Effects of Oral Inflammatory Diseases and Oral Hygiene on Atrial Fibrillation: A Systematic Review

Objective Research evidence suggests a link between periodontitis (PD) and atrial fibrillation, but the nature of this link is unclear. This study aimed to systematically review and evaluate the association between PD, other oral diseases, and atrial fibrillation and the role of oral hygiene in preventing atrial fibrillation. Methods We searched the Medline, Embase, Cochrane Library, and Web of Science databases for the clinical study of oral health and atrial fibrillation from inception to November 2022. Oral health conditions included PD and other oral inflammatory diseases, regular oral hygiene, and tooth brushing. The primary outcomes were the risk of new-onset atrial fibrillation in patients with oral disease, the effect of regular oral care on preventing atrial fibrillation, the effect of frequent tooth brushing on preventing atrial fibrillation, and the incidence of atrial fibrillation in PD patients. Results Eight clinical trials with a total of 4,328,355 patients were included. The result of the research showed that PD and other impaired oral health may be associated with new-onset atrial fibrillation, and its severity was dose-responsive to the risk of atrial fibrillation. The incidence of atrial fibrillation in patients with severe PD was about 16.3%. Moreover, PD may increase the risk of long-term arrhythmia in patients with atrial fibrillation. Regular oral care and frequent tooth brushing can reduce the incidence of atrial fibrillation. Conclusion Regular and moderate oral hygiene, frequent tooth brushing, and prevention of PD and other oral inflammatory diseases could reduce the occurrence of atrial fibrillation. It is recommended to strengthen the popularization of oral health knowledge in the publicity related to atrial fibrillation.


Introduction
Atrial fbrillation (AF) is a common tachyarrhythmia in clinical practice that can increase the risk of cardiovascular and cerebrovascular diseases such as stroke and heart failure and is an important public health problem [1,2]. Based on aging populations worldwide and the fact that the success rate of atrial fbrillation ablation still needs to be improved [3], how to efectively prevent the occurrence of atrial fbrillation has always been a key concern.
Multiple studies have shown that infammation could promote electrical remodeling and structural remodeling of the atrium, which plays an important role in the occurrence and development of atrial fbrillation [4,5]. In addition, Creactive protein, interleukin-6, tumor necrosis factor-α, and other infammatory factors can cause an abnormal electrical activity of pulmonary veins, shorten atrial action potential, and interact with heat shock protein or myeloperoxidase to promote atrial fbrosis [6], thereby promoting the occurrence and recurrence of atrial fbrillation and thromboembolic events.
Oral infammatory diseases are evolving chronic diseases. Periodontitis (PD) is a major oral health problem, leading to tooth loss and bacteremia and resulting in systemic infammatory responses in severe cases. Surveys show that approximately 50% of the world's population sufers from PD and 10% sufer from severe PD, which is considered to be the sixth global epidemic afecting every country [7,8]. Based on common risk factors and underlying pathophysiological mechanisms, increasing attention has been given to the association between oral diseases and cardiovascular diseases. Studies have shown that in PD patients, Porphyromonas gingivalis and infammatory factors could promote the progression of atherosclerosis and may be potential risk factors for coronary heart disease [9]. PD can increase the risk of hypertension through systemic infammation and oxidative stress [10,11]. Subsequently, related studies on oral infammatory diseases such as PD and atrial fbrillation have gradually increased. However, there is no consensus on the specifc relationship between oral infammatory diseases and atrial fbrillation and whether oral care can lessen the risk of atrial fbrillation. Terefore, this study analyzed relevant clinical trials published thus far and conducted a systematic review to analyze the efects of oral infammatory diseases and oral hygiene on atrial fbrillation.

Data Source and Search.
Clinical studies related to oral health and atrial fbrillation published in Medline, Embase, Cochrane Library, and Web of Science were searched. Te retrieval time was from the establishment of each database to November 2022. Tere was no restriction on the language of the included literature, and we attempted to translate non-English literature (if not available, the literature was excluded). Each database was searched in detail using Medical Subject Headings (MeSH) terms and associated free words. Te search keywords included "Atrial Fibrillation" and its related free words, "Periodontitis" and its related free words, "atrial futter," "atrial tachycardia," "atrial arrhythmia," "periodontal disease," "pulpitis," "pericoronitis," "periapical," "dental abscess," "tooth abscess," "endodontic abscess," "pulpal abscess," "apical abscess," "periradicular abscess," "radicular abscess," and "acute dental infection." Supplementary Table S1 summarizes the specifc retrieval strategies and results used for each database. In addition, in order to obtain more relevant studies, a manual search was conducted for references that might be included in the literature. Tis study was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines and statement.

Inclusion/Exclusion
Criteria. Te inclusion criteria were as follows: (1) Prospective or retrospective studies (randomized controlled trials, cohort studies, case-control studies, and cross-sectional studies) on the relationship between oral health and atrial fbrillation in adults (≥18 years of age) (2) Oral health conditions include oral infammatory diseases such as PD and dental periapical abscess and oral care such as dental cleaning and frequent tooth brushing (3) Outcome indicators were new-onset or recurrent atrial fbrillation (4) Complete baseline data and outcome indicators were available Te exclusion criteria were as follows: Studies with incomplete data, meta-analyses, reviews, reviews of the literature, case reports, conference abstracts, and other types of literature, and the full text of the literature could not be obtained. When duplicate studies were found, the study with relatively complete data was selected and analyzed. Two researchers independently searched the literature, extracted data, and cross-checked the data. Disagreements were resolved through discussion and negotiation, and remaining disagreements were resolved by a senior third person.

Data Extraction and Evaluation
Indicators. Te following information was extracted for each included study: general information, including title, frst author, journal, and publication year; the country or city where the study was conducted; research characteristics, including study design, sample size, average age, sex ratio, oral health situation, and so on; and study endpoint events (such as the incidence of atrial fbrillation). Follow-up times were extracted from cohort studies and randomized controlled clinical trials.
Evaluation indicators included association between oral infammatory disease and the risk of atrial fbrillation in univariate and multivariate analyses, such as the hazard ratio (HR), relative risk (RR), odds ratio (OR), and 95% confdence intervals (95% CI); the efect of frequent tooth brushing on atrial fbrillation in multivariate analysis; the efect of regular oral care on atrial fbrillation in multivariate analysis; the incidence of atrial fbrillation in patients with or without PD; and the prevalence of PD in patients with or without atrial fbrillation.

Literature Quality
Evaluation. Te quality of the included studies was evaluated independently by two researchers. For the included observational studies, the NOS (Newcastle-Ottawa scale, range 0-9) was used to evaluate the research quality. Tis scale includes 3 major sections (cohort studies include subject selection, comparability between groups, and outcome measurement; case-control studies include subject selection, comparability between groups, and measurement of exposure factors), with a total of 8 item evaluations and a full score of 9 points. A study with an NOS score ≥6 was considered a high-quality study. Te quality of the included randomized controlled trials (RCTs) was assessed using the RCT bias risk assessment tool recommended by the Cochrane Handbook for Systematic Reviews 5.1. Disagreements were resolved by consensus. When there is a disagreement, it should be resolved by consensus, and remaining discrepancies could be resolved by a third senior researcher.

Heterogeneity and Statistical Analysis.
Heterogeneity generally includes clinical heterogeneity, methodological heterogeneity, and statistical heterogeneity. Clinical heterogeneity includes diferences in patient, interventions, control, outcome, and study design. Methodological heterogeneity includes study type, blind method, completeness of outcome 2 International Journal of Clinical Practice report, and rigor of statistical method. When data could be meta-analyzed, Q test and I 2 value were usually used to evaluate the statistical heterogeneity. If I 2 > 50%, there was heterogeneity among the studies, and a random efects model was used to analyze the data; if I 2 ≤ 50%, the studies were homogenous, and a fxed efects model was used for analysis. When the data met the requirements, metaregression and subgroup analysis were used to further evaluate the source of heterogeneity, so as to explore the infuence of a factor on the efect size. Potential sources of heterogeneity included age, sex, country, study design, and sample size. In addition, sensitivity analysis was attempted to ensure the stability of the results and to analyze the sources of heterogeneity, which was usually conducted by excluding studies sequentially. Te sensitivity analysis referred to the pooled analysis of the remaining literature after the removal of a study, the comparison of the combined efect size before and after the removal, to further explore the impact of the excluded studies on the pooled efect size, and to fnd the source of heterogeneity. If there was no signifcant change in the pooled efect size after deleting a study, it indicated that the results of metaanalysis were relatively stable; on the contrary, it indicates that the stability of the meta-analysis was poor.
When the data met the requirements, Review Manager statistical software V5.3 was used for data processing and meta-analysis for each outcome index. All evaluation indexes in the included literature were analyzed. Te RR, OR, or HR was used as the efect index for categorical variables, and weighted mean square deviation (WMD) was used as the efect index for continuous variables, which were expressed with 95% CIs. P < 0.05 was considered statistically signifcant. When the heterogeneity was too obvious and cannot be resolved, meta-analysis should be abandoned and only systematic review should be conducted.

Publication Bias.
Large publication bias may afect the true result of the study. When the number of included studies was more than 10 papers, Egger's test and Begg's test in STATA statistical software V16.0 were used to draw a funnel plot to test for publication bias. Publication bias exists if the P values from the tests are all less than 0.1. When the test results of the two groups were inconsistent, considering that the previous studies posited that Egger's test was more sensitive than Begg's test, and the results obtained by Egger's test were selected.

Ethical Approval Statement.
Institutional review board approval was not required because the analysis was based on the secondary processing of data from previously published studies.

Literature Search and Screening Results.
A total of 479 studies were retrieved, of which 397 articles remained after 82 duplicate articles were removed. During the preliminary screening, two researchers independently read the title, abstract, and keywords. After excluding the irrelevant literature and other types of literature, such as reviews, comment, guideline, letter, meta-analysis, animal experiment, and case reports, 16 eligible studies were obtained. After in-depth reading of the full text, 8 studies were excluded according to the data evaluation results, and 8 studies were ultimately included [12][13][14][15][16][17][18][19]. Te specifc process is shown in Figure 1.

Basic Characteristics and Quality
Evaluation of the Included Literature. Te eight included articles were observational studies, one of which was a large prospective cohort study [12], fve were large retrospective cohort studies based on a national population [13][14][15][16][17], one was a case-control study [18], and one was a cross-sectional study [19]. A total of 4,328,355 patients were included. All six cohort studies included patients without a history of atrial fbrillation at the baseline. Four of the studies included PD patients and non-PD patients in the exposed and nonexposed groups, respectively [12][13][14]17]; one study included patients with apical abscesses and nonapical abscesses [15]; and one study included patients with regular oral hygiene and those without oral hygiene [16]. Te outcome measure in the above mentioned studies was diferences in new-onset atrial fbrillation. Two groups of patients (nonvalvular atrial fbrillation with PD and nonvalvular atrial fbrillation without PD) were included in the case-control study, and the outcome indicators were the efects of periodontitis on arrhythmia events and major adverse cardiac events in patients with atrial fbrillation [18]. Te sample sizes of the abovementioned study population ranged from 227 to 3,056,291, with follow-up periods ranging from 18 months to 17 years. A cross-sectional study, including 5,634 participants with complete data on periodontitis and atrial fbrillation, was conducted to assess the relationship between periodontitis and its severity and atrial fbrillation [19]. Specifc baseline data included in the literature are shown in Table 1.
Seven observational studies other than cross-sectional studies were assessed for quality based on NOS scores. In the case-control study by Im et al. [18], NOS scores based on the case-control study were used (scoring categories included selection, comparability, and exposure). Because of confounding factors such as age were not matched between the case group and the control group, the NOS score of this study was 7. For cohort studies, NOS scores based on the cohort study were used (scoring categories included selection, comparability, and outcome). NOS scores ranged from 7 to 9, indicating high quality of the included literature. Te kappa value of agreement between the two researchers at the quality evaluation stage was 0.73 (95% confdence interval [CI]: 0.38-1.00), indicating a high consistency (P < 0.001). Details of the quality scores for each included study are presented in Table 2.

Efects of Oral Infammatory Disease on Atrial
Fibrillation. Te efect of oral infammatory disease on the risk of atrial fbrillation was reported in seven studies International Journal of Clinical Practice [12][13][14][15]18]. Four of them analyzed the correlation between PD and atrial fbrillation. A retrospective cohort study [14] by Chen et al. found that PD patients had a signifcantly increased risk of new-onset atrial fbrillation/futter after adjusting for confounders (HR 1.31, 95% CI 1.25-1.36). A case-control study [18] by Im et al. reported that PD was an independent predictor of major adverse cardiac events (OR 17.78, 95% CI 3.46-91.34) and arrhythmic events (OR 9.19, 95% CI 1.24-67.96) after adjusting for the confounders' factor. In a retrospective cohort study [13] by Chang et al., univariate analysis suggested that PD increased the risk of new-onset atrial fbrillation (HR 1.1, 95% CI 1.02-1.20), but multivariate analysis showed no signifcant association between PD and atrial fbrillation. Hsu et al. [15] investigated the efect of PD on stroke and found that patients with PD had a signifcantly increased risk of AF compared with patients without PD (OR 1.39, 95% CI 1.30-1.48), but the study did not adjust for the infuence of confounding factors. After adjusting for confounding factors, the incidence of stroke in PD patients was 2.14 times that of non-PD patients. Both studies of Sen et al. (2021) and Struppek et al. (2021) included patients with diferent degrees of PD and only provided the risk of atrial fbrillation in diferent degrees of PD after adjusting for confounding factors and did not provide the total risk of atrial fbrillation in all the PD patients [12,19]. One article analyzed the association between dental periapical abscess and atrial fbrillation. Multivariate analysis of retrospective cohort studies [15] by Hassan et al. showed that dental periapical abscess was signifcantly associated with new-onset atrial fbrillation (HR 1.11, 95% CI 1.01-1.22).

Efects of Diferent Degrees of Periodontitis on Atrial
Fibrillation. Two studies reported the diferent efects of PD severity on the occurrence risk of atrial fbrillation [12,19], involving healthy patients and mild PD patients (4,588 patients), moderate PD patients (5,197 patients), and severe PD patients (2,382 patients). Te prospective cohort study [12] by Sen et al. included healthy individuals, mild PD, moderate PD, and severe PD patients. Univariate analysis found that the severity of periodontitis was associated with a dose-response relationship with atrial fbrillation, but only severe PD signifcantly increased the risk of new-onset AF (HR 1.31, 95% CI 1.06-1.62) after adjusting for confounding factors. Struppek et al. [19] included healthy/mild PD, moderate PD, and severe PD patients in a cross-sectional study, and only severe PD was associated with new-onset atrial fbrillation (OR 1.66, 95% CI 1.16-2.36) in univariate analysis, and there was no signifcant correlation between various degrees of periodontitis and atrial fbrillation after adjusting for confounding factors.

Incidence of Atrial Fibrillation in Patients with Oral
Infammatory Disease. Four studies [12][13][14][15] reported the incidence of atrial fbrillation in patients with and without oral infammatory disease, among which three cohort studies [12][13][14] showed that the incidence of atrial fbrillation in PD patients was signifcantly higher than that in non-PD patients (Chang Y study: 3.29% vs. 3.01%; Sen S study: 14.39% vs. 11.80%; and Chen DY study: 2.07% vs. 1.57%). A retrospective cohort study [15] showed that the incidence of atrial fbrillation in patients with apical abscess was     International Journal of Clinical Practice signifcantly lower than that in patients without apical abscess (9.27% vs. 10.69%), but apical abscess was an independent predictor of new-onset atrial fbrillation after adjusting for confounders. In addition, a prospective cohort study [12] showed that the incidence of atrial fbrillation in healthy individuals, mild PD, moderate PD, and severe PD patients was 11.8%, 11.9%, 15.3, and 16.3%, respectively. A cross-sectional study [18] showed a higher prevalence of atrial fbrillation in men than in women among patients with severe PD at the same age, and the diference was particularly signifcant in older patients >65 years (29.1% vs. 19.7%), which has not been explicitly reported in other studies.

Prevalence of Periodontitis in Patients with Atrial Fibrillation.
A case-control study [18] by Im et al. reported the prevalence of PD in patients with atrial fbrillation; 47 of 227 (20.7%) patients with atrial fbrillation had PD. Atrial fbrillation patients with PD and without PD were followed up for an average of approximately 18 months, and arrhythmia events in PD patients were signifcantly higher than those in patients without PD (93.6% vs. 17.4%, P < 0.001). Multivariate analysis suggested that PD was an independent risk factor for arrhythmia and major adverse cardiac events during follow-up in patients with atrial fbrillation.

Efects of Regular Oral Care on Atrial Fibrillation.
Four studies [12][13][14]16] reported the efect of oral care on the occurrence risk of atrial fbrillation, among which two reported the positive efect of regular oral care in reducing the risk of atrial fbrillation [12,16]. Multivariate analysis by Chen et al. [16] suggested that dental scaling at least once a year for 3 consecutive years was associated with a lower risk of new-onset atrial fbrillation (HR 0.67, 95% CI 0.52-0.86). Univariate and multivariate analyses by Sen et al. [12] both indicated that compared with episodic users, regular dental care had a signifcantly lower risk of new-onset atrial fbrillation (adjusted HR 0.88, 95% CI 0.78-0.99). However, a univariate analysis by Chang et al. [13] found that regular professional dental cleaning signifcantly reduced the risk of atrial fbrillation (HR 0.87, 95%CI 0.81-0.93), but multivariate analysis did not suggest a signifcant association.

Efects of Tooth Brushing on Atrial Fibrillation.
Two studies reported the efect of tooth brushing frequency on the occurrence of atrial fbrillation [13,19], of which a cross-sectional study by Struppek [19] reported that the incidence of atrial fbrillation was 25%, 7.53%, and 7.12% in patients with diferent tooth brushing frequencies of once a week, once a day, and twice a day, respectively, and the advantage of ≥2/d tooth brushing to reduce the occurrence risk of atrial fbrillation was more signifcant in people aged ≥65 years. A retrospective cohort study by Chang [13] reported that the incidence of atrial fbrillation was 3.99%, 3.22%, and 2.51% in patients with diferent tooth brushing frequencies of 0-1/d, 2/d, and 3/d, respectively. Univariate and multivariate analyses showed that brushing frequency ≥3 times per day signifcantly reduced the risk of new atrial fbrillation (adjusted HR 0.90, 95% CI 0.83-0.98).

Heterogeneity Test and Publication
Bias. Due to the high heterogeneity of the included literature, a systematic review was conducted to describe the abovementioned outcome indicators in detail, without summary analysis for every outcome indicators. Te reasons for the high heterogeneity were as follows: there were few included studies under each outcome indicator, with diferent designs of studies included case-control studies, retrospective cohort studies, prospective cohort studies, and cross-sectional studies, large span of publication years, diferences in sample size, diferences in population characteristics, and diferent defnitions of outcome indicators (included only new-onset atrial fbrillation or new-onset atrial fbrillation and atrial futter). Te efect size was diferent (including HR/OR/RR after univariate/multivariate analysis) and the follow-up time was diferent. Sensitivity analysis, metaregression, and subgroup analysis were not performed. According to the NOS scale, the quality of cohort studies included in the present study was high. However, due to the small number of included studies and high heterogeneity under each outcome indicator, publication bias was not carried out, which may afect the results about the relationship between oral infammatory diseases and atrial fbrillation.

Discussion
Te purpose of this study was to evaluate the association between oral health and atrial fbrillation and evaluating the impact of regular oral care or tooth brushing on the occurrence risk of atrial fbrillation, as well as a systematic review of previous studies. Te studies included in this systematic review included eight clinical studies with a total of 4,328,355 patients, of which fve studies were large retrospective cohort studies [13][14][15][16][17], one was a prospective cohort study [12], one was a case-control study [18], and one was a cross-sectional study [19].

Relationship between PD, Oral Infammatory Diseases, and Atrial Fibrillation.
Previous studies have shown that the relationship between oral infammatory diseases such as PD and atrial fbrillation is inconclusive. Aoyama et al. [20] found that the detection rate of P. gingivalis in atrial fbrillation patients aged 71∼90 years was signifcantly higher than that in patients with bradyarrhythmia. Miyauchi et al. [21] found that serum anti-P. gingivalis antibody type IV was an independent predictor of atrial fbrillation recurrence after catheter ablation (OR 1.937, 95% CI 1.301-2.884, and 8 International Journal of Clinical Practice P � 0.002). Te abovementioned two studies [20,21] indirectly suggested that oral infammatory diseases such as PD may promote the occurrence, development, and recurrence of atrial fbrillation. Holm-Pedersen et al. [22] found that patients with one to two active coronal caries lesions had 2.8 times higher odds (95% CI 1.1-7.0) of arrhythmia than those without active coronal caries, but there was no association between arrhythmia and periodontal disease. And this study did not further analyze the relationship between active coronal caries, periodontitis, and atrial fbrillation. In the recent years, a number of large retrospective cohort studies and prospective cohort studies have suggested that oral infammatory diseases such as periodontitis may be associated with an increased risk of atrial fbrillation, but the causal relationship still needs to be further verifed. Tis study did not conduct a pooled analysis about the relationship between oral infammatory diseases and atrial fbrillation because few studies could be included, with a large span of publication years, large diferences in sample size, diferent design (included retrospective cohort study, prospective cohort study, and cross-sectional study), diferent outcome indicators (only recurrence of atrial fbrillation and recurrence of atrial fbrillation/atrial futter), adjusted confounding factors, and varying follow-up time [12][13][14][15][16][17][18][19]. In addition, diferent characteristics of the study population may also afect the results of the study. For example, the prevalence rate of new-onset atrial fbrillation of male patients may be higher than that of female patients, and the prevalence rate of the elderly patients is signifcantly higher [18]. Te diferences of underlying diseases may also afect the results, such as heart failure, diabetes, chronic kidney disease, and coronary artery disease. A Mendelian randomization study, which intended to verify the causal relationship between PD and cardiovascular diseases, such as atrial fbrillation, showed that there was no causal relationship between dental caries, PD, and cardiovascular diseases such as atrial fbrillation, and the correlation between PD and atrial fbrillation may be related to the common etiological pathway in the investigation study [23]. PD shared the same genetic and environmental risk factors with cardiovascular diseases such as atrial fbrillation and hypertension [24]. Although confounding factors were adjusted in the abovementioned studies, it cannot be ruled out that other potential confounding factors may have infuenced the study results. Genetic polymorphisms, a possible confounding factor that is very difcult to control for, could increase the predisposition to atrial fbrillation and other cardiovascular diseases [25,26]. Combined with the current research results, it is not easy to conclude whether PD and other oral infammatory diseases afect the risk of new-onset atrial fbrillation. Future research is still needed to clarify the potential confounding factors between PD and atrial fbrillation, and more rigorous longitudinal studies will be needed to evaluate the association and specifc causal relationship between oral infammatory diseases such as PD and new-onset atrial fbrillation.
Sen et al. [12] revealed that severe PD signifcantly increased the occurrence risk of atrial fbrillation (RR � 1.31, 95% CI 1.06-1.62, P � 0.01). Tis fnding was supported by the results of Struppek et al. [19], which also found that the atrial fbrillation incidence in male was higher than in female. Only one prospective cohort study and one crosssectional study elaborated the relationship between severe PD and atrial fbrillation in this review. However, considering that approximately 10% of the global population sufers from severe PD [8], approximately 16.3% of severe PD is associated with atrial fbrillation [12]. Terefore, more attention should be given to the occurrence risk of atrial fbrillation with severe PD. In the future, more large prospective studies are needed to evaluate the impact of different degrees of PD and other oral infammatory diseases on the occurrence risk of atrial fbrillation. In addition, a cross-sectional study [18] suggested that the prevalence of new-onset atrial fbrillation in PD patients increases with age, and male patients at the same age were more likely to develop atrial fbrillation. Advanced research will be needed to evaluate the efects of severe PD on atrial fbrillation in diferent ages and sexes. In clinical practice, elderly male patients with severe PD should be considered.

Efects of Tooth Brushing and Oral Care on Atrial
Fibrillation. Other important fndings were that compared with long-term nonbrushing or tooth brushing <3/d, longterm ≥3/d tooth brushing signifcantly improved the occurrence risk of atrial fbrillation; compared with no oral hygiene or occasional oral hygiene, regular dental cleanings or oral care ≥1/year could signifcantly reduce the occurrence risk of atrial fbrillation. Although the current studies have not confrmed the correlation and causality between oral health and atrial fbrillation, the positive efect of oral care in reducing the risk of atrial fbrillation suggests that a better oral environment appears to be benefcial in improving the occurrence of atrial fbrillation. Te current study found the advantages of tooth brushing and oral care in improving new-onset atrial fbrillation but failed to confrm whether brushing frequency ≥3 times per day and oral hygiene at diferent frequencies had inconsistent efects on new-onset atrial fbrillation. In addition, Chen et al. [14] reported that dental cleanings 0-2/year were a protective factor for atrial fbrillation compared with patients without oral care (HR 0.39, 95% CI 0.38-0.41), but dental cleanings >2/year were a risk factor for atrial fbrillation (HR 6.06, 95% CI 5.38-6.83). Tis may be associated with preexisting periodontitis in patients with dental cleanings >2/year or recall bias in self-report questionnaires [27]. Abovementioned results may suggest that proper oral hygiene appears to be important in improving the risk of atrial fbrillation, but the fndings still need to be further validated in future studies, and more rigorous large-scale prospective studies are needed to explore the relationship between diferent frequency of oral care and the incidence of atrial fbrillation.
In addition, Omori et al. [28] showed that in hospitalized patients with heart disease complicated with periodontitis, six-step oral hygiene enhancement can improve the occurrence of atrial fbrillation after cardiac surgery. All of the abovementioned studies [12-14, 16, 19, 28] suggested that International Journal of Clinical Practice regular tooth brushing and oral care had an advantage in improving the occurrence and recurrence of atrial fbrillation. Terefore, the importance of long-term tooth brushing and oral hygiene should be emphasized in clinical practice and health promotion. At the same time, more studies are needed in the future to confrm the impact of diferent tooth brushing frequencies or oral care on the occurrence and recurrence of atrial fbrillation and whether high-frequency oral care increases the risk of atrial fbrillation.

Conjecture about Related Underlying Mechanisms.
Although the causal relationship between PD and atrial fbrillation remains unclear, studies have shown that oral pathogens and infammatory mediators may increase the occurrence risk and recurrence risk of atrial fbrillation, and the underlying mechanisms are as follows: First, regarding the role of oral pathogens, the oral cavity is a reservoir for many kinds of bacteria and microorganisms, and P. gingivalis can release lipopolysaccharide, downregulate the expression of L-type calcium channels in cardiomyocytes, and shorten the atrial efective refractory period [29]. P. gingivalis can increase the expression of tolllike receptor 2 (TLR-2) [30] and toll-like receptor 4 (TLR-4) [31], which can induce atrial fbrosis [32], reduce the transient outward potassium ion current [33], promote atrial structural remodeling and electrical remodeling, and increase the occurrence risk and recurrence risk of atrial fbrillation. Aggregator actinomycetes could promote infammatory cell infltration and induce cardiac remodeling, which may play an important role in increasing the occurrence risk of atrial fbrillation [34]. Second, regarding the roles of infammatory mediators and systemic infammation, periodontal disease could cause a persistent infammatory response or bacteremia, release infammatory mediators such as C-reactive protein and interleukin-6, stimulate myocardial cell hypertrophy and apoptosis, promote myocardial fbrosis, and shorten the atrial efective refractory period, which could increase the occurrence risk and recurrence risk of atrial fbrillation [35]. As the main virulence factor of P. gingivalis, fmbriae can regulate bacterial adhesion and invasion and stimulate a long-term chronic infammatory response, inhibit interleukin-12 expression, and reduce the host's ability to clear infammation [36]. Tird, regarding immune response, periodontal pathogens can stimulate the release of large amounts of matrix metalloproteinases (MMPs) from lymphocytes and promote the occurrence of cardiovascular diseases [37]. In addition, antibodies against heat shock protein 60 (HSP-60) expressed by periodontal pathogens can cross-react with hSP-60 in the host body to activate T cells, leading to endothelial damage and atherosclerotic plaque formation and mediating cardiovascular disease [38]. However, whether MMPs or HSP-60-related immune responses of periodontal pathogens play important roles in atrial fbrillation remains unclear.
Regular tooth brushing and oral hygiene could reduce the colonization and accumulation of pathogenic bacteria, reduce the levels of C-reactive protein, interleukin-6, and other infammatory mediators, and reduce the systemic infammatory response [39], which may play important roles in preventing the occurrence and development of atrial fbrillation. Some studies have shown that periodontal therapy can alleviate elevated blood pressure, decrease white blood cell count and oxidative stress response, and reduce the expression of MMPs [40]. In addition, periodontal treatment can reduce serum total cholesterol, low-density lipoprotein, oxidized low-density lipoprotein, and other lipid levels [23]. Te role of these mechanisms in preventing the occurrence and progression of atrial fbrillation remains unclear.

Summary and Outlook.
At present, considering the high recurrence rate and the high risk of thromboembolism after the occurrence of atrial fbrillation, the guidelines for atrial fbrillation gradually focus on the primary prevention of atrial fbrillation. To evaluate the efects of diferent degrees of PD, oral hygiene, and tooth brushing on the risk of atrial fbrillation, this study included clinical studies related to oral infammatory diseases such as PD, oral care, and atrial fbrillation. Eight clinical trials were included based on multiple database searches, and studies have shown that PD and other poor oral health condition may increase the risk of atrial fbrillation, of which severe PD has the highest risk, but the correlation and causality remained to be further verifed. Patients with better oral health seemed to have a positive impact on preventing AF or reducing AF recurrence. Regular and moderate oral care and tooth brushing 2-3 times per day are efective measures for improving oral health and preventing AF. Oral health and oral disease prevention should be an important part of preventing newonset atrial fbrillation. It is recommended to strengthen oral health publicity in future atrial fbrillation-related education.

4.5.
Limitations. Te limitations of this study are as follows: (1) Most included studies were retrospective cohort studies and cross-sectional studies, and the strength of the causal relationship was limited. (2) Te number of included studies was limited, pooled analysis was not conducted due to the heterogeneity of the studies, and the validation strength was limited. (3) Te correlation between tooth brushing frequencies of ≥3/d and higher and atrial fbrillation has not been determined. (4) Te relationship between oral care ≥2/ year and atrial fbrillation remains uncertain. (5) Te relationship between antibiotic prevention of periodontal infection and atrial fbrillation is not clear. (6) Te relationship between gargling or other forms of oral care and atrial fbrillation was also not included in the analysis.

Conclusion
Regular and moderate oral care, moderate frequent tooth brushing, and prevention of PD and other oral infammatory diseases may be benefcial in reducing the occurrence and recurrence of atrial fbrillation. It is recommended to strengthen the popularization of oral health knowledge in the publicity related to atrial fbrillation.

Data Availability
Te original contributions presented in the study are included within the article in the Supplementary Material section (Supplementary Table S1: Retrieval strategies used to flter literatures in Medline, Embase, Web of Science, and Cochrane Library), and further data can be obtained from the corresponding author upon request.

Conflicts of Interest
Te authors declare that there are no conficts of interest.