Association between Dental and Cardiovascular Diseases: A Systematic Review

Background: The link between dental, infective and obstructive cardiovascular diseases is debatable. Aim: To systematically review the literature to assess the association between dental conditions and development of cardiovascular disease. Methods: The systematic review was conducted following the PRISMA guidelines using PubMed (Medline), Web of Science, Scopus, EMBASE and SciELO. Results: Out of 6680 records, 82 articles were eligible for inclusion after reviewing titles and abstracts. No association between dental disease and cardiovascular disease has been observed in 10 studies while a potential link has been suggested by the remaining trials. Tooth loss and periodontitis are the main evaluated oral conditions while coronary artery disease, stroke, atherosclerosis and myocardial infarction represent the major cardiovascular events. The interaction between these two clinical entities is based on direct mechanism mediated by systemic inflammatory response, leakage of cytokines and endothelial cells invasion by oral pathogens and indirect mechanism mediated by common risk factors or confounders. Conclusions: It seems that tooth loss, periodontitis and poor oral hygiene increase the risk of atherosclerotic cardiovascular events, and subsequently oral health care professionals could contribute to public health cardiovascular control efforts.


Introduction
Despite the recommendations on aggressive management of cardiovascular risk factors for primary and secondary prevention in parallel to the impressive progression of the available medical and interventional therapeutic strategies, cardiovascular diseases (CVD) are still the main cause of death in the developed and developing countries [1,2].CVD includes a broad spectrum of infective and obstructive diseases like endocarditis, myocarditis, pericarditis, acute coronary syndrome including myocardial infarction, chronic coronary artery disease (CAD), stroke and peripheral artery disease.In the acute setting of cardiovascular events or during the follow-up of patients suffering from chronic coronary syndrome, medical practitioners systematically screened for the classical risk factors like smoking, diabetes mellitus, dyslipidemia, systemic hypertension, family history of CAD, and obesity [3].However, searching for the potentially cardiogenic atypical factors and understanding how they could affect the cardiovascular system may minimize the burden of CVD on the eco-nomic and health systems respectively [4].For decades, researchers have been concerned by the link between oral disease and heart disease.Data from literature are conflicting and heterogeneous.Up to date, it is unclear whether the linking between these two diseases is a direct connection based on pathophysiological mechanisms making periodontal disease as independent predictor of CVD or indirect connection since these two entities commonly share multiple risk factors like smoking and unhealthy diet [5,6].People with oral disease are at higher risk for stroke, heart attack, and serious cardiovascular events [7][8][9][10].Periodontal disease, vertical bone lesions, endodontic disease, dental caries, dental infection were considered as dental conditions with some risk of entrapping a relationship with CVD [11][12][13][14][15]. Study findings revealed a positive association between the reduction in teeth number, abdominal aortic calcification [16], ischemic events [9,10] and cardiovascular mortality [7,8].In addition, lesion originating from endodontic disease is able to trigger a systemic illness [17,18].Simultaneously, patients with CVD significantly present a lower teeth number and poor oral hygiene [19].Considering that oral health status could directly influence the incidence, pathophysiology, and course of CVD, it is important to summarize the literature to better describe this potential association and the mechanisms which can explain this link.Herein, this paper aimed to systematically review the association between dental conditions and development of CVD.

Study Design
A systematic review of clinical trials that examine the association of dental disease and CVD disease was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA statement) [20].The registration protocol was carried out in Open Science Framework with the registration number 0000-0002-2759-8984.The following PICOS strategy was used: population, human; intervention, dental disease, control, patients without CVD; outcome: CVD; type of study, observational studies, clinical trials.The research question was: Does the presence of dental disease is associated with the development of CVD?

Search Strategy
An unlimited literature search was performed by two independent reviewers (RB and CECS) until November 11th, 2021 using PubMed (MEDLINE), Web of Science, Scopus, EMBASE and SciELO.The MeSH search terms in the previously cited databases are summarized in Table 1.All research studies were imported into Rayyan QCRI platform.

Inclusion Criteria
The title and abstract of each recognized manuscript were examined by two independent reviewers (RB and CECS) to determine if the article should be considered for full-text review according to the following eligibility criteria: (1) Case-control and cross-sectional studies, cohorts, and randomized clinical trials reporting the relationship of any cardiovascular condition with the presence of any oral disease; (2) studies where the presence of an oral disease was clinically diagnosed; (3) studies where CVD was clearly defined; and (4) peer-reviewed articles published in the English, Spanish or Portuguese languages.

Exclusion Criteria
Case reports, case series, pilot studies, expert opinions, conference abstracts and reviews were excluded.In case of disagreements at the time of the collection of the papers for the full-text review, they were resolved by discussion and agreement by a third reviewer (LH).

Data Extraction
Data of interest were extracted from the enrolled manuscripts via the Microsoft Office Excel 2019 program (Microsoft Corporation, Redmond, WA, USA) and subsequently placed on a standardized form.Two reviewers (RB and LH), who received training in this software, performed data analysis.The extracted data from each manuscript include author names, year of publication, study type, number of participants, oral health condition, CVD, biomarkers, and principal outcomes.In the setting of prior myocardial infarction, the risk of major cardiovascular events was not increased in association with the levels of circulating periodontopathogens antibodies.

Coronary heart disease
Serum CRP levels In the context of coexisting periodontitis and coronary artery disease, non-surgical mechanical periodontal approach decreased the levels of hs C-reactive protein, fibrinogen and white blood cells.
Fibrinogen and white blood cells
Regarding oral health conditions, most of the studies evaluated the tooth loss and periodontal disease while the assessed cardiovascular events were stroke, CAD, acute myocardial infarction, peripheral artery disease, and atherosclerotic disease.Findings from the included studies in this systematic review were in favor of an association between the poor oral conditions (especially for the reduction in tooth number and periodontal disease) and the incidence of cardiovascular events (particularly for stroke and CAD).Also, the presence of periodontal disease was associated with higher level of inflammatory biomarkers.

Discussion
In this review, the association between dental conditions and development of CVD was studied and results were in favor for a positive association between tooth loss, periodontal disease, and CVD (Fig. 2).Conventional risk factors for atherosclerosis and CAD such as smoking, diabetes, hypertension, high low-density lipoprotein (LDL) serum level, obesity, male gender, and genetic predisposition have been evidently recognized and systematically searched after cardiovascular event [111].Smoking and familial history play the pivotal role in the development of CVD in young patients [112].Unconventional risk factors like chronic inflammatory reactions have also been identified as predictors of CVD.When the inflammation occurs, circulating markers and hemostatic factors were diligently linked with the development of myocardial infarction [113].Particularly, chronic oral infection was associated with chronic heart diseases [114,115].Dental infections were associated with an increased prevalence of heart disease [75,116], as the oral cavity was the main site of inflammation and chronic infection, especially in cases of tooth loss and chronic periodontal diseases [75,117].Many studies have discovered that the long-standing inflammatory stimuli of dental infection was implicated in the pathogenesis of CVD [117,118], though further analyses have failed to notice a strong relationship between CVD and dental infection .Oikarinen et al. [119] have documented a higher rate of periodontal infection among patients with CAD and Söder B et al. [118] have revealed that a high dental calculus score was correlated with increased incidence of angina pectoris.With regards to tooth loss and CAD and stroke risk, there are several unsolved issues [120].The results obtained from this review suggest that there is a relationship between the number of teeth loss and the presence of cardiovascular events, like CAD, peripheral arterial disease, and increased risk of stroke death.This could be explained by the fact that first the number of tooth loss might be linked to some inflammatory, hemostatic, and cardiac biomarkers [45].Second, one should consider that the main cause of tooth loss is dental caries, and carbohydrate intake is the chief dental caries cause.If specialist consider that carbohydrate intake is associated with increased risk of CVD and stroke, then the number of tooth loss could have indirect impact on these two last mentioned diseases [121].Third, as the progress of tooth damage destroys periodontal tissues, thus oral microbial will accumulate into oral tissue, therefore promoting its growth and resulting in an increased risk of CVD and stroke [122].All these factors were trustworthy for elucidating the relation between the CVD and tooth loss.Also, the release and persistence of early inflammatory biomarkers of periodontitis like TGF-β, transglutaminases and NLRP3 accelerate atherosclerotic plaque development [123].Inflammatory proteins have been associated in several observational studies with endothelial dysfunction, atheroma plaque development and cardiovascular events [124].Details of the biological processes that lead to the systemic inflammatory reaction in the setting of periodontal diseases are not well understood.It maybe seems that these elevations of systemic inflammatory markers occur in response to the exposure to oral bacteria.Another hypothesis considers that cytokines secreted by the inflamed periodontal tissues would cross the blood stream causing a systemic inflammation [125].
In this context studying the link between oral and cardiovascular diseases, there is another topic of great importance that is worth mentioning.It is the concern of patients taking anticoagulant for cardiovascular disease and who undergo dental procedures.The management of such as patients seems much more complicated by dentists especially in the absence of a clear implemented protocol [126].
Several hypotheses have been raised to explain the association between dental and CVD.For example, pathogens causing gingivitis and periodontitis can travel into blood vessels elsewhere in the organism resulting in inflammation of the vascular wall, parietal damage and blood clots formation [122].This rational was supported by polymerase chain reaction detection of oral bacterial remnants like streptococcus mutans, porphyromonas gingivalis, prevotella intermedia and tannerella forsythia in the fatty deposits within the atherosclerotic vessels [127][128][129].It remains unclear by which mechanism periodontal pathogens could influence atherosclerosis after direct endothelial cells invasion.Triggering foam cell formation or provoking a state of secondary inflammation through their intracellular persistence leading to endothelial dysfunction have been suggested [130].Another theory depends on the body's immune response to chronic inflammatory process that sets off a cascade of vascular damage throughout the body including heart and brain.Periodontitis activates a systematic inflammatory response that produces high levels of different cytokines like Il-1β, Il-6, Il-8 and TNF-α also playing a role in the pathophysiology of atherosclerotic vascular disease [131].Lastly, it could be possible that gum disease and CVD are not directly connected but they may occur together in the presence of third common factor or potential confounders such as smoking, unhealthy diet, poor hygiene, lack of exercise and poor access to healthcare.Indeed, individuals without health insurance or who don't take care of their global health are more likely to have worse oral conditions and CVD.Noteworthy that periodontal disease and CVD share genetic predisposition via at least one susceptibility locus [132,133].
Overall, gum disease and CVD are multifactorial disorders requiring interaction between several factors and any potential contribution of one disease to the pathology of other should be carefully interpreted as many confounding variables affect both conditions.Health care professionals have to be aware of this association.Thus, dental practitioners should advise patients with severe periodontitis to check with physicians for atherosclerosis and cardiologists should insist on the importance of good oral hygiene.

Conclusion
In conclusion, the results obtained from this systematic review suggests that oral condition, especially the number of remaining teeth and the presence of periodontal disease increase the risk of cardiovascular events.It is likelihood that the association is mainly related to a chronic persistent systemic inflammatory reaction.Future research must be directed, especially randomized controlled clinical trials, with the purpose of gaining a better understanding of the link between oral and cardiac diseases.
OR Dental health OR Periodontal disease OR Periapical Disease OR Tooth Diseases OR Oral pathology OR dental infection OR oral infection OR Dental Pulp Disease OR Oral Health # 2 Heart Disease OR Vascular Disease OR Coronary Artery Disease OR Coronary heart disease OR Atherothrombotic cardiovascular disease # 3 Clinical trials OR Controlled Clinical Trial OR Retrospective Studies OR Randomized Controlled Trial OR Prospective clinical trial OR Retrospective Study OR Prospective Studies OR Prospective Study OR Clinical Trial OR Randomized clinical trial # 4 # 1 AND # 2 AND # 3

Findler
Non measuredThis study provided essential dental treatment for severe heart failure patients with special attention to their medical problems and the use of medications and supporting means to prevent health-compromising situations is recommended.Skilton 2011[95] A randomized, controlled trial study450 adults Periodontal disease Vascular health and inflammationInflammatory mediators (IL-1, IL-6, TNF) Periodontal disease was related to CVD.
relation between remaining teeth, grading of periodontal disease, deep of periodontal pockets, bleeding on probe and cause of mortality CVD is linked to oral health status.protein, fibrinogen An improvement of 27% in CVD survival has been observed after incrementation of 10 teeth.

Fig. 2 .
Fig. 2. Review's rational and findings with the potential mechanisms linking gum disease and development of cardiovascular disease.

Table 2 . Characteristics of the included studies.
[22]keAoyama 2018[22]Clinical trial 897 Periodontal conditions Coronary heart disease Not measured The coronary artery disease patients generally had worse oral condition than the non-coronary artery disease patients.Batty 2018 [23] Cohort 975,685 Tooth loss Coronary heart disease Not measured There was a moderate, positive association between tooth loss and coronary artery disease.

Table 2 . Continued.
[40]l serum cholesterol level There is no evidence of a causal association between periodontal disease and coronary artery disease.Hung 2003[40]Prospective cohort 45,136 Tooth loss Peripheral arterial disease High-density Tooth loss is associated with peripheral arterial disease, especially among men with periodontal diseases.Periodontal disease was not associated with coronary heart disease.Tooth loss may increase the risk of the later one.
90ree-armed observer-blinded randomized controlled trial90Severe periodontitis Peripheral arterial disease C-reactive protein Periodontal treatment did not reduce vascular inflammation in patients with peripheral arterial disease.
Missing teeth, restorations, probing depth (PD) and bleeding on probing (BOP) were recorded.Blood samples were taken on admission for measurements of serum total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-cholesterol), low density lipoprotein cholesterol (LDLcholesterol), and fasting blood glucose level Periodontal disease might be linked with acute myocardial infarction.
Congenital heart disease Oral examinationChildren with cardiac problems should be identified in early infancy through liaison with medical colleagues and the family offered all the preventive advice and regular dental care necessary to prevent dental disease.
Serum IgG and IgM aCL antibodiesThe phase I periodontal therapy altered levels of serum IgG and IgM aCL antibodies in patients with AMI associated with chronic periodontitis.