to avoid discriminating
papers not written in English (“tower of Babel bias”) [26].

2.2. Data Sources and Searches

Candidate studies were searched through MEDLINE, Scopus, Web of Science, and
CINHAL, using research Methodology Filters [27]. The following research terms were
used: “SARS-CoV-2”, “COVID-19”, “2019-ncov”, “coronavirus”, “blood pressure”, “hyper-
tension”, and “adverse events”. We made a further screening of review articles, published
proceedings of conferences, and regulatory agencies files [28] in order to identify other
relevant studies.

2.3. Data Synthesis

Table 2 shows the clinical studies identified on the basis of the above criteria. Overall,
studies accrued 357,387 subjects. Figure 1 shows the flow diagram with the criteria used
for selection of studies. We used the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) statement (Table S1) [29]. Data were independently extracted by
two authors (FA and PV). Disagreements were discussed in conference.
J. Cardiovasc. Dev. Dis. 2022, 9, 150
J. Cardiovasc. Dev. Dis. 2022, 9, x FOR PEER REVIEW 4 of 10
3 of 9

Search for potentially relevant studies

Identification
Records screened from:

PubMed SCOPUS WOS CINHAL

N=489 N=326 N=235 N=70

N=1120

Records exploring adverse events (including raise in BP)

and duplicates removed
N=9

Excluded (N=3) for:

• Number of patients with raise in BP not fully
Screening

reported (N=2)
• Case series (N=1)

Relavant records
N=6
Eligibility and inclusion

Studies addressing hypertension as adverse drug reaction:

Surveys (N=2)

Analyses of pharmacovigilance databases (N=3)

Clinical Study (N=1)

Figure 1.
Figure 1. Criteria
Criteria used
usedfor
forselection
selectionofofstudies.
studies.

We excluded
Three reviewerstwoindependently
studies because of lackthe
assessed of data onbias
risk of the ofprecise number
each of of adverse
the included studies
drugdiscussed
and reactions their
(ADRs) or a clear definition
assessments to achieveofconsensus.
raise in BPThe
[37,39]. Among
included the remaining
studies were scored
seven
for studies,
quality we removed
using one study reporting
the Newcastle-Ottawa scale.a case
The series of vaccinated
scale items patients (Figure of
assess appropriateness
1) [24]. Thus, six studies entered the final analysis (Table 2) [25,35,36,38,40,41].
research design, recruitment strategy, response rate, representativeness of sample, Of these,
objec-
two were cross-sectional surveys [25,40], three analyzed data from pharmacovigilance
tivity/reliability of outcome determination, power calculation, and appropriate statistical da-
tabases [36,38,41],
analyses and one
[30,31]. Score evaluated BP
disagreements afterresolved
were 15 min from vaccination
by consensus andamong
a finala agreed-upon
cohort of
patients and healthcare workers [35].
rating was assigned to each study (Table S2) [30,31].
Table
2.4. 2. Main
Data features of studies included in the analysis.
Analysis
Cohort
Proportions were calculated by dividing the number of patientsSevere
with Increase
the specific
Study Source Year Vaccine Outcome
(N)
endpoint by the total number of patients for each study. We used a generalized in BP * (N) linear
mixed model (GLMM)—i.e., a random intercept Definition
logistic regressionNmodel—for the meta-
Bouhanick Pharmacovigilance analysis of proportions BNT162b2, ChAdOx1nCoV-19,
[32]. We also tested forAbnormal
the presence of statistical outliers using
91,761 2021 BP 1776 -
et al. [36] database Ad26.COV2.S
the method described by Harrer et al. [33]. Studies are defined as outliers when their 95%
Persistent BP ≥
Bouhanick Patients and confidence interval lies outside the 95% confidence interval of the pooled effect.
21,909 2022 BNT162b2 140/90 (15 min after 5197 709
et al. [35] healthcare workers The null hypothesis of homogeneity across individual studies was tested by using the
vaccination)
Kaur et al. Pharmacovigilance Q test. Pooled estimates were assessed
BNT162b2, for heterogeneity by using the I2 statistic [34].
ChAdOx1nCoV-19,
30,523 2021
Analyses were performed Abnormal
using R version 4.1.3 BP
(R Foundation 283 36 Comput-
for Statistical
[38] database mRNA-1273
Lehmann et Pharmacovigilance ing, Vienna, Austria)BNT162b2,
and Stata,ChAdOx1nCoV-19,
version 16 (StataCorp LP, College Station, TX, USA).
212,053 2021 Abnormal BP 6130 551
al. [41] database Ad26.COV2.S, mRNA-1273
Tran et al. Cross-sectional online3. Results Self reported
1028 2021 ChAdOx1nCoV-19 52 -
[40] survey hypertension
Literature search initially yielded 1120 reports. After removal of duplicates and
Angeli et al. Cross-sectional online
studies113not focused Raise inwe
home BP >
2021 on safetyBNT162b2
of COVID-19 vaccines, reviewed nine
6 clinical
2 studies in
[25] survey full text [24,25,35–41]. 10 mmHg
J. Cardiovasc. Dev. Dis. 2022, 9, 150 4 of 9

Table 2. Main features of studies included in the analysis.

Severe
Cohort
Study Source Year Vaccine Outcome Increase in
(N)
BP * (N)
Definition N
BNT162b2,
Bouhanick Pharmacovigilance
91,761 2021 ChAdOx1nCoV-19, Abnormal BP 1776 -
et al. [36] database
Ad26.COV2.S
Patients and Persistent BP
Bouhanick
healthcare 21,909 2022 BNT162b2 ≥ 140/90 (15 min 5197 709
et al. [35]
workers after vaccination)
BNT162b2,
Pharmacovigilance
Kaur et al. [38] 30,523 2021 ChAdOx1nCoV-19, Abnormal BP 283 36
database
mRNA-1273
BNT162b2,
Lehmann Pharmacovigilance ChAdOx1nCoV-19,
212,053 2021 Abnormal BP 6130 551
et al. [41] database Ad26.COV2.S,
mRNA-1273
Cross-sectional Self reported
Tran et al. [40] 1028 2021 ChAdOx1nCoV-19 52 -
online survey hypertension
Cross-sectional Raise in home
Angeli et al. [25] 113 2021 BNT162b2 6 2
online survey BP > 10 mmHg
* severe increase in BP included stage III hypertension, hypertensive urgencies, and hypertensive emergencies.

We excluded two studies because of lack of data on the precise number of adverse
drug reactions (ADRs) or a clear definition of raise in BP [37,39]. Among the remain-
ing seven studies, we removed one study reporting a case series of vaccinated patients
(Figure 1) [24]. Thus, six studies entered the final analysis (Table 2) [25,35,36,38,40,41]. Of
these, two were cross-sectional surveys [25,40], three analyzed data from pharmacovigi-
lance databases [36,38,41], and one evaluated BP after 15 min from vaccination among a
cohort of patients and healthcare workers [35].

3.1. Excluded Studies

Meylan and co-workers reported a case series of nine patients with stage III hyper-
tension documented within minutes of vaccination, of which eight were symptomatic [24]
(Table S3). BP was measured with an oscillometric validated manometer with at least
three sets of separate values at 5-min intervals [24]. Median age was 73 years, and eight of
nine patients had a history of arterial hypertension with most patients on antihypertensive
therapy [24]. All but one patient received the BNT162b2 vaccine. Of note, patients had a
previous well controlled hypertension. All patients recovered but required at most several
hours of monitoring at tertiary center’s emergency department [24].
Sanidas and co-workers [37,39] (Table S3) investigated the effects of vaccination on
BP in patients with known hypertension and healthy controls. A total of 100 patients
between the age of 50 to 70 years old were included [37,39]. They were randomly assigned
to one of the approved and available vaccines (BNT162b2, mRNA-1273, Ad26.COV2.S, and
ChAdOx1nCoV-19) [37,39]. All participants had systolic BP < 140 mmHg and diastolic
BP < 90 mmHg before vaccination and volunteered for home BP measurements and ambu-
latory BP measurements between the 5th and the 20th day after fully COVID-19 vaccina-
tion [37,39]. Patients with known history of hypertension showed a mean home BP equal to
175/97 mmHg. Similar results were also recorded for 24-h mean BP (177/98 mmHg) [37,39].
Healthy controls showed a BP of 158/96 mmHg and 157/95 mmHg during home and
ambulatory monitoring, respectively [37,39]. Five of 50 hypertensive patients received addi-
tional medication whereas some of the non-hypertensive patients started life modification
changes and systematic BP measurements for a possible diagnosis of hypertension [37,39].
Finally, a recent analysis by Ch’ng and coworkers [37,39] (Table S3) collected data from
4906 healthcare workers. BP was measured three times for each staff member using an
automated BP monitor. Pre-vaccination BP was recorded when the staff members arrived
J. Cardiovasc. Dev. Dis. 2022, 9, 150 5 of 9

at the vaccination site; post-vaccination BP was measured immediately after vaccination

and 15–30 min later in a waiting room [37,39]. Mean pre-vaccination systolic and diastolic
BP were 130.1 mmHg and 80.2 mmHg, respectively. When compared with baseline, BP was
increased in more than half of the subjects immediately and 30 min post vaccination. The
mean changes immediately after vaccination were +2.3/2.4 mmHg for systolic/diastolic
BP [37,39].

3.2. Included Studies

The retrospective analysis by Bouhanick and co-workers, describing the prevalence of
high BP after vaccination, exhibited the largest proportion of this phenomenon [35]. They
retrospectively investigated BP profile of vaccinated patients and healthcare workers to de-
scribe the course of BP values after the first and the second injection of vaccine and to assess
the prevalence of high BP values in this population. Notably, BP was measured 15 min after
vaccine injection and measurements were performed with a validated automatic electronic
device [35]. A total of 21,909 subjects had complete data on BP (61.7% were women, mean
age was 59 years). Among these subjects, 8121 people (37.1%) exhibited systolic and/or
diastolic BP above 140 and/or 90 mmHg after the first injection. Among the subjects with
high BP after the first injection, 64% were still hypertensive after the second one [35].
Interrogations of pharmacovigilance databases [36,38,41] showed proportions of ab-
normal or increased BP after vaccination ranging from 0.93% to 2.89%.
Proportions from surveys, specifically designed to evaluate BP changes after vacci-
nation, was about 5% (5.06% in the analysis by Tran and co-workers [40] and 5.31% in the
sample from Angeli and co-workers [25]).
More specifically, the Italian prospective survey [25] showed that among 113 health
care workers who received the Pfizer vaccine, 6 subjects (5.3%) showed a rise in systolic or
diastolic BP at home ≥ 10 mmHg during the first five days after the first dose of the vaccine
when compared with the five days before the vaccine (the BP rise required an intensification
of BP-lowering treatment in 4 subjects) [25]. Interestingly, the subjects with documented
infection by SARS-COV-2 over the previous year showed a higher frequency of systemic
reactions to vaccine when compared with those without history of documented infection
(38% vs. 10%, p = 0.004). History of COVID-19 was associated with a higher incidence of
rise in BP when compared with subjects without previous exposure to SARS-CoV-2 (23%
vs. 3%, p = 0.002). Symptomatic tachycardia was noted in 7 and 3 respondents after the
first and second dose of vaccine, respectively, and there were no cardiovascular events or
severe or immediate allergic reactions during a follow-up of 103 days [25].
Similarly, Tran and co-workers performed a cross-sectional survey including 1028 sub-
jects (899 had one ChAdOx1nCoV-19 dose and the rest received 2 doses) [40]. Abnormal
BP after vaccination was recorded in 52 subjects.
Quality assessment of the included studies is reported in Table S2.

3.3. Pooled Analyzses

Overall, the pooled estimated proportion of abnormal or increased BP after vaccination
was 3.91% (95% confidence interval [CI]: 1.25–11.56, p < 0.01; Figure 2). Nonetheless, two
studies were identified as statistical outliers [35,38]. As depicted in Figure 3, after the
exclusion of these 2 studies [35,38], the pooled proportion of abnormal or increased BP
after vaccination was 3.20% (95% CI: 1.62–6.21, p < 0.01).
We also evaluated the proportion of cases of stage III hypertension or hypertensive
urgencies and emergencies. Four studies reported the proportion of patients who developed
these outcomes after COVID-19 vaccination (range: 0.1% to 3.2%). The pooled proportion
of these events was 0.6% (95% CI: 0.1–5.1%).
 two studies were identified as statistical outliers [35,38]. As depicted in Figure 3, after the
exclusion of these 2 studies [35,38], the pooled proportion of abnormal or increased BP
after vaccination was 3.20% (95% CI: 1.62–6.21, p < 0.01).
We also evaluated the proportion of cases of stage III hypertension or hypertensive
urgencies and emergencies. Four studies reported the proportion of patients who devel-
J. Cardiovasc. Dev. Dis. 2022, 9, 150 6 of 9
oped these outcomes after COVID-19 vaccination (range: 0.1% to 3.2%). The pooled pro-
portion of these events was 0.6% (95% CI: 0.1–5.1%).

J. Cardiovasc. Dev. Dis. 2022, 9, x FOR PEER REVIEW 7 of 10

Figure 2. Proportions of increased BP after vaccination.
Figure 2. Proportions of increased BP after vaccination [25,35,36,38,40,41].

Figure 3. Proportions of increased BP after vaccination, after the exclusion of outlier studies.
Figure 3. Proportions of increased BP after vaccination, after the exclusion of outlier studies [25,35,36,38,40,41].

4.4. Discussion
Discussion
Tothe
To thebest
bestofofour
ourknowledge,
knowledge,this thisisisthe
thefirst
firstsystematic
systematic review
review designed
designed to to investi-
investigate
gate the occurrence of abnormal or increased BP after COVID-19
the occurrence of abnormal or increased BP after COVID-19 vaccination. The main novelty vaccination. The main
novelty of our study is the evidence that a raise in BP after COVID-19
of our study is the evidence that a raise in BP after COVID-19 vaccination is not unusual. vaccination is not
unusual.
The The proportions
proportions of patientsofwith patients with abnormal
abnormal BP or withBP or with a significant
a significant increase inincrease
BP ranged in
BP ranged
from 0.93%from 0.93% with
to 23.72%, to 23.72%, withpoint
a pooled a pooled pointofestimate
estimate of 3.91%
3.91% (3.20% (3.20% excluding
excluding statistical
statisticalMoreover,
outliers). outliers). Moreover,
the estimate theofestimate
stage IIIofhypertension
stage III hypertension
or hypertensiveor hypertensive
urgencies ur- and
gencies and emergencies
emergencies following COVID-19followingvaccination
COVID-19 was vaccination
0.6% (95% wasCI: 0.6% (95% CI: 0.1–5.1%).
0.1–5.1%).
As aforementioned,
As aforementioned, the design design of of the
the study
study largely
largely affected
affectedsuch suchproportions,
proportions,with with
the highest
the highest valuevalue recorded in a retrospective study carried out in healthcare
study carried out in healthcare workers whoworkers who
received the
received the BNT162b2
BNT162b2 vaccine in a University University Hospital
Hospital in in Toulouse
Toulouse [35].[35]. Specifically,
Specifically,
Bouhanickand
Bouhanick and co-workers
co-workers [35] reported the course of of BP
BPafter
afterthetheinjection
injectionofofvaccine
vaccineand and
assessed the
assessed the incidence
incidence of high BP values in this this population
population [35]. [35].BP BPwas
wasmeasured
measured15 15min
min
aftervaccination
after vaccinationininallall patients
patients whowho received
received a first
a first or a or a second
second injection.
injection. Subjects
Subjects remainedre-
mained
seated seated
for 15 minforafter
15 min after injection,
injection, and hypertension
and hypertension was definedwas defined as BP than
as BP greater greateror than
equal
or140/90
to equal tommHg140/90 (grade
mmHgIII (grade III hypertension
hypertension was declared
was declared if BP was if BPgreater
was greater
than orthan or
equal
equal to 180/111 mmHg) [35]. As remarked by the authors,
to 180/111 mmHg) [35]. As remarked by the authors, the main limitation of this study the main limitation of this
study
was thewaslackthe
oflack of pre-vaccination
pre-vaccination control control
of BP of BP thus,
and, and, thus, the proportion
the proportion of subjects
of subjects with
with BP
high high BP observed
observed after
after the the injection
injection may reflect
may reflect an unknown
an unknown or insufficiently
or insufficiently con-
controlled
trolled hypertension
hypertension [35]. [35].
Conversely, analyses
Conversely, analyses of of pharmacovigilance
pharmacovigilance databases databasesand andclinical
clinicalsurveys,
surveys,showed
showed
ratesof
rates ofabnormal
abnormalBP BPor orsignificantly
significantlyincreased
increasedBP BPafter
aftervaccination
vaccinationranging rangingfrom
from0.93%
0.93%to
to 2.89%
2.89% (Figure
(Figure 2). 2).
The precise
The precise basic
basic mechanism of this phenomenon phenomenon is is still
stillunclear
unclearand andfurther
furtherstudies
studies
are required to investigate
are required to investigate the association
association between COVID-19 vaccination andhyperten-
between COVID-19 vaccination and hyperten-
sion [2,23,42]. Stress response, white-coat effect, and the possible role of excipients [24]
might contribute to explain the high prevalence of abnormal BP values recorded immedi-
ately after vaccination. Nonetheless, the resulting features of COVID-19 vaccination re-
semble those of active COVID-19 disease [2,23,43,44]. It is well known that the entry of
J. Cardiovasc. Dev. Dis. 2022, 9, 150 7 of 9

sion [2,23,42]. Stress response, white-coat effect, and the possible role of excipients [24]
might contribute to explain the high prevalence of abnormal BP values recorded imme-
diately after vaccination. Nonetheless, the resulting features of COVID-19 vaccination
resemble those of active COVID-19 disease [2,23,43,44]. It is well known that the entry
of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs through the
angiotensin-converting enzyme 2 (ACE2) receptors of the host cells [1,3,6,45–48]. Recent
observations support the notion that when a vaccinated cell dies or are destroyed by the
immune system, the debris may release a large amount of Spike proteins and protein
fragments (free-floating Spike proteins) [2,23]. Spike proteins produced upon vaccination
have the native-like mimicry of SARS-CoV-2 Spike protein’s receptor binding functionality
and prefusion structure [49]. The native-like conformation of the Spike protein produced
by vaccines has the potential to interact with ACE2, leading to its internalization and degra-
dation [50]. The loss of ACE2 receptor activity from the outer layer of the cell membrane,
as mediated by the interaction between ACE2 and SARS-CoV-2 Spike proteins, leads to
less angiotensin II inactivation resulting from a reduced generation of antiotensin1–7 . It
is well known that angiotensin1–7 binds to the Mas receptor and reduces several effects
of angiotensin 2 including inflammation, reabsorption of renal sodium, release of vaso-
pressin and aldosterone, and fibrosis [46,47,51]. Thus, the imbalance between angiotensin
II overactivity and of antiotensin1–7 deficiency after vaccination may trigger a raise in
BP [45–47].
Our systematic review and meta-analysis has several limitations. First, studies in-
cluded in our analysis did not use a control group to unmask the real effect of COVID-19
vaccination on BP and showed a low accounting comparability (Table S2). Second, and as
aforementioned, time of BP recording (from 15 min to several days after vaccination) clearly
affects the rates of BP increase after vaccination. Finally, pharmacovigilance databases pro-
vided the largest cohorts of subjects exploring this phenomenon. However, they analyzed
the rates of BP increase as a self-reported phenomenon.

5. Conclusions
Vaccines to prevent SARS-CoV-2 infection elicit an immune neutralizing response, and
they are the most promising approach for curbing the pandemic.
However, some concerns regarding the safety of COVID-19 vaccines have been re-
cently raised, including an increase in BP. Our systematic review and meta-analysis of
observational studies specifically investigated this phenomenon.
Overall, included studies accrued 357,387 subjects with 13,444 events of abnormal or
increased BP. The pooled proportions of abnormal/increased BP or stage III hypertension
recorded following vaccination (3.20% and 0.6%, respectively) showed that this event
should not be considered sporadic. However, in view of the small number of included
studies and their inherent quality limitations (different times of observation, definition
of BP increase, and a lack of a control group), the observed phenomenon requires further
investigation in controlled settings.

Supplementary Materials: The following supporting information can be downloaded at: https://
www.mdpi.com/article/10.3390/jcdd9050150/s1, Table S1: PRISMA checklist; Table S2: Assessment
of the quality of included studies using the Newcastle-Ottawa Scale; Table S3: Main characteristics of
excluded studies.
Author Contributions: Conceptualization, F.A., G.R., M.T. and P.V.; methodology, F.A, G.R. and P.V.;
formal analysis, investigation, and data curation, F.A., P.V., G.R., G.S. and M.Z.; writing—original draft
preparation, F.A., G.R., M.T. and P.V.; writing—review and editing, F.A., G.R., M.T., G.S., M.Z. and P.V.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Data Availability Statement: The data underlying this article is fully reported in tables and figures.
Conflicts of Interest: The authors declare no conflict of interest.
J. Cardiovasc. Dev. Dis. 2022, 9, 150 8 of 9

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