Mouth-Heart Connection: A Systematic Review on the Impact of Periodontal Disease on Cardiovascular Health

Periodontal diseases (PDs) and cardiovascular diseases (CVDs) are highly prevalent global diseases with increasing percentages of morbidity and mortality. Both PD and CVDs independently have multifactorial causation, and emerging evidence shows an association between PD and CVDs. Periodontal diseases like gingivitis and periodontitis are chronic inflammatory conditions that eventually cause systemic inflammation, leading to many systemic diseases like rheumatoid arthritis, cardiovascular diseases, and others. In this study, we followed a systematic review approach to give an overview of the current evidence on the association between PD and CVDs. We used a relevant search strategy to retrieve articles from databases such as PubMed and Google Scholar from 2013 to July 2023. Upon applying filters and screening through titles and abstracts, we could narrow down articles to 21. On full-text screening, we selected 10 articles for in-depth analysis. This study showed a significant correlation between PD and CVDs. Poor oral hygiene, infection, and inflammation in the oral cavity lead to systemic inflammation, causing endothelial dysfunction. There are controversial views about PD acting as an independent risk factor for CVD development, as there are other risk factors such as age, gender, smoking, etc. acting as confounding factors while establishing the link between PD and CVDs. Knowledge about oral health, maintaining good oral hygiene, and proper treatment for PD could reduce the incidence of CVDs. Further research is needed to prove that PD is an independent risk factor for CVDs.


Introduction And Background
In the world of emerging diseases, cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality [1].According to the World Health Organization (WHO), around 17.9 million deaths happened in 2019 from CVDs, which accounts for about 32% of global deaths [1].Among all the CVD deaths, 85% occurred due to myocardial infarction and cerebrovascular attacks [1].Other cardiovascular diseases include coronary artery disease, hypertension, arrhythmias, and peripheral artery disease.Periodontal disease (PD) is a chronic inflammatory condition with multifactorial causation that destroys tooth-supporting tissues (gingiva, alveolar bone, and periodontal ligament) and eventually progresses to premature tooth loss [2].It has been reported that periodontal disease affects about 20-50% of the population globally, and its prevalence has been increasing consistently since the last two decades [3].People with periodontal disease may have tooth loss, excess tartar, gum inflammation and bleeding, infection, tooth mobility, decay, and gum recession with bone loss [4].According to the literature, PD is found to have a significant association with systemic diseases like diabetes mellitus, heart diseases, systemic lupus erythematosus, and rheumatoid arthritis [5].This study focuses on the association between PD and CVDs.
Many observational studies have reported a significant association between periodontal diseases and CVDs.According to Belinga et al., a considerable proportion of people suffering from periodontal diseases like gingivitis and periodontitis had CVDs (hypertension, heart failure, and stroke) [6].One of the causative factors for PD is infection of the oral cavity by microbes like Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Streptococcus sanguis, Tannerella forsythia, Campylobacter rectus, Prevotella intermedia, Fusobacterium nucleatum, and Treponema denticola [3,[6][7][8].It is reported that these microbes are present in atheromatic plaques in patients with PD [6].Two pathways establish the causation link between PD and CVD: one being transient bacteremia, while the other being increased levels of inflammatory markers in the body.Dissemination of bacteria or bacterial endotoxins like lipopolysaccharides, heat shock proteins through blood vessels leads to increased production of inflammatory cytokines, pro-thrombotic factors, and upregulation of endothelial adhesion molecules [9].High vascularity of the oral cavity and thin, friable sulcular epithelium facilitate easy dissemination of microbes into blood [8].Local inflammation in the oral cavity in PD manifests systemically through an increase in inflammatory markers and cytokines like C-

Search Strategy
We used the population, intervention/condition, control/comparison, and outcome (PICO) strategy to frame a research question.Using keywords and MeSH terms, we formed a search strategy and used it to conduct searches on databases like PubMed (including Medline) and Google Scholar.The detailed search strategy used and the results obtained are mentioned in Table 1.texted articles as primary filters in PubMed.Duplicates were removed, and selection criteria were applied for the remaining articles.We excluded articles that did not meet the selection criteria.Studies such as randomized clinical trials, case-control studies, cohort studies, systematic reviews, and meta-analyses were included, while studies such as review articles, letter to editorial, and animal models were excluded.The inclusion and exclusion criteria used in the review are depicted in Table 2.We then independently screened through the abstracts and full text for the remaining articles to find their relevance to the present study.

Inclusion criteria Exclusion criteria
Human

Quality Appraisal
We employed certain quality assessment tools to assess the quality of papers chosen after screening and evaluate their reliability for this review.Table 3 shows the tools for quality assessment of different types of studies.

Randomized clinical trial Cochrane bias tool assessment
Non-randomized clinical trials and observational studies Newcastle-Ottawa tool

Systematic reviews PRISMA checklist
Other studies SANRA checklist

Results
We got 14,87,497 articles using the search strategy in PubMed and Google Scholar.We excluded 14,84,333 after applying primary filters like text availability, human-specific studies, associated data, age limit, and English texted studies on PubMed and Google Scholar.From the remaining 3164, we excluded 3143 studies after finding duplicates, screening through titles/abstracts and applying eligibility criteria.We thoroughly evaluated the remaining 21 studies and found 10 studies appropriate for our study.At last, we performed a quality check on 10 articles that met all the eligibility criteria.Table 4 shows all the articles that we included in our systematic review.A total of 10 studies were recruited after thorough screening.The included studies were published between 2013 and 2023.Three of the selected studies are China-based, two from the UK, and the rest from Cameroon, Germany, Brazil, the USA, and Iran.Of all the 10 studies included, six are meta-analysis studies, while the remaining four are prospective observational studies, longitudinal cohort studies, case-control studies, and cross-sectional studies.All the studies included both men and women; gender-specific studies were excluded as part of the eligibility criteria.In most of the studies, risk factors were adjusted.Among the studies included, four of them evaluated the association between PD and any CVD, while others assessed the association between PD and specific CVDs such as PAD, MI, hypertension, and stroke.

Discussion
In this systematic review, we found a significant association between PD and CVD, which proves the impact of poor oral hygiene on cardiovascular health.According to Larvin et al., the PD population had a significantly higher risk of CVDs than the non-PD population (RR = 1.20, 95% CI: 1.14-1.28)[3].In a Cameroon-based prospective observational study, there were statistically significant results, with about 28.9% of patients suffering from PD having CVDs [6].Having said that, some findings are contradictory to the earlier-mentioned findings.In a longitudinal cohort study by Reichert et al., the outcomes during the follow-up of patients with PD were quantified, and their association with PD was not statistically significant in both univariate and multivariate analyses.They concluded that periodontitis was not an independent risk factor for adverse events in patients with CVDs [13].
The impact of oral health on cardiovascular well-being can be explained by many pathways to establish the causal link between CVD and PD.Gingiva is usually composed of many microbes, such as Streptococcus sanguis, Streptococcus mutans, Streptococcus oralis, Actinomyces naeslindii, Actinomyces odontolyticus, Vellionella parvula, and F. nucleatum in supra and subgingival spaces [14].Poor oral hygiene, plaque formation, or any other condition triggers gingival inflammation, which changes the microbial composition to gram-negative bacilli and anaerobes such as P. gingivalis, T. forsythia, T. denticola, Selenomonas noxia, A. actinomycetemcomitans, C. rectus, spirochetes, and P. intermedia [14].Bacterial colonization further aggravates the inflammation, which leads to the deepening of the gingival sulcus and the formation of a periodontal pocket, as well as the loss of supporting tissues and alveolar bone [14].Eventually, periodontal inflammation causes systemic inflammation, which could be induced by bacteria or inflammatory mediators [15].Translocation of bacteria, bacterial endotoxins, and increased inflammatory markers like IL-1, IL-6, IFNgamma, TNF-alpha, CRP, haptoglobin, and fibrinogen initiate the catastrophic pathway.
According to Samani et al., there is an increased risk of MI in patients who lost more than 10 teeth (OR = 2.73).They found a significant difference in the mean Periodontal Disease Index (PDI) among the case and control groups, with more risk of MI in cases with PDI>4 (OR = 7.87) [14].In a meta-analysis by Xu et al., there was a statistical correlation between PD and MI, with patients having PD at a one-fold increased risk of MI [14].According to Larvin et al., the association between MI and PD was not statistically significant, though there was an increased risk of MI [3].In a cohort study by Reichert et al., spillage of microbes and bacterial endotoxins like lipopolysaccharides trigger the release of inflammatory mediators and prothrombotic factors, which increases the chance of atherosclerotic plaques and progression of which leads to MI [16,17].
According to Fagundes et al., there is an increased chance of stroke in patients with periodontitis (RR = 2.31 (95% CI = 1.39, 3.84)) [18].On subgroup analysis based on the type of study, cohort studies (RR = 1.88 (1.55, 2.29)) and case-control studies (RR = 2.72 (2.00, 3.71)) showed an increased risk of stroke and ischemic stroke, respectively [18].In a meta-analysis where any CVD is the common endpoint for evaluation of the impact of PD on cardiovascular health, the risk of stroke (RR = 1.24; 95% CI:1.12-1.38)was highest among other CVDs [3].In a Cameroon-based prospective observational study, stroke was found in only 5% of all the CVDs identified among PD patients [6].This difference in the incidence of stroke among PD cases can suggest that PD is not an independent risk factor for stroke, though the results are statistically significant.Inflammation increases the risk of stroke with increased inflammatory markers like CRP, IL-6, and lipoprotein association phospholipase A2 [19].Evidence shows that PD is associated with increased intima thickness of the carotid artery and the formation of carotid calcifications [8].
A systematic review and meta-analysis by Muñoz Aguilera et al. reported a positive association between PD and hypertension (an increase in the severity of PD is associated with increased mean systolic and diastolic blood pressures) [20].In a cross-sectional study by Zhan et al., severe periodontitis (stages III and IV) was associated with hypertension, and there was no significant difference in periodontal status in hypertensive and normotensive patients with increasing age [21].In a Cameroon-based prospective observational study, 87.6% of identified CVDs in PD patients were hypertensive [6].Local inflammation in the oral cavity leads to systemic inflammation, causing endothelial dysfunction that affects the regulation of hypertension [22].Increased reactive oxygen species in periodontitis are associated with vascular inflammation and vasoconstriction [22].
In a systematic review and meta-analysis on the impact of periodontitis on PAD, there is a significant difference in missing teeth between PAD and non-PAD patients, proving the statistical association between periodontitis and PAD [5].Thus, through this review, we could derive the association between PD and CVDs such as MI, stroke, hypertension, and PAD.
There are controversial views regarding PD as an independent risk factor for CVDs.All the studies conducted in this arena mentioned other risk factors like age, sex, smoking, obesity, socio-economic status, and alcohol as confounding factors while evaluating the link between PD and CVDs.Hypertension risk was increasing in severity of periodontitis, and this association was more among individuals aging between 35 and 44 years [21].According to Larvin et al., men with PD had a high risk for CVDs (RR: 1.16, 95% CI: 1.08-1.25)[3].In a cross-sectional study by Zhan et al., among all the current smokers, the prevalence of PD is higher in hypertensive (76.2%) than in normotensive (68.1%) individuals [21].
Oral health could be easily affected by many factors, such as an improper diet, alcohol intake, smoking, and poor oral hygiene [23].Poor oral health overtime influences the quality of life by affecting the cardiovascular system.Good knowledge of oral hygiene and its impact on health is essential in order to be determined about maintaining proper oral hygiene.According to Farsi et al., females and medical faculties have better knowledge of oral health than males and non-medical faculties [24].Lower educational qualifications and low socio-economic status also have an effect on oral health knowledge [25].A larger proportion of people do not know the impact of oral diseases on systemic health [24].Thus, spreading knowledge about practicing good oral health is highly important in order to prevent oral diseases and maintain a good quality of life.
In a randomized controlled trial by Paju et al., clarithromycin showed beneficial effects in the prevention of recurrent cardiovascular events in non-PD patients, which suggests that oral cavity infection could lead to cardiovascular morbidity [26].In a cohort study by Holmlund et al., patients suffering from periodontitis were given treatment, and the treatment effect was categorized as good or poor responders.Poor responders had a higher risk of getting CVDs than good responders [27].Thus, timely treatment for periodontal disease could reduce the risk of CVDs.
There has been a lot of heterogeneity in the studies because of study type (cross-sectional study, cohort study, and case-control study), study region, confounding factors (gender, smoking, and others), and PD diagnosis method (CAL, missing teeth).All these factors are reported to affect the risk of PD on CVDs.According to Yang et al., there was a statistically significant association between missing teeth and PAD, while CAL did not show any association with PAD [5].In a study, subgroup analysis based on study type showed that the high risk of MI in PD patients is statistically significant in cross-sectional and case-control studies while marginally significant in cohort studies [16].Heterogeneity in results due to these factors is a limitation in evaluating the impact of PD on CVDs.Thus, there is a need for further research to prove that PD is an independent risk factor for CVDs by limiting confounders and other factors.

Conclusions
This systematic review identifies a positive correlation between PD and CVDs.Transient bacteremia and local inflammation are the causal links for this association.Poor oral hygiene, plaque formation, and infections initiate the local inflammation in the oral cavity that eventually spreads to the blood.The independent association of PD with CVD is yet to be established.There are many confounders like gender, smoking, and others that need to be taken care of while performing studies in this arena.We could find a significant association between periodontal disease and CVDs like MI, PAD, hypertension, and stroke.Proper oral hygiene and adequate treatment for periodontal disease could lower the risk of CVDs.There is a need for further research to know whether or not PD is an independent risk factor for CVDs.

FIGURE 1 :
FIGURE 1: PRISMA flowchart showing the study selection process for the systematic review.PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
adjusted) Increased risk of CVD in patients with PD, with risk more pronounced in males and patients having severe PD.

TABLE 3 : Showing tools used for quality appraisal.
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses; SANRA: Scale for the Assessment of Non-Systematic Review Articles.