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 economic 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.

The search resulted in the retrieval of 6680 records. After removal of duplicates, 6384 articles were screened, and 6294 were excluded based on the title or abstract. A total of 90 full-text articles were assessed for eligibility [20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110]. Of these, eight were not considered for the qualitative analysis: two were reviews [24, 54], two did not evaluated any CVD [51, 63], one was a pilot intervention study [32], one was an editorial letter [37], one was a clinical protocol [56] and one was a congress abstract [67]. Finally, 82 manuscripts were considered for the qualitative analysis (Fig. 1). Characteristics of the included studies in this systematic review are summarized in Table 2 (Ref. [21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52, 53, 55, 57, 58, 59, 60, 61, 62, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110]).

Fig. 1.

Search flowchart according to the PRISMA Statement.

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.

Out of the 84 studies, ten studies failed to reveal a link between gum disease and CVD [5, 27, 38, 39, 42, 50, 58, 59, 99, 101]. Two studies declined the connection between periodontitis and ischemic heart disease while it showed an association between tooth loss and ischemic heart disease [43, 78]. Otherwise, tooth loss was associated with increased in cardiac mortality [21, 46], death from stroke [21], CAD [23, 85, 76], adverse cardiovascular outcomes [69], atherosclerosis [34], peripheral artery disease [40], inflammatory, hemostatic, and cardiac biomarkers [45] and impaired cardiovascular survival [41]. Periodontal disease was associated with CAD [25, 44, 64, 96], peripheral artery disease [30, 83], acute myocardial infarction [31, 77], stroke [31], adverse cardiovascular events [31, 70, 72, 107], coronary artery ectasia [36], valvular heart disease [60], cardiovascular disease [79, 91, 95, 102] and atherosclerosis [82]. In parallel, patients with CAD express higher level of periodontal disease indicators and have poor oral conditions [22, 68]. A reduction in systemic inflammatory and cardiac biomarkers [33, 48, 57, 62], improvement in lipid profile [33], decreasing in prevalence of acute myocardial infarction [55], heart failure [55], cardiovascular events [87], heart disease [89] and improvement in endothelial function [86] have been observed after periodontitis treatment and good oral health care. Lastly, increment of 10 teeth from the edentulous state resulted in 27% improvement in CVD survival [110].

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 [39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114]. 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-$\beta$, 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].

Fig. 2.

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

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-1$\beta$, Il-6, Il-8 and TNF-$\alpha$ 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.

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.

AM, LH and JR designed the research study. RB, CECS and LH performed the research. All authors analyzed the data. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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Toulouse University Hospital provides article processing charge.

The authors declare no conflict of interest. Anthony Matta and Jerome Roncalli are serving as Guest Editors of this journal. We declare that Anthony Matta and Jerome Roncalli had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Gary Tse, Sharen Lee and Tong Liu.