Le Infezioni in Medicina, n. 4, 501-515, 2022

doi: 10.53854/liim-3004-4

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

Edinson Dante Meregildo-Rodriguez1, Luis Gianmarco Robles-Arce1, Eleodoro Vladimir Chunga-Chévez1, Martha Genara Asmat-Rubio2, Petterson Zavaleta-Alaya2, Gustavo Adolfo Vásquez-Tirado3

1Escuela de Medicina, Universidad César Vallejo, Trujillo, Perú;

2Escuela de Posgrado, Universidad Privada Antenor Orrego, Trujillo, Perú;

3Escuela de Medicina, Universidad Privada Antenor Orrego, Trujillo, Perú

Article received 18 June 2022, accepted 21 September 2022

Corresponding author

Edinson Dante Meregildo-Rodriguez

E-mail: dante_meregildo@hotmail.com

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.

Keywords: Periodontitis, periodontal diseases, acute coronary syndrome, myocardial infarction, systematic review.

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).

Table S1 - Search strategy

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.

Table S2 - List of excluded studies

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).

Table S3 - General characteristics of the studies included.

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.

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).

Figure 2B - Forest plot on the effect of periodontal disease on acute coronary syndrome according to continent of origin of the study.

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).

Figure 2C - Forest plot the effect of periodontal disease on acute coronary syndrome according to type of diagnosis.

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).

Figure 2D - Forest plot on the effect of periodontal disease on acute coronary syndrome according to gender.

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.

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.

Conflict of interest

None to declare.

Funding

None

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