doi:10.1111/iej.

13364

REVIEW
Association between cardiovascular diseases and
apical periodontitis: an umbrella review

A. Jakovljevic1 , H. F. Duncan2 , V. Nagendrababu3 , J. Jacimovic4 , J. Milasin5

& P. M. H. Dummer6
1
Department of Pathophysiology, School of Dental Medicine, University of Belgrade, Belgrade, Serbia; 2Division of Restorative
Dentistry and Periodontology, Dublin Dental University Hospital, Trinity College Dublin, Dublin, Ireland; 3Division of Clinical
Dentistry, School of Dentistry, International Medical University, Kuala Lumpur, Malaysia; 4Central Library, School of Dental
Medicine; 5Department of Human Genetics, School of Dental Medicine, University of Belgrade, Belgrade, Serbia; and 6School of
Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK

Abstract search, data extraction and quality assessment of

Jakovljevic A, Duncan HF, Nagendrababu V,
Jacimovic J, Milasin J, Dummer PMH. Association
between cardiovascular diseases and apical periodontitis: an
umbrella review. International Endodontic Journal, 53, 1374–
1386, 2020.
Background The existence of an association
between cardiovascular diseases (CVDs) and apical
periodontitis (AP) remains unclear because results
obtained from previous clinical studies and reviews
are inconsistent or inconclusive.
Objective To conduct an umbrella review to deter-
mine whether there is an association between CVDs
and the prevalence of AP in adults.
Methods The protocol of the review was registered in
the PROSPERO database (CRD42020185753). The lit-
erature search was conducted using the following
electronic databases: Clarivate Analytics’ Web of
Science Scopus, PubMed and Cochrane Database of Sys-
tematic Reviews, from inception to May, 2020, with no
language restrictions. Systematic reviews with or with-
out meta-analysis that evaluated the association
between CVDs and AP were included. Other types of
studies, including narrative reviews, were excluded.
Two reviewers independently performed a literature
included studies. Any disagreements or doubts were
resolved by a third reviewer. The quality of the reviews
was assessed using the AMSTAR 2 tool (A measurement
tool to assess systematic reviews), with 16 items. A final
categorization of the systematic reviews classified each
as of ‘high’, ‘moderate’, ‘low’ or ‘critically low’ quality.
Results Four systematic reviews were included in
the current review. Three reviews were graded by
AMSTAR 2 as ‘moderate’ quality, whereas one review
was graded as ‘critically low’ quality.
Discussion Only one systematic review included a
meta-analysis. Substantial heterogeneity amongst the
primary studies included within each systematic
review was notable in preventing a pooled analysis.
Conclusions From the limited ‘moderate’ to ‘critically
low’ quality evidence available, the current umbrella
review concluded that a weak association exists between
CVDs and AP. In the future, well-designed, longitudinal
clinical studies with long-term follow-up are required.
Keywords: apical periodontitis, cardiovascular dis-
ease, meta-analysis, systematic review, umbrella
review.
Received 1 June 2020; accepted 6 July 2020

Correspondence: Aleksandar Jakovljevic, School of Dental Medicine, University of Belgrade, dr Subotica 8, 11 000 Belgrade,
Serbia (e-mail: dr.sasuli@hotmail.com).

1374 International Endodontic Journal, 53, 1374–1386, 2020 © 2020 International Endodontic Journal. Published by John Wiley & Sons Ltd

Introduction
Apical periodontitis (AP) is a persistent inflammatory
process within the periapical tissues of teeth with an
infected root canal system (Nair 2006). Untreated
pulpitis and the colonization of a range of microor-
ganisms within the root canal system leads to pulp
necrosis and the development of inflammatory disease
in the periapical region of the affected teeth (Nair
2006). Thus, AP is the consequence of a complex
interplay between microbes, their virulence factors
and the immune system of the host (M
arton & Kiss
2014). The local activation of the host’s innate and
adaptive immune system is characterized by the
recruitment of various cell types and cell-specific
mediators, which results in the destruction of tooth-
supporting tissues and the formation of periapical
lesions (i.e. granuloma, abscess and/or cyst; M
arton &
Kiss 2014).
Epidemiological data indicate a considerable global
burden of AP. Pak et al. (2012) systematically
reviewed 33 observational cross-sectional studies pub-
lished between 1987 and 2011, which demonstrated,
in a sample of over 300 000 teeth, a high prevalence
of AP (approximately 5% of all teeth, broadly equiva-
lent to one periapical lesion per patient) and conven-
tional root filled teeth (approximately 10% of all
teeth, broadly equivalent to two treatments per
patient) in the worldwide adult population. Neverthe-
less, the seriousness of the problem and the conse-
quences of ongoing chronic inflammation have not
been fully accepted and as a result, AP has not
attracted the attention required for such a common
disease.
Even though AP is generally considered as a local
pathological disorder, numerous studies have
attempted to evaluate whether it is associated with
the development of adverse systemic health condi-
tions, including cardiovascular diseases (CVDs; Berlin-
Broner et al. 2017, Jim
enez-S
anchez et al. 2020) and
diabetes (Nagendrababu et al. 2020, P
erez-Losada
et al. 2020). CVDs are a heterogenic group of disor-
ders that includes coronary heart disease, cerebrovas-
cular disease, peripheral arterial disease, rheumatic
heart disease, congenital heart disease and deep vein
thrombosis and pulmonary embolism (Mendis et al.
2011). They are the leading global cause of noncom-
municable disease deaths, costing an estimated 17.9
million lives annually (Mendis et al. 2011). Further-
more, it is forecast that the prevalence of CVDs will
increase by approximately 10% over the next
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Jakovljevic et al. Cardiovascular diseases and apical periodontitis
20 years, with associated direct healthcare costs
growing almost threefold (Vasan & Benjamin 2016).
Atherosclerosis is an inflammatory process, and an
underlying pathological mechanism of the most com-
mon CVDs, such as coronary heart disease and cere-
brovascular disease (Hansson et al. 2006). It is
characterized by the accumulation of inflammatory/
immune, endothelial and smooth muscle cells, con-
nective tissue elements, lipids and debris, which are
organized into atherosclerotic plaques in the inner-
most layer of the artery (Wolf & Ley 2019). Proin-
flammatory cytokines released by T helper-1 cells and
macrophages stimulate local inflammation and
growth of the plaque. In most cases, such increased
inflammatory activation leads to plaque rupture and
thrombus formation, which causes ischaemia and
infarction of affected tissues (Hansson et al. 2006,
Wolf & Ley 2019). Moreover, it is well known that a
variety of microorganisms may infect cells in the arte-
rial wall, stimulate local inflammation, activate adap-
tive immune responses and induce cellular alterations
which results in the development of atherosclerotic
plaques (Lawson 2016, Di Pietro et al. 2017). There-
fore, transient bacteraemia (Kazanci et al. 2005) and
consequent low-grade systemic inflammation (Geor-
giou et al. 2019) caused by persistent AP may be a
trigger for the development of CVDs.
Several systematic reviews and meta-analyses have
attempted to evaluate whether there is an association
between CVDs and the development and persistence
of AP (Khalighinejad et al. 2016, Berlin-Broner et al.
2017, Gonz
alez Navarro et al. 2017, Aminoshariae
et al. 2018). Each of these reviews assessed a range of
epidemiological studies, which compared the preva-
lence of periapical lesions in root filled and nonroot
filled teeth in cardiovascular and noncardiovascular
subjects. Khalighinejad et al. (2016) systematically
reviewed eight studies related to the association
between endodontic pathosis and CVDs. The authors
concluded that although a link between endodontic
pathosis and CVD was possible, further well-designed
longitudinal studies were needed to strengthen the
evidence to support a potential association. Similar
conclusions were made by Gonz
alez Navarro et al.
(2017), who reported the association between CVDs
and AP but also stressed the need for additional
prospective and interventional studies. Conversely,
Berlin-Broner et al. (2017) concluded that the quality
of the existing evidence related to the association
between CVDs and AP was moderately low and that
a causal relationship could not be established.
International Endodontic Journal, 53, 1374–1386, 2020 1375

Cardiovascular diseases and apical periodontitis Jakovljevic et al.
Furthermore, Aminoshariae et al. (2018), in system-
atic review and meta-analysis of four cohort studies
with a high risk of bias and inconsistency, concluded
that there was a very low certainty that AP influ-
enced the development of CVDs.
Notably, the existence of an association between
CVDs and AP remains unclear because the results
obtained from previous reviews are inconsistent or
inconclusive. Nevertheless, an overview compiling all
evidence from the existing systematic reviews on this
topic has not been performed to date. In 2014, a
methodology working group at the Joanna Briggs Insti-
tute developed the guidelines for a comprehensive over-
view of systematic reviews on a defined topic or
question (i.e. ‘umbrella’ review) in order to summarize
the evidence from multiple research syntheses. It is a
helpful approach in order to identify reliable or conflict-
ing findings when considering whether the independent
systematic reviews assessed the question and arrived at
consistent conclusions (Aromataris et al. 2015).
Thus, this umbrella review aimed to analyse the
available relevant systematic reviews in an attempt to
(i) determine whether there is an association between
CVDs and AP in the adult population and (ii) compre-
hensively evaluate and report deficiencies and gaps in
knowledge in this area.
Methods
The current umbrella review followed Preferred Report-
ing Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines (Moher et al. 2009). The protocol
of the current umbrella review was registered in the
PROSPERO database (CRD42020185753).
Review questions
Is there an association between cardiovascular dis-
eases (CVDs) and apical periodontitis (AP)?
Outcome measures
Prevalence of AP in human adults with or without
CVD when diagnosed using intra oral periapical radio-
graphs or panoramic radiographs or computerized
tomography.
Selection criteria
Systematic reviews with or without meta-analysis
that evaluated the relationship between CVDs and AP
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were included. Case reports, clinical studies, labora-
tory studies, animal studies and narrative reviews
were excluded.
Literature search
The literature search was conducted using the follow-
ing electronic databases: Clarivate Analytics’ Web of
Science (including Web of Science Core Collection –
WoS, Korean Journal Database – KJD, Russian
Science Citation Index – RSCI, SciELO Citation Index
– SCIELO), Scopus, PubMed and Cochrane Database
of Systematic Reviews (CDSR), from inception to May,
2020. No language restrictions were applied during
the literature search. Preliminary searches were per-
formed in databases to identify relevant articles, index
or free terms, and synonyms related to the key con-
cepts of interest (AP and CVDs). In the current
review, an iterative trial-and-error approach was used
to develop and evaluate several information retrieval
strategies in order to achieve the optimum search
strategy. Key terms and syntax differ according to the
database being searched, using the combination of
the most common free keywords and relevant con-
trolled vocabulary (Medical Subject Headings – MeSH,
https://www.ncbi.nlm.nih.gov/mesh), Boolean opera-
tors, truncation and proximity operators. The search
strategies for all databases are provided in Table S1.
Unpublished manuscripts, conference papers and
other grey literature were searched in Google Scholar
(first 100 returns) and doctoral dissertations (e.g. Net-
worked Digital Library of Theses and Dissertations, Open
Access Theses and Dissertations, DART-Europe E-theses
Portal – DEEP, Opening access to UK theses – EThOS).
Additional searches were performed in reference lists of
the included reviews and relevant narrative reviews.
Two independent reviewers (A.J., J.J.) were involved
in screening titles and abstracts and then reading the
full text to identify relevant systematic reviews. Dis-
agreements between reviewers were resolved by the
help of the third reviewer (H.D.). Duplicates were
eliminated from the search results of the various data-
bases using EndNote Online (Clarivate Analytics
2020, https://www.myendnoteweb.com) reference
management software.
Data extraction
A data extraction form was created and customized
for the current review and included: name and coun-
try of the first author, year published, name of the
© 2020 International Endodontic Journal. Published by John Wiley & Sons Ltd

journal, number of databases used to search, number
of studies included, quality assessment tool used, out-
comes assessed, meta-analysis model, effect size (95%
confidence interval) and I2 statistic. Data extraction
was performed by two independent reviewers (V.N.,
A.J.) and disagreements were resolved by discussing
with a third reviewer (H.D.). Authors were contacted
to obtain missing information or to clarify informa-
tion that was unclear.
Quality assessment of included reviews using the
AMSTAR 2 tool
The quality of included systematic reviews was
appraised by using the AMSTAR 2 tool (Shea et al.
2017). Two independent reviewers (V.N., A.J.) provided
their decision of ‘yes’, ‘partial yes’ or ‘no’ using the 16
items of the AMSTAR 2 checklist. Disagreements were
resolved by a third reviewer (H.D.). The information
included in each review was collected based on what
the systematic reviews reported. The project leader (A.J)
completed the online AMSTAR 2 checklist available on
the AMSTAR website (https://amstar.ca/Amstar_Check
list.php) and a final categorization of each systematic
review was generated to classify them as of ‘high’,
‘moderate’, ‘low’ or ‘critically low’ quality.
Results
Literature search process
The PRISMA flow diagram (Fig. 1) sets out the entire
literature search process. The total number of articles
identified from the four electronic databases were 1080,
of these 165 were duplicates and removed. Title and
abstract screening identified 907 studies for exclusion
while eight studies were selected for full text retrieval.
Four studies were excluded after full text reading for the
following reasons: three were narrative reviews (Cotti &
Mercuro 2015, Segura-Egea et al. 2015, Cintra et al.
2018) and one did not address the aim of the present
umbrella review (Aminoshariae et al. 2017). Finally,
four systematic reviews were included in the current
umbrella review (Khalighinejad et al. 2016, Berlin-
Broner et al. 2017, Gonz
alez Navarro et al. 2017, Ami-
noshariae et al. 2018).
Characteristics of included reviews
Table 1 shows the characteristics of the included sys-
tematic reviews. The reviews were published between
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Jakovljevic et al. Cardiovascular diseases and apical periodontitis
2016 and 2018 in the Journal of Endodontics (n = 2),
International Endodontic Journal (n = 1) and Medicina
Clinica (n = 1). The individual reviews used MEDLINE,
Embase, Cochrane and PubMed databases to identify
relevant studies. The search period within the reviews
ranged from inception to 2018. The number of stud-
ies included in each systematic review ranged from 4
to 19. Two reviews (Berlin-Broner et al. 2017, Ami-
noshariae et al. 2018) used the Newcastle-Ottawa
Quality Assessment tool to assess the quality of the
studies that were included, one review (Khalighinejad
et al. 2016) used a specific quality assessment scale,
based on three domains (selection bias, detection bias
and reporting bias), while one review did not perform
a quality assessment (Gonz
alez Navarro et al. 2017).
Summary of meta-analysis
Among the four reviews, only one conducted a meta-
analysis (Aminoshariae et al. 2018). In the review
reported by Aminoshariae et al. (2018) the meta-
analysis was conducted using the Mantel-Haenszel,
random-effects model to estimate effect size such as
pooled risk ratio (RR) and 95% confidence intervals
(CI). The heterogeneity was assessed using I2 statis-
tics. The primary meta-analysis revealed a hetero-
geneity of 66.6%, whereas for subgroup analysis it
was 0%.
Methodological quality
The methodological quality of the systematic reviews
included in this umbrella review is shown in Fig. 2.
Among the four reviews, three (Khalighinejad et al.
2016, Berlin-Broner et al. 2017, Aminoshariae et al.
2018) were graded as ‘moderate’ quality, whereas
one review (Gonz
alez Navarro et al. 2017) was graded
as ‘critically low’ quality. None of the four reviews
addressed Item 3 (Did the review authors explain
their selection of the study designs for inclusion in
the review?) nor Item 10 (Did the review authors
report on the sources of funding for the studies
included in the review?).
Principal findings
Two (Khalighinejad et al. 2016, Gonz
alez Navarro
et al. 2017) out of four systematic reviews concluded
that the majority of primary studies they included
demonstrated an association between AP and CVDs.
However, Gonz
alez Navarro et al. (2017) did not
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Cardiovascular diseases and apical periodontitis Jakovljevic et al.

Figure 1 PRISMA flow diagram of the study search and identification. n – number of hits; WoS – Web of Science Core Collec-
tion; KJD – Korean Journal Database; RSCI – Russian Science Citation Index; SCIELO – SciELO Citation Index; Cochrane Data-
base of Systematic Reviews – CDSR; SR – Systematic review; MA – Meta-analysis.

perform a quality assessment of the individual studies
they included, while five out of the eight studies anal-
ysed by Khalighinejad et al. (2016) were categorized
as having a ‘moderate’ or ‘high’ risk of bias. Due to
the heterogeneity amongst the studies they included,
both reviews did not include a meta-analysis. Berlin-
Broner et al. (2017) examined 19 studies, namely 10
case–control, five cross-sectional and four longitudinal
cohort studies. The authors did not conduct a meta-
analysis due to the heterogeneity of these primary
studies in terms of their (i) study design, (ii) study
population, (iii) outcomes of interest and (iv) diagno-
sis of AP. Nevertheless, based on a quality assessment
and risk of bias analysis, the authors concluded that
the evidence for the association between AP and
CVDs was of ‘moderate-low’ quality. Furthermore,

1378 International Endodontic Journal, 53, 1374–1386, 2020 © 2020 International Endodontic Journal. Published by John Wiley & Sons Ltd
 Table 1 Main characteristics of the included systematic reviews

Country Number
Name of of the Meta- of
S the journal Database first Search analysis included Study design of Instrument of quality
No Author, year published searched author period Language performed studies included studies assessment

1 Khalighinejad Journal of MEDLINE, USA 1997 to English No 8 related Clinical trials, case- Specific quality assessment scale
et al. (2016) Endodontics Embase, 2016 only to control studies, cross- (based on three doains)
Cochrane CVD sectional studies, or
and PubMed cohort studies
2 Gonza
lez Medicina MEDLINE, Spain 1989 to No No 15 Clinical trials, case- NP
Navarro Clinica PubMed and 2016 restriction related control studies, cross-

© 2020 International Endodontic Journal. Published by John Wiley & Sons Ltd
et al. (2017) Scopus only to sectional studies, or
CVD cohort studies
3 Berlin-Broner International MEDLINE, Canada Inception English No 19 All types of studies that The Newcastle-Ottawa Quality
et al. (2017) Endodontic PubMed and – 2015 researched the Assessment for case–control, cross-
Journal Embase relationship between sectional and cohort studies and
AP and CVD GRADE system
4 Aminoshariae Journal of MEDLINE, USA 1997 to English Yes 4 Cohort studies The Newcastle-Ottawa Quality
et al. (2018) Endodontics Embase, 2018 Assessment for cohort studies, and
Cochrane GRADE system
and PubMed

AP, apical periodontitis; CVD, cardiovascular disease; GRADE, Grading of Recommendations Assessment, Development and Evaluation; NP, not performed; USA, United States of
America.

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Jakovljevic et al. Cardiovascular diseases and apical periodontitis

1379
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 13652591, 2020, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.13364 by Cochrane Saudi Arabia, Wiley Online Library on [27/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Cardiovascular diseases and apical periodontitis Jakovljevic et al.

Figure 2 Critical appraisal of the included systematic reviews. AMSTAR 2 – Assessing the Methodological Quality of System-
atic Reviews 2; PICO – Population, Intervention, Comparison, Outcome; * – AMSTAR 2 critical domain; 1. Did the research
questions and inclusion criteria for the review include the components of PICO?; 2. Did the report of the review contain an
explicit statement that the review methods were established prior to the conduct of the review and did the report justify any
significant deviations from the protocol?*; 3. Did the review authors explain their selection of the study designs for inclusion in
the review?; 4. Did the review authors use a comprehensive literature search strategy?*; 5. Did the review authors perform
study selection in duplicate?; 6. Did the review authors perform data extraction in duplicate?; 7. Did the review authors provide
a list of excluded studies and justify the exclusions?*; 8. Did the review authors describe the included studies in adequate
detail?; 9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were
included in the review?*; 10. Did the review authors report on the sources of funding for the studies included in the review?;
11. If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?*; 12.
If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results
of the meta-analysis or other evidence synthesis?; 13. Did the review authors account for RoB in individual studies when inter-
preting/discussing the results of the review?*; 14. Did the review authors provide a satisfactory explanation for, and discussion
of, any heterogeneity observed in the results of the review?; 15. If they performed quantitative synthesis did the review authors
carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the
review?*; 16. Did the review authors report any potential sources of conflict of interest, including any funding they received
for conducting the review?.

they used the Bradford Hill criteria of a causal rela-
tionship between an incidence and a possible conse-
quence (McMichael 2005) and concluded there was
no causal relationship between AP and CVDs based
on the evidence. Aminoshariae et al. (2018) evaluated
the relationship between AP and CVDs using data
derived only from longitudinal cohort studies, with
the result that the scores for quality of evidence they
reported were higher compared to the reviews that
included cross-sectional and/or case–control studies.
The authors performed a meta-analysis with pooled
data of four longitudinal cohort studies and revealed
no significant difference (P = 0.39) in the incidence of
CVDs between patients with and without AP. At the
same time, the authors reported a ‘high’ risk of bias,
inconsistency and very low certainty of evidence that
AP influenced the development of CVDs. Although
epidemiological evidence from primary studies appears
to suggest an association between AP and the devel-
opment of CVDs, the results of the meta-analysis,
quality/risk of bias assessment and evaluation of cau-
sal relationship criteria in two (Berlin-Broner et al.
2017, Aminoshariae et al. 2018) of the four system-
atic reviews do not support such an association. All

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systematic reviews included in this umbrella review
stressed the need for future high-quality longitudinal
studies to clarify this issue.
Discussion
Need for umbrella reviews
Epidemiological evidence from primary studies sug-
gests the presence of an association between AP and
the development of CVDs, however, the results
obtained from previous systematic reviews are incon-
sistent or inconclusive. An umbrella review evaluates
and integrates the results of multiple systematic
reviews in order to enhance comprehensibility, reduce
ambiguities, identify potential gaps in knowledge and
summarize with an overarching reference publication
the fundamental information on the topic of interest
(Silva et al. 2012, 2015). Therefore, an umbrella
review approach was used in an attempt to define
categorically whether evidence of an association
between CVDs and AP could be established from the
existing literature. Also, this review aimed to compre-
hensively evaluate and report deficiencies and gaps in
knowledge in this area and to identify methodological
limitations in previous clinical studies and systematic
reviews that may improve reporting in this area in
the future.
Presence of AP promotes the development of CVDs:
myth or reality?
For more than half a century, scientists have investi-
gated whether AP, as a localized oral infection, could
impair the systemic immune response and compro-
mise the general health of individuals. Untreated AP
leads to progressive periapical bone resorption and
can be accompanied by tooth mobility, combined with
periodontal disease, exhibit a persisting sinus tract
and lead to cyst formation. Numerous primary studies
have reported a potential association between sys-
temic diseases (e.g. CVDs, diabetes, chronic liver dis-
ease, blood disorders) and the pathogenesis of AP
(Cotti & Mercuro 2015, Segura-Egea et al. 2015, Kha-
lighinejad et al. 2016, Aminoshariae et al. 2017, Ber-
lin-Broner et al. 2017, Gonz
alez Navarro et al. 2017,
Cintra et al. 2018, Aminoshariae et al. 2018, Nagen-
drababu et al. 2020, Jim
enez-S
anchez et al. 2020,
P
erez-Losada et al. 2020). Previous systematic reviews
and meta-analyses have demonstrated that AP is
associated with elevated levels of systemic
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Jakovljevic et al. Cardiovascular diseases and apical periodontitis
inflammation in humans (i.e. increased immunoglob-
ulin [Ig] A, IgM, IgG, C-reactive protein (CRP), inter-
leukin (IL) 6, asymmetric dimethylarginine, C3 levels;
Gomes et al. 2013, Georgiou et al. 2019). The
increase of circulating inflammatory markers may be
the consequence of oral infection spreading through
the blood system and activation of the systemic
immune response, which could lead to the develop-
ment of generalized low-grade inflammation in the
human body. There is robust evidence that systemic
inflammation is associated with the development of
CVDs (Kaplan & Frishman 2001). The principal
underlying pathological mechanism in the pathogene-
sis of coronary heart disease and cerebrovascular dis-
ease is the presence of atherosclerosis (Hansson et al.
2006). It is a chronic inflammatory condition charac-
terized by the presence of atherosclerotic plaques in
the innermost layer of the artery, initiated and pro-
moted by a range of inflammatory cells and cell-speci-
fic mediators (Wolf & Ley 2019); this pathological
event may be induced by various microorganisms
(Lawson 2016, Di Pietro et al. 2017). Therefore, it
seems reasonable to assume that untreated AP could
have a proatherogenic effect with a potential impact
on a patient’s vascular risk. Zhang et al. (2016) con-
firmed on an experimental animal model, that AP
increased the levels of CRP, IL-2 and IL-6 in rat blood
serum, causing reversible changes in the aortic arch,
myocardium and spleen as well as irreversible
changes in the liver. The present results reinforce the
biological plausibility of an association between the
presence of AP and the development of CVDs. How-
ever, the quality of evidence that has been evaluated
in previous systematic reviews is ‘moderate-low’, and
the results of included primary studies are conflicting.
The current review demonstrated a weak associa-
tion between CVDs and AP. This finding does not
imply a cause-effect relationship and should be inter-
preted with caution. Critically, both conditions share
common confounding factors, such as smoking and
genetic predisposition. Recent systematic reviews
reported an association between smoking and the
development of CVDs and AP (Pan et al. 2019, Pinto
et al. 2020). Similarly, several other studies have
reported that genetic predisposition may also influ-
ence the development of CVDs (Bis et al. 2008, Bhatti
et al. 2018) and AP (Salles et al. 2018, Jakovljevic
et al. 2020) respectively. In this context, polymor-
phisms of gene encoding molecules implicated in the
immune response may increase the predisposition to
CVDs and at the same time, increase the susceptibility
International Endodontic Journal, 53, 1374–1386, 2020 1381

Cardiovascular diseases and apical periodontitis Jakovljevic et al.
of the affected individuals to AP or delay the repair of
periapical pathosis. The existence of the risk factors
(e.g. smoking and heredity), simultaneously in the
aetiology of CVDs and AP, could potentially explain
the association between both diseases observed in pri-
mary studies. However, it should be stressed that
within the limits of the available evidence the
observed association does not imply causation.
Quality of the individual systematic reviews
In the current umbrella review, methodological qual-
ity was assessed using the AMSTAR 2 tool developed
for the appraisal of systematic reviews including ran-
domized and nonrandomized studies of healthcare
interventions (Shea et al. 2017). AMSTAR 2 gives a
broad assessment of quality, including flaws that
might have occurred through poor conduct of the
review (Shea et al. 2017). This revised tool retains 10
of the original domains (AMSTAR) and has 16 items
in total. Unlike the original instrument, AMSTAR 2
identifies seven critical weaknesses/domains (‘protocol
registered before the commencement of the review,
adequacy of the literature search, justification for
excluding individual studies, risk of bias from individ-
ual studies being included in the review, appropriate-
ness of meta-analytical methods, consideration of the
risk of bias when interpreting the results of the
review, and assessment of the presence and likely
impact of publication bias’) that may reduce confi-
dence in the findings of a review (Shea et al. 2017).
Although AMSTAR 2 is not intended to generate an
overall score, it provides an overall rating (e.g. ‘high’,
‘moderate’, ‘low’ and ‘critically low’) based on weak-
nesses in key domains. Among the four included
reviews, three (Khalighinejad et al. 2016, Berlin-
Broner et al. 2017, Aminoshariae et al. 2018) were
graded as ‘moderate’ quality, whereas one (Gonz
alez
Navarro et al. 2017) was graded as ‘critically low’
quality review by AMSTAR 2. According to the rating
of overall confidence, reviews of ‘moderate’ quality
provide an accurate summary of the results of the
available studies that were included in the analysis.
On the other hand, ‘critically low’ quality suggests
that a review has more than one critical flaw and
should not be relied on to provide an accurate and
comprehensive summary of the available studies
(Shea et al. 2017). Therefore, any association between
CVDs and AP suggested in systematic review graded
as ‘critically low’ (Gonz
alez Navarro et al. 2017) must
be interpreted with extreme caution.
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All evaluated reviews did not address two areas: (i)
Item 3: Did the review authors explain their selection
of the study designs for inclusion in the review?
Authors must justify the inclusion of various study
designs (randomized controlled trials or nonrandom-
ized studies, or both) in their review; (ii) Item 10: Did
the review authors report on the sources of funding
for the studies included in the review? Authors must
discuss sources of funding in their review as studies
funded by industry are less likely to be published than
research that is independently funded (Shea et al.
2017). Moreover, in all reviews included in this
umbrella review, the literature search process was
conducted without including a grey literature search,
Item 4, which could potentially increase publication
bias and reduce the comprehensive nature of the
review (Paez 2017). Additionally, three out of four
reviews (Khalighinejad et al. 2016, Berlin-Broner
et al. 2017, Gonz
alez Navarro et al. 2017) did not
provide an explicit statement that the review methods
were established before conducting the review itself
(Item 2). Not having a protocol before starting a sys-
tematic review may lead to significant methodological
flaws, bias, risk of duplication and decreased trans-
parency and visibility to potential researchers (Straus
& Moher 2010, de Vries et al. 2015). Thus, protocol
development and registration are likely to benefit evi-
dence-based practice and eventually patient care.
Strengths of the review
The following facets can be considered as a strength:
(i) an a priori protocol was developed and registered
in the PROSPERO database, (ii) a comprehensive liter-
ature search with no language restriction was per-
formed in four electronic databases, including the
grey literature, in an attempt to avoid relevant
reviews being missed, (iii) the literature search and
data extraction process were conducted by two inde-
pendent reviewers, and disagreements were resolved
by a third experienced reviewer, and (iv) the process
followed standard recommendations to critically
appraise the quality of reviews using the AMSTAR 2
tool.
Limitations of the review
The current umbrella review has several limitations:
(i) among the included reviews, only one performed a
meta-analysis, (ii) the relatively small time interval
spanned by the included systematic reviews (2016–
© 2020 International Endodontic Journal. Published by John Wiley & Sons Ltd

2019) resulted in a small pool of the same original
studies being incorporated in more than one system-
atic review, (iii) the selected systematic reviews had
serious methodological inadequacies, and (iv) the sub-
stantial heterogeneity amongst the primary studies
included within each systematic review (e.g. study
design, study population, outcomes of interest and AP
evaluation).
Reporting deficiencies and gaps in knowledge/
methodology
During the process of reviewing primary clinical stud-
ies and systematic reviews on the topic of CVDs and
their association with AP, several inconsistencies in
methodology and reporting were identified. To
improve the quality of future clinical studies and sys-
tematic reviews, the following recommendations on
how to conduct and report them are proposed.
Future recommendation for clinical studies
1. Selection criteria: The criteria for the selection of
subjects (inclusion and exclusion criteria) must be
described clearly for all groups under investigation.
For example, from Alghofaily et al. (2018) ‘The
study included patients who received well-per-
formed initial nonsurgical root canal treatment or
retreatment (evaluated radiographically as dense,
obturated canals between 0.5 and 1.0 mm of the
radiographic apex, and all visible canals were trea-
ted with a coronal restoration that was clinically
and radiographically determined to have well-
sealed margins). All teeth had preoperative radio-
graphic evidence of a periapical lesion at least
3 mm in diameter. Patients were excluded if they
were taking any medications known to alter bone
metabolism such as hormone replacement therapy,
immunosuppressive drugs, corticosteroids, selective
serotonin reuptake inhibitors, tumour necrosis fac-
tor blockers, intravenous bisphosphonates, and/or
antiresorptive treatment or if they discontinued
their statin medications more than 1 year before
the follow-up examination. Two hundred fifty
endodontic records fulfilled these inclusion and
exclusion criteria for patients on statin medications
and patients who were not on statins’.
2. Patient information: The demographic data of the
patients, anamnestic data from medical and den-
tal history, and radiographic status are essential.
For example, from Alghofaily et al. (2018) ‘For
© 2020 International Endodontic Journal. Published by John Wiley & Sons Ltd
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Jakovljevic et al. Cardiovascular diseases and apical periodontitis
patients who met the study’s inclusion criteria
and completed a follow-up examination 2 to
5 years post-treatment, data were collected from
the Maryland Endodontics Record, and a Health
Insurance Portability and Accountability Act of
1996 waiver and waiver of consent were applied
to them. Patients who had not yet completed a
follow-up examination 2 to 5 years post-treat-
ment were contacted through mail and then
phone (if needed) and were invited to schedule an
appointment for a follow-up examination’.
3. Sample size: A sample size calculation must be
based on previous studies or a pilot study. Only
an appropriate sample size will have sufficient
power to identify statistically significant results.
4. Drop outs: The number of drop outs must be
reported including when and why.
5. Outcome measurement: The outcome measure for
both evaluation of AP and CVD must be defined
explicitly. AP must be assessed by discriminative
radiographs (e.g. periapical or cone beam com-
puted tomography rather than panoramic) evalu-
ated under standardized conditions (e.g. same
screen, dark room etc.), using a validated scoring
system (e.g. PAI; Ørstavik et al. 1986) by trained
and calibrated evaluators. Intra and interoperator
variability must be assessed and reported. The
diagnosis of CVD must be clearly defined, objec-
tively measured, rigorously implemented and
reported in detail. If surrogate markers of disease
are used as the primary outcome measure, such
as circulating inflammatory markers or patient
morbidity, they must be reported in detail.
6. Type of CVDs and related diagnostic procedures:
In the existing primary studies CVDs were repre-
sented by many conditions, including angina pec-
toris, myocardial infarction, cerebrovascular
insult, acute myocardial infarction, chronic
ischaemic heart disease, coronary calcified ather-
oma, hypertension, initial endothelial impair-
ment/reduced endothelial flow rate, aortic
atherosclerosis, oxidative balance and mortality
related to CVD. Moreover, various diagnostic
methods were employed to detect CVDs (i.e. self-
reporting of CVD/hypertension, measuring the
aortic atherosclerotic burden by a calcium scoring
method, Doppler ultrasound, and measurement of
plasma inflammatory mediators). This variability
in diagnostic methods makes it impossible to com-
bine the results from different studies and makes
a clear decision on the association between CVDs
International Endodontic Journal, 53, 1374–1386, 2020 1383

Cardiovascular diseases and apical periodontitis Jakovljevic et al.
and AP impossible. CVDs are a heterogeneous
group of diseases, with coronary heart disease
and cerebrovascular disease being the most fre-
quent. Future studies should evaluate the devel-
opment of these specific conditions in relation to
the presence of AP. There is high probability that
coronary heart disease and cerebrovascular dis-
ease will eventually develop in a previously deter-
mined follow-up period. Moreover, each clinical
study must report the method(s) used to assess
the CVD. It should be based on the latest guideli-
nes from the European Society of Cardiology for
coronary heart diseases (Knuuti et al. 2020) and
the American Heart Association/American Stroke
Association for cerebrovascular diseases (Powers
et al. 2018).
7. Coexistence of other systemic diseases and con-
founding risk factors: Various nonmodifiable
(heredity and diabetes) and modifiable factors (i.e.
physical inactivity, smoking habits, inadequate
diet and obesity, low level of HDL cholesterol, high
level of triglycerides and high blood pressure) are
well-defined risk factors for CVDs (Mendis et al.
2011). Some of these factors are also risk factors
for AP. The control of these factors is difficult but
would allow a more accurate estimation of the
odds ratio in future clinical studies. Potential con-
founders for CVDs and AP, such as periodontitis,
age and gender of patients, genetic polymorphisms
and teeth with/without a permanent restoration
should be managed at the initial stage of study
design, or during the investigation, by meticulous
matching of the groups for confounding factors
and finally, in the statistical analysis by making
the adjustments for these factors.
8. Systemic medications: Systemic medications that
are used for the treatment of the wide range of
CVDs should be considered in clinical trials. For
example, Alghofaily et al. (2018) reported a signif-
icant association between long-term statin intake
and healing of AP after root canal treatment.
However, such therapy may increase glycemia
(Maki et al. 2016), which could induce deteriora-
tion of diabetes, one of the risk factors for CVDs.
Hence, in future clinical studies, the authors must
report the medications taken by patients analysis.
9. Follow-up: One of the principle reasons that
Endodontology has a limited number of meticu-
lously planned, adequately powered longitudinal
studies investigating the relationship between AP
and CVD is that a sufficient number of patients will
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have to be followed for a number of years. This is
costly, challenging to persuade patients to return
for assessment and problematic if the population
under study is not static. There is no obvious solu-
tion to this other than a comment that epidemio-
logical research of importance has to be funded
over a number of years and requires considerable
manpower and financial as well as institutional
support. CVDs do not develop quickly so research-
ers and importantly research funders must plan for
follow-up over a prolonged period in order to
address the limitations of research in this area.
Future recommendation for systematic reviews and
meta-analyses
Researchers conducting and reporting systematic
reviews and meta-analyses in future should consider
the following criteria:
1. an a priori protocol must be prepared and regis-
tered in an appropriate database; authors must
report the name of the database and the registra-
tion number;
2. literature searches must be conducted in grey lit-
erature databases;
3. the inclusion of various study designs in the
review must be justified;
4. the methods used to appraise the risk of bias of
individual studies must be reported. The results of
the risk of bias assessment should be considered
in the analysis, and when developing the conclu-
sions of the review and formulating recommenda-
tions (Moher et al. 2009, Shea et al. 2017);
5. subgroup/sensitivity analysis must be conducted
considering the confounding factors, in addition
to primary meta-analysis; and
6. the sources of funding for the included studies
must be reported as this might affect the results
of the study.
Conclusion
From the ‘moderate’ to ‘critically low’ quality evidence
available, the current umbrella review concluded that
a weak association exists between CVDs and AP. More-
over, there is very limited evidence that the develop-
ment of CVDs coincides with the presence of AP, and a
causal relationship cannot be established. In the future,
well-designed, longitudinal clinical studies with long-
term follow-up are required. The recommendations
from this umbrella review must be actioned.
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 13652591, 2020, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.13364 by Cochrane Saudi Arabia, Wiley Online Library on [27/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Jakovljevic et al. Cardiovascular diseases and apical periodontitis

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Supporting Information
Additional Supporting Information may be found in
the online version of this article:
Table S1. Electronic Databases and Search Strat-
egy.
© 2020 International Endodontic Journal. Published by John Wiley & Sons Ltd