Periodontal disease as a non-traditional risk factor for acute coronary syndrome: a systematic review and meta-analysis

SUMMARY

Objectives

Previous observational studies have suggested an association between periodontal disease (PD) and cardiovascular and cerebrovascular diseases. Nonetheless, evidence linking PD with coronary heart disease (CHD) and acute coronary syndrome (ACS) is still contradictory. We aim to systematically review the role of PD as a risk factor for ACS (myocardial infarction and unstable angina).

Methods

The protocol was registered in PROSPERO (CRD42021286278) and we followed the recommendations of the PRISMA and AMSTAR 2 guidelines. We systematically searched for 7 databases and electronic thesis repositories from inception to February 2022. We included articles without language restriction following the PECO strategy (population: “adult participants”; exposure: “periodontal disease”; comparator: “no periodontal disease”; outcome: “acute coronary syndrome” OR “acute myocardial infarction” OR “unstable angina”). Odds ratios (OR) with 95% confidence intervals (95% CI) were pooled using random effects and heterogeneity was quantified by Cochran’s Q and Higgins’ I² statistics. Subgroup analyses were carried out according to the participants’ sex, type of diagnosis of PD, type of study, and continent of origin of studies.

Results

We included 46 papers (17 cohort, 25 case-control, and 4 cross-sectional studies) that met the inclusion criteria. This meta-analysis includes a total of 6,806,286 participants and at least 68,932 ACS events, mainly myocardial infarction (MI). In accordance with our results, PD is associated with a higher risk of ACS (OR 1.35; 95% CI 1.25–1.45). However, clinical and methodological heterogeneity was significant (I²=86%, p<0.05). In the sensitivity analysis, the exclusion of some studies with “extreme” results (outliers) did not significantly affect the overall estimate or heterogeneity. In subgroup analysis, we found no statistically significant differences between men and women according to subgroup difference tests (I²=0%, p=0.67). Conversely, there were differences according to the type of diagnosis of PD (clinical or self-reported diagnosis), type of study (cohort, case-control, or cross-sectional study), and the continent of origin (North America, South America, Asia, or Europe) of the studies (I²=79%–96%, p<0.10). Of the 46 studies, only 4 had a high risk of bias. Additionally, the funnel plot suggested publication bias.

Conclusion

PD may be an important non-traditional risk factor for ACS. Although, this meta-analysis brings together more studies, and therefore more evidence, than any other previous similar study, its results should be interpreted with caution due to the great heterogeneity and the potential presence of bias.

INTRODUCTION

Since the 1990s, an association has been reported between periodontal disease (PD) and some systemic diseases such as rheumatoid arthritis, premature birth, low-birth weight, and cardiovascular and cerebrovascular diseases [1, 2]. The latter two diseases deserve special attention because they are the main causes of morbidity and mortality around the world [3]. PD could contribute to the onset of various diseases, either through direct infection by periodontal pathogens or indirectly through chronic inflammation [4].

PD is defined as a multifactorial chronic immuno-inflammatory disease that affects the supporting structures of the teeth (periodontium). Symptoms include: gingivitis, gingival pocket formation, periodontitis, tooth mobility, tooth loss, and ultimately edentulism. PD is present in more than 50% of the general population, making it one of the most common chronic diseases [5, 6]. PD contributes to the global burden of cardiovascular diseases, which in turn are responsible for 80% of deaths worldwide [7]. Cardiovascular diseases (CVD) patients also have PD more frequently; however, the results vary according to the periodontal indicator, the cardiovascular clinical entity and the follow-up time [1, 3, 8, 9].

Patients with acute coronary syndrome (ACS) - which includes MI with or without ST-segment elevation and unstable angina - have a high prevalence of PD and its most severe forms [2, 8, 9]. However, evidence linking PD with coronary heart disease (CHD) is still scarce and contradictory, since there are studies that have not confirmed this association [10, 11]. Therefore, there is a need to systematically review the role of PD as a risk factor for ACS.

MATERIALS AND METHODS

The protocol was registered in PROSPERO (CRD42021286278) and we followed the recommendations of the PRISMA and AMSTAR 2 guidelines [12, 13]. We carried out a meticulous search for randomized clinical trials (RCTs), observational (cohort, case-control, and cross-sectional) studies, systematic reviews, and theses published until February 28, 2022. Electronic searches were accomplished in Medline via PubMed, Google Scholar, Scopus, ScienceDirect, EMBASE, Web of Science and digital thesis repositories. We combined different keywords, controlled vocabulary terms (i.e., medical sub-heading MeSH and Emtree terms) and free terms, using Boolean operators and synonyms according to the PECO strategy (population: “adult participants”; exposure: “periodontal disease”; comparator: “no periodontal disease”; outcome: “acute coronary syndrome” OR “acute myocardial infarction” OR “unstable angina”) (Supplementary material, Table S1).

We included articles in full text and abstract. The search was not limited by the year or language of publication. We excluded case reports, case series, studies not available in full text, duplicated publications, and studies with pediatric patients (<18 years). Articles were assessed by five independent, blinded reviewers, and discrepancies were resolved by a sixth reviewer. References from retrieved articles and narrative or systematic reviews were screened for additional articles. The study selection process is detailed in Figure 1.

Figure 1.

Flow chart of the selection process of the primary studies included.

The articles found were analyzed using the terms of the PECO strategy and the inclusion and exclusion criteria. Relevant data from each article were extracted and recorded in a spreadsheet: name of authors, year and country of publication, type of study, number of patients, number of events, measure of association, and adjusted confounders.

In the meta-analysis, we combined adjusted odds ratios (OR), relative risks (RR), or Hazard ratios (HR) with their respective 95% confidence intervals (95% CI) following the generic inverse variance method. The statistical heterogeneity among studies was assessed using the p-value of the Cochrane Q test and the Higgins I² statistic [14]. Since the heterogeneity was significant (p-value <0.05 and I² statistics >40%) we performed a random effects analysis. We addressed significant heterogeneity according to the recommendations of the Cochrane Handbook. The quantitative synthesis was represented by forest plots. We carried out sensitivity and subgroup analyses. The risk of bias was assessed using the Newcastle-Ottawa scale (NOS) tool and publication bias was examined using a funnel plot [14, 15].

RESULTS

We collected a total of 254 articles; 156 in the primary search and 98 in the secondary search. After eliminating duplicates, 85 publications remained which were evaluated in title and abstract. Subsequently, 56 articles remained that were analyzed in full text, of which 46 papers were selected for qualitative and quantitative assessment. We only included studies that reported association measures - odds ratios (OR), relative risks (RR), and hazard ratios (HR) - adjusted for at least two of the main cardiovascular risk factors. Of the ten excluded studies, five articles were found in PubMed, three articles were found in Scopus, and two papers were found in EMBASE. Lack of adjustment for confounders was the main cause for the exclusion of primary studies (Table S2, Supplementary material). We combined data from individual studies using the generic inverse variance method, entering the effect size adjusted for the greatest number of potential confounding variables for which results were available and the 95% CI.

This meta-analysis included a total of 6,806,286 participants and at least 68,932 ACS events, mainly MI. Of the 46 included studies, 17 were cohort studies, 25 were case-control studies, and 4 were cross-sectional studies. The follow-up period was variable (from 2 months to 21 years) (Table S3, Supplementary material).

According to our results, PD is associated with a higher risk of ACS (OR 1.35; 95% CI 1.25–1.45) (Figure 2A–D); however, the heterogeneity was significant (I²=86%, p<0.05). In the sensitivity analysis, the exclusion of some studies with “extreme” results (outliers) did not significantly affect the overall estimate or heterogeneity.

Figure 2A.

Forest plot on the effect of periodontal disease on acute coronary syndrome according to the type of study design.

Figure 2B.

Forest plot on the effect of periodontal disease on acute coronary syndrome according to continent of origin of the study.

Figure 2C.

Forest plot the effect of periodontal disease on acute coronary syndrome according to type of diagnosis.

Figure 2D.

Forest plot on the effect of periodontal disease on acute coronary syndrome according to gender.

Tests for subgroup differences showed statistically significant differences according to the type of study design (I²=95.4% and p<0.10). The association between PD and ACS was stronger in case-control studies (OR 2.62; 95% CI 2.05–3.55), followed by cohort studies (OR 1.13; 95% CI 1.05–1.21), and was not significant in cross-sectional studies (OR 1.67; 95% CI 0.79–3.50). In the sensitivity analysis, excluding cross-sectional studies did not significantly alter the overall estimate or heterogeneity (Figure 2A).

Similarly, we found statistically significant differences between subgroups according to the continent of origin (I²=92% p<0.10). The risk of ACS in patients with PD was statistically significant in studies conducted in South America (OR 4.43; 95% CI 2.39–8.23), Europe (OR 1.92; 95% CI 1.59–2.31), and North America (OR 1.30; 95% CI 1.16–1.46) and was not significant in the studies conducted in Asia (OR 1.09; 95% CI 0.96–1.25). In the sensitivity analysis, excluding Asian studies did not significantly affect the overall heterogeneity estimate (Figure 2B).

Similarly, subgroup analysis showed that the association between PD and ACS was greater in those studies that measured exposure (PD) based on clinical diagnosis (OR 1.38; 95% CI 1.28–1.50) compared to self-reported PD (OR 1.20, 95% CI 1.08–1.33). Tests for subgroup differences confirmed these differences (I²=78.9%, p<0.10). When performing the sensitivity analysis, excluding studies in which the diagnosis of PD was made by self-report, the overall estimate and heterogeneity did not change significantly (Figure 2C).

In contrast, we found no statistically significant differences between men and women according to subgroup difference tests (I²=0%, p=0.67); however, the risk of ACS associated with PD was lower in men (OR 1.48; 95% CI 1.11–1.97), compared to women (OR 1.96; 95% CI 0.62–6.17), although the latter estimate was not significant (Figure 2D). Of the 46 included studies, 42 had a low risk of bias and 4 high risk of bias according to the NOS tool (Table 1) [15]. The funnel plot diagram suggests significant publication bias (Figure 3).

Table 1.

Bias assessment of the included primary studies.

Author	Study design	Tool	Selection	Comparability	Outcome	Total	Conclusion
Starkmammart 2008 [16]	CC	NOS	***	**	**	7	Low risk
Andriankaja 2006 [17]	CC	NOS	***	**	**	7	Low risk
Andriankaja 2007 [18]	CC	NOS	***	**	**	7	Low risk
Rech 2007 [10]	CC	NOS	***	**	**	7	Low risk
Geerts 2004 [19]	CC	NOS	***	**	**	7	Low risk
Geismar 2006 [46]	CC	NOS	***	**	**	7	Low risk
Briggs 2006 [20]	CC	NOS	***	**	**	7	Low risk
Noguchi 2015 [51]	RC	NOS	****	*	**	7	Low risk
Holmlund 2017 [67]	PC	NOS	****	**	**	8	Low risk
Hansen 2016 [68]	RC	NOS	****	**	**	8	Low risk
Lee 2017 [44]	PC	NOS	****	**	**	8	Low risk
Lee 2015a [70]	RC	NOS	****	**	**	7	Low risk
Lee 2015b [71]	RC	NOS	***	**	**	7	Low risk
Yu 2015 [33]	RC	NOS	***	**	**	7	Low risk
Dorn 2010 [45]	RC	NOS	****	**	**	8	Low risk
Liljestrand 2015 [35]	RC	NOS	****	**	**	8	Low risk
Lee 2019 [34]	RC	NOS	***	**	**	8	Low risk
Morrison 1999 [72]	RC	NOS	****	**	**	8	Low risk
DeStefano 1993 [69]	PC	NOS	****	**	**	8	Low risk
Arbes 1999 [52]	CS	NOS	****	*	*	6	High risk
Holmlund 2006 [74]	CS	NOS	****	*	*	6	High risk
Parkar 2013 [53]	CS	NOS	****	*	*	6	High risk
Bazile 2002 [73]	CS	NOS	****	*	*	6	High risk

CC: case-control study; PC: prospective cohort study; RC: retrospective cohort study; CS: cross-sectional study.

Note: an asterisk (*) represents a star in each domain of the Newcastle–Ottawa scale (NOS) tool.

Figure 3.

Funnel plot of the 46 included studies.

DISCUSSION

According to the present study, PD is associated with a 35% increased risk of developing ACS compared to those without PD (OR 1.35; 95% CI 1.25–1.45) (Figure 2A–D). These findings are consistent with other primary studies [16–35] and meta-analyses [8, 27, 36–39]. Although, some studies had not found any association between PD and ACS [34, 40–45], and other studies have reported mixed results depending on the definition of PD or ACS used [11, 46–53]. The authors of a systematic review even concluded that the evidence linking PD and ACS was insufficient [54].

In concordance with our analysis, the risk of ACS in patients with PD is consistent between men and women, but it differs significantly according to the study design (cohort, case-control, or cross-sectional), the continent of origin of the study (South America, North America, Asia, or Europe), and the type of PD diagnosis (clinical diagnosis or self-report). In the sensitivity analysis performed to determine the effect of these factors (type of study, continent, type of diagnosis, and gender) on the risk of ACS, they did not significantly affect the overall estimate, which suggested it was viable to combine them in a meta-analysis.

Blaizot et al. performed a meta-analysis to assess the association between periodontitis and CVD (CHD, angina pectoris, MI, and mortality from cardiac disease) [55]. They explored seven databases and included observational studies. The combination of 25 cross-sectional and case-control studies showed severe statistical heterogeneity (Q=195.56, p<0.0001, I²=87.7%), which was significantly reduced (Q=41.88, p=0.0044, I²=49.9%) by excluding three studies. The combination of seven cohort studies into a meta-analysis gave low statistical heterogeneity (Q=11.66, p=0.39, I²=5.6%) and showed that patients with severe PD had an increased risk of CVD (RR 1.34; 95% CI 1.27–1.42). A similar trend was found with the combination of a meta-analysis of the 22 case-control and cross-sectional studies (OR 2.35; 95% CI 1.87–2.96). Blaizot et al. performed a separate meta-analysis for each group of studies (i.e., a meta-analysis of cohort studies and a meta-analysis of case-control and cross-sectional studies). However, it would be most appropriate to carry out a subgroup analysis showing in a single forest plot a separate diamond for each subgroup and an overall diamond for the estimate of the joint effect, presenting an interaction test to understand if the effect varies between the two subgroups [14].

Coelho et al. sought to determine the association between PD and ischemic cardiovascular events (ICVE) in a meta-analysis [27]. Three databases were searched for case-control studies published between 1999 and 2009, which had diagnosed PD according to clinical parameters including probing depth and/or clinical attachment level. ICVE were represented by coronary artery disease (CAD), MI with or without angina pectoris, or ACS. The authors combined 16 case-control studies into a meta-analysis and found that individuals with PD have an increased chance of developing ICVE compared to those without PD (OR 2.52; 95% CI 2.109–3.009, p<0.001). They performed subgroup and sensitivity analyses. The authors concluded that further studies are required to draw definitive conclusions.

Xu et al. performed a meta-analysis of observational (cohort, case-control, and cross-sectional) studies to assess the association between PD and MI [8]. They searched 3 databases up to July 2016 and identified 4 cohort, 6 cross-sectional, and 12 case-control studies, including 129,630 participants. They found that patients with PD have an increased risk of MI (OR 2.02; 95% CI 1.59–2.57), although they found substantial heterogeneity. They performed sensitivity and subgroup analyses to identify the source of heterogeneity and assessed potential publication bias. The subgroup analysis showed a higher risk of MI in patients with PD in the case-control (OR 2.93; 95% CI 1.95–4.39) and cross-sectional studies (OR 1.71; 95% CI 1.07–2.73) and this association was not significant in the cohort studies (OR 1.18; CI 95% 0.98–1.42). In addition, subgroup analysis by location (Americas, Europe, or Asia), EP exposure (PIC or others), study quality (high or low-moderate), and the number of participants (>1000 or <1000) showed that PD was significantly associated with a high risk of MI.

A problematic issue of the three meta-analyses discussed above is that they combined crude and adjusted effect sizes (OR and RR) [8, 27, 55]. A meta-analysis is a method primarily designed to combine effect sizes from RCTs, where confounders and biases have been controlled for by the randomization process. A meta-analysis of observational (non-randomized) studies has this limitation, which could be overcome by including only adjusted effect sizes [14]. Pooling unadjusted results is simpler but not more informative than the results of univariate analysis of the original observational studies [56]. The Cochrane manual recommends using the estimation of the model that includes the greatest number of confounding factors, since if unadjusted results are combined, a large effect could be seen that, when controlled for these covariates, could be reduced or even disappear [14, 57].

Bodanese et al. analyzed the association between periodontitis and MI [36]. They systematically searched eight databases and gray literature for observational studies published up to October 2018. They combined four (two cross-sectional and two cohort) studies in a meta-analysis, including 1,035,703 individuals. They reported that periodontitis was associated with a high risk of MI (RR 5.99; 95% CI 1.17–30.68), but the heterogeneity was high (I²=100%; p<0.01). Excluding a cross-sectional study, the risk of MI in patients with periodontitis remained high (RR 2.62; 95% CI 1.47–4.70), but the heterogeneity was still significant (I²=85.5%; p<0.01). The authors concluded that their study demonstrated an association between periodontitis and MI, but with a high heterogeneity level. We note some concerns about the study by Bodanese et al. First, the association measure was not adequate (they reported RR in a meta-analysis that combined cross-sectional and cohort studies). Second, although they performed sensitivity analyses, they did not perform subgroup analyses to assess the cause of the high heterogeneity. Third, publication bias was not analyzed.

Larvin et al. examined in a meta-analysis the risk of incident CVD in patients with and without PD [38]. They searched three databases for studies published up to October 2019. CVD outcomes were any CVD, MI, and stroke. They included 32 cohort studies, of which 30 were combined into a meta-analysis. They found that CVD risk was significantly higher in patients with PD compared to those without PD (RR 1.20; 95% CI 1.14–1.26). CVD risk did not differ between self-reported and clinically diagnosed PD (RR=0.97; 95% CI 0.87–1.07). CVD risk was higher in men (RR 1.16; 95% CI 1.08–1.25) and in those with severe PD (RR 1.25; 95% CI 1.15–1.35). Among all types of CVD, the risk of stroke was higher (RR 1.24; 95% CI 1.12–1.38), followed by CAD (RR 1.14; 95% CI 1.08–1.21). The authors concluded that their study demonstrated a modest but consistently increased risk of CVD in PD populations. Some of these findings conflict with our results, because according to our meta-analysis, the risk of ACS does not differ significantly by gender, but it does by the type of diagnosis (clinical or self-reported). However, Larvin et al. included studies with very varied outcomes in addition to ACS, such as tachyarrhythmias, stroke, PAD, and any CVD. Therefore, our results are not directly comparable.

Dietrich et al. conducted a study to systematically review the epidemiological evidence on the association between clinically or radiologically diagnosed PD and incident atherosclerotic CVD, CAD, cerebrovascular disease, and peripheral arterial disease (PAD) [58]. They included 12 cohort or case-control studies: six studies on CAD, three studies on cerebrovascular disease, two on both CAD and cerebrovascular disease, and one study on PAD. The authors included only studies that at least controlled for confounding effects of age and gender, either by design (restriction) or by statistical analysis (stratification/adjustment). All but one study reported a positive association between various measures of PD and incident atherosclerotic CVD, at least in specific subgroups. The association was the strongest in young adults, and they found no evidence of an association between periodontitis and incident CAD in patients >65 years old. The investigators concluded that there was evidence of an increased risk of incident atherosclerotic CVD in patients with periodontitis compared to those without periodontitis; however, these findings could not apply to all population groups. The authors did not perform a meta-analysis due to significant heterogeneity among studies. In our meta-analysis, we tried to overcome the limitations reported by Dietrich et al., including studies whose exposure was PD, delimiting the result only to ACS (MI or unstable angina), and including studies that reported adjustment of confounders, even though the heterogeneity in our study was significant.

Qin et al. performed a meta-analysis seeking to assess the association between PD and MI [39]. They systematically searched three databases for studies published up to August 2020, finding a total of ten cohort studies including 5,369,235 participants. The meta-analysis showed an increased risk of MI in patients with PD (RR 1.13; 95% CI 1.04–1.21), although there was statistically serious heterogeneity between the studies (I²=78.0%). According to the authors, in the sensitivity analysis this result was robust. Subgroup analysis indicated that the results were affected by gender (female or male), effect value (OR, RR, or HR), study quality (moderate or high), the form of the survey (questionnaire or no-questionnaire), and the type of research (prospective or retrospective). They also examined the possibility of publication bias. It is worthy to note that the authors only combined studies that adjusted for potential confounders. The authors concluded that their meta-analysis suggested that PD is modestly associated with MI, especially in women. From the methodological point of view, the meta-analysis by Qin et al. is the most comparable to ours:

1. they only included studies adjusting for potential confounders;

2. they performed subgroup, sensitivity, and publication bias analyses;

3. the exposure (PD) and outcome (MI) were very similar to ours;

4. they included a measure of association consistent with the type of studies included (OR).

Therefore, this would explain why their results are very similar to ours, including the finding that the association between PD and ACS would be stronger in women than in men.

Various direct and indirect mechanisms have been proposed to explain the association between PD and ACS [59–62]. Periodontitis is a chronic pathology resulting from the colonization of dental surfaces by microorganisms, which induces a local, systemic, and immune-inflammatory reaction. This response causes destruction of the periodontal tissues and rupture of their protective epithelial barrier. As a result, periodontal pathogens and their endotoxins enter the bloodstream and attack tissues distant from the oral cavity [59, 60]. The systemic inflammatory response can trigger cytokine release; increase plasmatic levels of leukocytes, fibrinogen, C-reactive protein, prothrombotic antibodies (anticardiolipin), and cell adhesion molecules; and even increase the synthesis of metalloproteinases, reactive oxygen species, and lipoproteins. All these lead to the recruitment and proliferation of inflammatory cells such as T lymphocytes and macrophages. In addition, the entry of microorganisms into endothelial cells and platelets can cause endothelial dysfunction, platelet aggregation, hypercoagulability, and changes in pre-existing atheromatous plaques, contributing to their instability and increasing the risk of thromboembolic events [35, 61–63].

Although the evidence linking PD and ACS there seems to be strong, the question if PD treatment could reduce the cardiovascular risk and the incidence of ACS remains unsolved. Some studies reported that periodontal treatment positively affects some clinical and biochemical parameters in patients with CHD such as pulse, respiratory rate, blood pressure, C-reactive protein, lipid profile, white blood cell count, IL-6, and IL-8 [75, 76]. However, randomized clinical trials have failed to show that periodontal treatment influences the risk of adverse or serious adverse events in a population with a history of cardiovascular disease [77, 78].

We highlight some strengths of this study:

1. our search strategy was broad;

2. we included the most recent and relevant evidence covering a greater number of studies, participants, and events than any other previous review;

3. we included primary studies that specifically examined the association of PD and ACS, excluding studies that only evaluated intermediate outcomes;

4. we only included studies that reported adjusted effect sizes.

We also found some important limitations:

1. We did not perform subgroup analysis according to PD severity because of the diversity of definitions of PD severity.

2. Although we performed subgroup, sensitivity, and publication bias analyses, the source of the heterogeneity was not entirely clear, but is probably explained by varying definitions of exposure and outcome, and different adjustments of confounders. It is possible that a meta-regression analysis could explain further the origin of the heterogeneity, although we did not perform this analysis due to limited data.

3. We did not perform subgroup analyses according to the smoking status given the scarcity of studies that included smokers and non-smokers separately.

In conclusion, this study shows that PD would be a non-traditional risk factor for developing ACS. Our results support the hypothesis that chronic inflammation caused by PD is involved in the pathogenesis of atherosclerosis and ACS. Given the high prevalence of PD in the population, this would have a profound impact on public health, health policy and clinical specialties, such as cardiology and neurology [5, 6]. Therefore, maintaining adequate periodontal health could be an effective measure to reduce the risk of ACS. However, our results should be taken with caution due to the quality of the evidence and the heterogeneity of the studies.

Supplementary Information

Table S1.

Search strategy

1. MEDLINE VIA PUBMED		Results	Date
#1	“Periodontal Diseases” [Mesh]	92,961	10/February/2022
#2	“Acute Coronary Syndrome” [Mesh]	18,845
#3	#1 AND #2	22
#4	Search: (“Periodontal Diseases” [Mesh]) AND “Acute Coronary Syndrome”[Mesh] Filters: Clinical Trial, Meta-Analysis, Randomized Controlled Trial, Review, Systematic Review Sort by: Most Recent	2

2. GOOGLE SCHOLAR		Results	Date
#1	All in title “periodontal disease”	40	22/February/2022
#2	All in title “acute coronary syndrome”	32
#3	#1 AND #2	1

3. SCOPUS		Results	Date
#1	TITLE-ABS-KEY (‘periodontal AND disease’)	77,822	28/February/2022
#2	TITLE-ABS-KEY (‘acute AND coronary AND syndrome’)	71,653
#3	#1 AND #2	91

4. SCIENCE DIRECT		Results	Date
#1	“periodontal disease”	32,256	25/February/2022
#2	“acute coronary syndrome”	73,093
#3	#1 AND #2	304
#4	#3: Refine by: Article type, Subject areas.	70

5. EMBASE		Results	Date
#1	‘periodontal disease’/exp	120,263	26/February/2022
#2	‘acute coronary syndrome’/exp	68,575
#3	#1 AND #2	145
#4	#1 AND #2 AND ([article]/lim OR [article in press]/lim OR [conference abstract]/lim OR [conference paper]/lim OR [conference review]/lim OR [letter]/lim OR [review]/lim OR [preprint]/lim)	32

6. WEB OF SCIENCE		Results	Date
#1	“periodontal disease” (Title)	4,554	25/February/2022
#2	“acute coronary syndrome” (Title)	16,474
#3	#1 AND #2	5

Table S2.

List of excluded studies

Author	Year	Títle	DOI	Journal	Reason for exclusion
Stein JM et al.	2009	Clinical periodontal and microbiologic parameters in patients with acute myocardial infarction.	10.1902/jop.2009.090170.	J Periodontol.	The main outcome was to evaluate the impact of Porphyromonas gingivalis (Pg) on myocardial infarction.
Accarini R et al.	2006	Doença periodontal como potencial fator de risco para síndromes coronarianas agudas	https://doi.org/10.1590/S0066-782X2006001800007	Arq. Bras. Cardiol.	Confounders adjustment are not reported.
Latronico M et al.	2007	Periodontal disease and coronary heart disease: an epidemiological and microbiological study	-	New Microbiol.	Confounders adjustment and effect measures are not reported.
Samani MK et al.	2013	The relationship between acute myocardial infarction and periodontitis	-	Caspian J Intern Med.	Confounders adjustment are not reported.
Lipari ZV et al.	2004	Periodontitis como factor de riesgo en pacientes con enfermedad aterosclerótica aguda y crónica.	-	KIRU	Confounders adjustment are not reported.
Mohitey J et al.	2012	Case control study to assess association between periodontal infection and coronary heart disease.	-	JKIMSU	Confounders adjustment are not reported.
Renvert et al.	2010	Periodontitis: A Future Risk of Acute Coronary Syndrome? A Follow-Up Study Over 3 Years.	10.1902/jop.2010.090105.	J Periodontol.	Confounders adjustment are not reported.
Mattila et al.	1995	Dental Infection and the Risk of New Coronary Events: Prospective Study of Patients with Documented Coronary Artery Disease.	10.1093/clinids/20.3.588.	Clin Infect Dis.	Effect measures are not reported.
Buhlin et al.	2002	Oral health and cardiovascular disease in Sweden: Results of a national questionnaire survey.	10.1034/j.1600- 051x.2002.290312.x	J Clin Periodontol.	Confounders adjustment are not reported.
Senba et al.	2008	The Association between Self- reported Periodontitis and Coronary Heart Disease — From MY Health Up Study—	10.1539/joh.l7066.	J Occup Health.	Confounders adjustment are not reported.

Table S3.

General characteristics of the studies included.

Study, year (Country)	Participants (cases), study design	Sample characteristics	Exposition (PD)	Outcome (ACS)	Adjustment factors	OR /RR /HR (95% IC)
Starkmammart 2008 [16] (Sweden)	321 (161), CC	Both genders. Age: cases 61.0 ± 8.9 (range 33–76); controls 62.0 ± 8.8 (range 35–78 y). Follow-up 3 y.	Severity grading of PD (Hugoson & Jordan).	Angina (diagnosed as CHD by coronary angiography)	Age, smoking	OR 5.74 (2.07–15.9) for PD and CAD.
Andriankaja 2006 [17] (USA)	1 337 (537), CC	Both genders. Age: cases 54.6 ± 8.5 (range 35–70); controls: 55.0 ± 0.0, (range 36–70 y). Follow-up 4 y.	CAL, PDe, ACH, NMT	MI	Age, sex, HT, cholesterol, DM and smoking.	OR 2.08 (1.51–2.87) for PD and incidence of non-fatal MI.
Andriankaja 2007 [18] (USA)	1375 (574), CC	Both genders. Age 35–69 y. Follow-up 4 y.	CAL	Non-fatal MI (WHO criteria).	Age, sex, BMI, physical activity, HT, cholesterol, DM, smoking.	OR 1.34 (1.15–1.57) for men and MI. OR 2.08 (1.47–2.94) for women and MI. OR 1.40 (1.06–1.86) for non-smokers and MI. OR 1.49 (1.26–1.77) for smokers and MI.
Rech 2007 [10] (Brazil)	115 (58/57), CC	Both genders. Age: cases 59.3 y; controls 70 y. Follow-up 1 y.	Gingivitis or Periodontitis.	STEMI and non-STE ACS.	Age, sex, DM, smoking.	OR: 4.5 (1.3–15.6) for PD and MI. OR: 1.8 (0.7–4.7) for PD and ACS.
Geerts 2004 [19] (Belgium)	170 (108), CC	Both genders. Age: cases 59.2 ± 11 y; controls 57.7 ± 9 y. Follow-up 4 y.	PDe, PPBI, PI, FI, TM.	CAD	Age, sex, smoking, alcohol, diet, physical activity, HT, DM, and dyslipidemia.	OR 6.5 (1.8–23) for CAD and PD.
Geismar 2006 [46] (Denmark)	250 (110), CC	Both genders. Age: cases 62.5 ± 11.5 y; controls 62.6 ± 10.5 y. Follow-up 1 y.	PDe, CAL, BOP, ABL on radiographs	CHD	Age, DM, smoking.	OR 6.6 (1.69 –25.6) for individuals <60 years, CHD and mean ABL >4. OR 0.8 (0.26 – 2.69) for individuals ≥60 years, CHD and mean ABL >4.
Briggs 2006 [20] (Ireland)	171 (92). CC	Men >40 y. Age: cases 56.7 y ± 6.3 y; controls 58.2 ± 6.7 y. Follow-up NR.	PI, BOP, PDe.	CHD	Smoking, academic performance, alcohol, unemployment, body weight, exercise, ability to relax daily, hobby, plaque, and CRP.	OR 3.06 (1.02– 9.17) for periodontal status and CHD.
Spahr 2006 [21] (Germany)	789 (263). CC	Both genders. Age: cases and controls: 61 ± 7.1 y. Follow-up 3 y.	CPITN	CHD	Age, sex, BMI, smoking, alcohol, DM, HT, dyslipidemia, education, physical activity, statins use.	OR 1.67 (1.08–2.58) from an increase in mean CPITN score by 1 and CHD
Cueto 2005 [22] (Spain)	149 (72). CC	Both genders. Age: cases 62.5 ± 9.9 y; controls 58.5 ± 10.2 y. Follow-up 2 mo.	Grade of periodontitis: percentage of sites with ICP ≥ 3mm.	MI	Sex, age, smoking, HT, DM, hypercholesterolemia, exercise.	OR 3.31 (1.42 – 7.71) for PD and MI.
Anyaipoma 2011 [23] (Peru)	105(35). CC	Both genders. Subjects >35 y, non-smokers. Follow-up 6 mo.	NT, PDe, adhesion level.	Unstable angina, MI	HBP, DM, hyperlipidemia, obesity	OR 5.899 (1.725 – 20.173) for PD and ACS.
Rutger 2003 [24] (Sweden)	160 (80). CC	Both genders. Age: cases 63.4 ± 8.9 y; controls 61.9 ± 9.1 y. Follow-up NR.	Marginal ABL.	MI	Sex, smoking, socio-economic factors	OR 7.0 (2–24.3) for periodontitis and MI among non-smokers. OR 14.1 (5.8 – 34.4) for PD and MI regardless of smoking status.
Nonnemacher 2007 [25] (Germany)	90 (50). CC	Men. Age: cases 48–80 y, controls 63.6 ±7.3 y. Follow-up 3 y.	PDe, CALe, BOP, TL	CAD (>30% stenosis)	Smoking, BMI.	OR 3.2 (1.2–9.0) for PD and CAD.
Buhlin 2005 [26] (Sweden)	193 (143). CC	Women. Age: cases 65.9 ± 8.6 (range 43–79 y); controls: 64.5 ± 8.3 (range 45–77 y). Follow-up NR.	Remaining teeth, pathological PP (≥ 4 mm).	CHD (treated for MI, PTCA, CABG)	Age, smoking, DM, BMI, education, place of birth.	OR 3.8 (1.68–8.74) for number of PP and CHD
Montebugnoli 2004 [40] (Italy)	113 (63) CC	Men. Age: cases 52.3 ± 4.9 (range 40–65 y); controls: 54.5 ± 6.1 y. Follow-up NR.	TDI, PTS, CPSS, CRSS.	MI <6 months and CHD (≥50% of stenosis) in at least one coronary artery.	Age, smoking, hypertension, DM, education, social class, BMI, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and glucose.	OR 4.61 (1.0–23.20) for CPSS and CHD.
Coelho 2005 [41] (Brazil)	149 (21) CC	Both genders. Age: NR. Follow-up NR.	PDe, CALe	MI and angina	Age, sex, smoking, marital status.	OR 4.03 (0.42– 32.43) for PD and MI/angina.
Coelho 2010 [27] (Brazil)	621 (207). CC	Both genders. Age: 59 (range 40– 81 y). Follow-up 7 mo.	PDe ≥4 mm y PIC ≥ 3mm, y SS	First MI event	Smoking, education level, occupation, DM, HDL cholesterol.	OR 1.92 (1.13 – 3.23) for PD and MI.
Górski 2016 [28] (Poland)	289 (134) CC	Both genders. Age <70 y. Mean age: cases 54.3 ± 8.1 y; controls 54.9 ± 10.0 y. Follow-up 2 y.	Severity (Page & Eke), extent of periodontitis (Arbes Index), TL >10.	STEMI and STNEMI (ESC).	*Age, sex, smoking, HT, DM, BMI, education, and income. **Age, gender. ***Age, sex, smoking, HT, DM.	OR* 2.4 (1.1 –5.2) for extension de PD and MI. OR** 2.0 (1.2–3.5) for severity of PD and MI. OR*** OR 2.1 (1.2–5.9) for TL and MI.
Wojtkowska, 2021 [47] (Poland)	111 (71) CC	Both genders. Age: cases 54.22 ± 7.05 y; controls 52 ± 8.43 y. Follow-up 10 mo.	Teeth preserved, approximal PI, BOP, PDe, NoPD ≥ 4 mm, %PD ≥ 4 mm, CAL.	MI (4th universal definition).	Age, sex, medication, smoking, DM, BMI, triglycerides, HDL, HT, FBG	OR 1.07 (1.03–1.11) for approximal PI [%]and MI. OR 0.95 (0.9–1.00) for BOP [%]and MI.
Holmlund 2011 [29] (Sweden)	200 (100). CC.	Both genders. Age: cases 57.1 ± 5.5 y; controls 57.9 ± 5.2 y. Follow-up NR.	PBL, NDP, BOP, NT	MI: ECG + CK and troponin T.	Age, sex, CRP, HBP, smoking, IL- 6, cholesterol, HDL, DM, TG, BMI, education.	OR 4.61 (1.52–13.94) for NDP >4 and MI
Willershausen, 2014 [48] (Germany)	497 (248). CC	Both genders. Age: cases 62.3 ± 10.1 (range 51–83); controls 63.5 ± 10.5 y. Follow-up 4 y.	Caries frequency (DMFT indices), NT, PPD, BOP, CALe, radiographs	Recent MI history, catheterization, reperfusion therapy (PTCA, bypass, or thrombolytics)	Sex, age, smoking.	OR 0.879 (0.527–1.466) for generalized PD and MI. OR 1.210 (1.148–1.276) for missing teeth and MI. OR 1.541 endodontic origin and MI.
	306 (204). CC	Both genders. Not DM. Age: cases 64.7 ± 12.9 y; controls 64.2 ± 10.1 y. Follow-up 2 y.	CAL, PDe, NMT.	MI (ESC)	Sex, age, smoking, HT, total cholesterol.	OR 2.17 (1.32–3.73) for PDe and MI. OR 1.78 (1.30–2.54) for CAL and MI. OR 1.08 (1.06–1.13) for NMT and MI.
Rydén 2016 [32] (Sweden)	1610 (805). CC	Both genders. Age 62.5 ± 8 y. Follow-up 6–10 y.	Healthy (≥80% RB), mild- moderate (79%–66% RB), severe PD (<66% RB).	MI (3rd universal definition)	Smoking, DM, education, marital status.	OR 1.28 (1.03–1.60) for PD and MI.
Oe 2009 [31] (Japan)	174 (99). CC	Both genders. Age 65.5 ± 10.6 y. Follow-up 3 y.	PRS (Renvert et al.).	CAD	Statin therapy, DM or glucose intolerance, PRS, HT, smoking	OR: 2.317 (1.162–4.624) for PRS and CAD.
Khosravi 2013 [64] (Iran)	123 (60). CC.	Both genders. Age: cases 54.97 ± 9.68 y; controls: 55.89 ± 11.9 y. Follow-up NR.	PDI (Ramfjord), NMT	Cardiac enzymes and ECG.	Age, DM.	OR 8.79 (2.36–32.66) for LOA (< or > 3mm) and MI. OR 5.44 (1.65–17.94) for NMT (< o > 10) and MI. OR 2.32 (0.59–8.42) for PDI score (< or > 4) and MI.
Li 2013 [65] (China)	155 (103). CC.	Both genders. Age: cases 68 (range 41–84) y; controls 62 (range 42–78) y. Follow-up: NR.	PI, BI, PDe, AL, NMT	Blood tests, ECG and US.	Sex, age, smoking, BMI, DM, HT, serum lipid.	OR 4.89 (1.26–18.94) for AL≥4.00 mm and MI.
Beck 1996 [66] (USA)	1 147 (207) PC	Men only. Age: 21–80 y. Follow-up 18 y. Follow-up NR.	ABL, worst clinical PDe.	Non-fatal MI, angina pectoris, and CHD deaths.	Age, BMI, SBP, cholesterol, DM.	OR 1.49 (1.04–2.14) for ABL and total CHD
Hujoel 2000 [42] (USA)	8032 (1265). PC	Both genders. Age: 25–74 y. Follow-up 8–10 y.	Russell PI: periodontitis, gingivitis, and no PD.	First event of death from CHD or hospitalization due to CHD, or revascularization procedures. Death certificates and medical records	Multiple cardiovascular risk factors; demographic, socioeconomic factors, race, poverty rate, education, etc.	HR 1.05 (I0.88–1.26) for gingivitis and CHD. HR 1.14 (0.96–1.36) for periodontitis and CHD.
Joshipura 1996 [49] (USA)	44119 (757). RC	Men. Age 40–75 y. Follow-up 6 y.	Self-reported NT (0, 1–10, 11–16, 17–24, 25+).	Incident cases of CHD, including fatal and non-fatal MI and sudden death.	Age, BMI, exercise smoking, alcohol, family history of MI, vitamin E	RR 1.67 (1.03–2.71) for men with positive PD history, NT ≤ 10 compared with those with NT ≥ 25 and CHD. RR 1.11 (0.74–1.68) for men with negative PD history, NT ≤ 10 compared with those with NT ≥ 25 and CHD.
Howell 2001 [43] (USA)	2653 (797) RC	Men. Age 40–84 y. Follow-up 12.3 y.	Self-reported TL.	Nonfatal MI, nonfatal stroke, CV death, all important CV events (WHO criteria).	Age, treatment (aspirin, β-carotene), smoking, alcoholism, HT, BMI, DM, physical activity, paternal history of MI, and history of angina.	RR 1.01 (0.82–1.24) for PD and nonfatal MI. RR 1.00 (0.79–1.26) for PD and CV death. RR 1.01 (0.88–1.15) for PD and all-important CV events.
Wu 1999 [50] (USA)	9962 (803). PC	Both genders. Age 25–74 y. Follow-up 21 y.	Periodontal status: 1) no PD, 2) gingivitis, 3) periodontitis, 4) edentulousness.	CVD events ascertained by hospital records for non-fatal events and death certificates for fatal events.	Demographic variables and various known CV risk factors.	RR 1.03 (0.87–1.21) for gingivitis and CHD; RR 1.14 (0.98–1.34) for periodontitis and CHD; 1.13 (0.98–1.32) for edentulousness and CHD.
Noguchi 2015 [51] (Japan)	3081 (17). RC	Men 36–59 y. Follow-up 5 y.	Self-administered questionnaire: 1) PS, 2) periodontitis, 3) TL (<5 and ≥5 teeth)	Participants reports of for MI at annual health examinations	Age, BMI, smoking, HT, DM, dyslipidemia, family history of heart disease.	OR 2.11 (1.29–3.44) PS and MI. OR 2.26 (0.84–6.02) for periodontitis and MI. OR 1.97 (0.71–5.45) for TL and MI.
Holmlund 2017 [67] (Sweden)	8999 (672). PC.	Both sexes. Age 50 ± 13 y. (range 20–85 y. Follow-up 15.8 y.	NDP, NT, BOP	CVD: MI, stroke, and HF. CVD diagnosis from the Swedish cause of death and the hospital registers.	Age, sex, educational level and smoking.	RR 1.13 (0.98–1.30) for NDP >4 mm and MI.
Hansen 2016 [68] (Denmark)	100 694 (NR). RC.	Both sexes. Age ≥18 y. Follow-up 15 y.	Clinical examination and radiographic findings. Periodontitis according to ICD-8 and ICD-10.	ICD-10.	Age, sex, smoking, comorbidities, medication and socioeconomic status.	RR: 1.16 (IC 95% 1.04– 1.30) for periodontitis and MI.
Lee 2017 [44] (Korea)	354850 (8164). PC.	Both genders. Age 40–79 y. Follow-up 12 y.	Oral examinations. Assessments of MT, gingivitis, periodontitis, and the deposition of calculus (CDC/AAP criteria).	Diagnosis was made by physicians during visits using ICD-10 codes.	Sex, age, income, insurance, residence, health status, and smoking.	OR: 0.88 (0.81–0.97) for PD and MI.
Yu 2015 [33] (USA)	39 863 (642). RC.	Women ≥ 45 y. Follow-up 15.7 y.	Self-reported PD.	CV deaths confirmed by family members, postal authorities, autopsy reports, MR and the National Death Index. MI was assessed by physician review of MR and cardiac enzymes or ECGs.	Age, race, BMI, education, smoking, DM, HT, dyslipidemia, family history of MI, physical activity.	HR 1.72 (1.25–2.38) for women with incident PD and MI. HR 1.27 (1.04–1.56) for women with prevalent PD and MI.
Dorn 2010 [45] (USA)	884 (154). RC.	Both genders. Age 54 ± 8.5 y. Follow-up 2.9 y.	Mean CAL.	Recurrent overall CVD events (non-fatal, fatal CVD, or cardiac revascularization)	Age, sex, education, DM, total cholesterol, statins, antihypertensives, BMI, physical activity, intake of fruits and vegetables, CPK-MB, ejection fraction.	HR 1.48 (0.95–2.31) for CAL and overall CVD events among never- smokers. HR 1.00 (0.82–1.23) for CAL and overall CVD events among ever-smokers.
Liljestrand 2015 [35] (Finland)	7629 (253). RC.	Both genders. Follow-up 13 y.	NMT	CHD events: a history of MI, revascularizations, or PTCA.	Age, sex, smoking, geographical variable (east/west).	HR 2.39 (1.32–4.31) for NMT 5–8 and incident MI. HR 2.1 (1.19–3.71) for NMT 9–31 and incident MI.
Lee 2019 [34] (Korea)	4440970 (31868). RC.	Both genders. Mean age 41.5 y. Follow-up 7.59 y.	NMT	De novo occurrence of MI, HF, ischemic stroke, and all-cause death (ICD-10).	Age, sex, BMI, DM, HT, dyslipidemia, COPD, CKD, smoking, alcohol, exercise, income.	HR 1.010 (1.007–1.014) for MT and MI.
DeStefano 1993 [69] (USA)	9760 (NR). PC	Both sexes. Age 25–74 y. Mean follow-up 14 y.	1) Number of decayed permanent teeth. 2) Periodontal classification: no PD; gingivitis; periodontitis; no teeth. 3) PI. 4) OHI.	CHD: mortality and hospital admission.	Age, sex, race, education, poverty rate, marital status, SBP, total cholesterol, DM, BMI, physical activity, alcohol consumption, and smoking.	RR 1.72 (1.10–2.68) for periodontitis and death from CHD in men aged 25–49 y. RR 1.25 (1.06–1.48) for periodontitis and death from CHD in men and women aged 25–74 y.
Lee 2015a [70] (Korea)	1025340 (8179). RC.	Both genders. Age: 1–80+ y. Follow-up 12 y.	Diagnosis of periodontitis according to AAP and ICD-10.	Diagnosis made by physician and defined according to the KCD-6.	Sociodemographic variables, comorbidities (cerebral infarction, angina pectoris, MI, HT, DM, rheumatoid arthritis, erectile dysfunction, osteoporosis, obesity.	OR 0.98 (0.86–1.12) for periodontitis and MI.
Lee 2015b [71] (China)	720343. (10046). RC	Both genders. Age 20–65+ y. Follow-up 11 y.	NR	NR	Age, sex, socioeconomic status, residence, comorbidities	HR 1.23 (1.13–1.35) for PD and MI.
Morrison 1999 [72] (Canada)	9331(416). RC.	Both genders. Age 35–84 y. Follow-up 49 y.	None, mild gingivitis, severe gingivitis, pockets, loose teeth, edentulous.	Fatal CHD.	Age, sex, DM, total cholesterol, smoking, HT, and province.	RR 2.15 (1.25–3.72) for severe gingivitis and fatal CHD. RR 1.90 (1.17–3.10) for edentulous and fatal CHD.
Bazile 2002 [73] (EUA)	80 (30). CS	Both genders. Mean age 54 y. (range 23–83).	PI, GI, BOP, PDe, CAL, NMT	MI, SA, UA	Age, sex.	OR 1.23 (0.29–5.23) for CAL and MI. OR 6.10 (1.14–3.26) for CAL UA.
Arbes 1999 [52] (EUA)	5564 (244). CS.	Both genders. Age ≥40 y.	The percent of periodontal sites per person with CAL ≥ 3 mm.	Self-reported history of heart attack (HA)	Age, sex, race, poverty, smoking, DM, HT, BMI, cholesterol	OR 1.38 (0.75–2.54) for CAL >0–33% and HA. OR 2.28 (1.18–4.39) for CAL >33–67% and HA. OR 3.77 (1.46–9.74) for CAL >67% and HA.
Holmlund 2006 [74] (Sweden)	3352 (NR). CS.	Both genders. Age: 20–70 y.	ABL, X-ray, BOP, involvement of furcations.	Self-reported history of HT and MI.	Age, sex, NT, smoking.	OR 2.69 (1.12–6.46) for PD and MI in subjects aged 40–60 y.
Parkar 2013 [53] (India).	60 (30). CS	Both genders. Age: cases 54.3 ± 11.0 y; controls 53.1 ± 10.5 y.	Simplified OHI, CPI, LOA (WHO).	STEMI and NSTEMI verified by ECG and serum troponin I level.	Age, sex, smoking, alcohol, BMI.	OR 0.224 (0.03–1.68) for CPI and MI. OR 0.127 (0.02–1.06) for OHIS and MI. OR 0.79 (I0.009–0.69) for LOA and MI

CAL: clinical attachment loss; PDe: probing depth; alveolar crest height (ACH); PPBI: periodontal pocket bleeding index; PI: plaque index; FI: furcation involvements; TM: tooth mobility; BOP: bleeding on probing; ABL: alveolar bone loss; CPITN: Community Periodontal Index of Treatment Needs; TL: tooth loss; PP: periodontal pockets; TDI: total dental index; PTS: panoramic tomography score; CPSS: clinical periodontal sum score; CRSS: clinical and radiographic sum score; NoPD ≥ 4 mm: the number of bleeding periodontal pockets ≥ 4 mm in depth; %PD ≥ 4 mm: the percentage of bleeding periodontal pockets ≥ 4 mm in depth; NT: number of teeth; PBL: periodontal bone loss; NDP: number of deepened pockets; PPD: probing pocket depths; CALe: clinical attachment level; NMT: number of missing teeth; RB: remaining bone; Periodontal diseases index (PDI); BI: bleeding index; AL: attachment level; PI: periodontal index; OHI: oral hygiene index; PS: periodontal score; GI: gingival index; CPI: community periodontal index; LOA: loss of attachment; PRS: Periodontal risk score; CHD: coronary heart disease; CAD: coronary artery disease; STE: ST segment elevation; ACS: acute coronary syndrome; MI: myocardial infarction; STEMI: ST segment elevation MI; NSTEMI: non-ST segment elevation MI; CV: cardiovascular; CVD: cardiovascular disease; HF: heart failure; ECG: electrocardiogram; PTCA: percutaneous transluminal coronary angioplasty; SA: stable angina; UA: unstable angina; CABG: coronary artery bypass grafting; BMI: body mass index; HT: hypertension; DM: diabetes mellitus; FBG: fasting blood glucose; SBP: systolic blood pressure; US: ultrasonography; WHO: World Health Organization; ESC: European Society of Cardiology; CDC: Centers for Disease Control and Prevention; AAP: American Academy of Periodontology; MR: medical records; KCD-6: Korean Classification of Disease 6TH edition; CC: case-control study; PC: prospective cohort study; RC: retrospective cohort study; CS: cross-sectional study; NR: no reported.