Myocardial infarction (MI), one type of cardiovascular disease (CVD), is caused by coronary artery occlusion resulting from atherosclerotic plaques. MI events can cause necrosis and apoptosis in a large number of myocardial cells and a severe reduction in the number of myocardial cells, which can directly lead to heart dysfunction and failure (He et al., 2016). Currently, CVD and subsequent myocardial infarctions remain leading causes of morbidity and mortality worldwide (Ferrero et al., 2014; GBD 2013 Mortality and Causes of Death Collaborators, 2015; Baron et al., 2016; Mozaffarian et al., 2016). The World Bank estimates that by 2030, 23 million Chinese patients will experience acute MI annually, which poses a serious challenge to the nation's healthcare system (Zhang et al., 2015; Tao et al., 2016). Therefore, it is of great importance to explore relevant risk factors and propose useful methods for the prevention and treatment of MI.

Periodontitis is a chronic inflammatory disease that damages the soft and hard tissue supporting the teeth, which results in loss of connective tissue attachment, erosion of the alveolar bone, and tooth loss (Lundmark et al., 2015). In the adult USA population, nearly half of individuals aged >30 years have some periodontitis, and almost 10% of the population has severe periodontitis (Eke et al., 2012, 2015, 2016a,b). There is growing evidence suggesting that periodontitis is associated with increased MI risk (Wożakowska-Kapłon et al., 2013; Kodovazenitis et al., 2014; Noguchi et al., 2015; Rydén et al., 2016). Periodontitis shares some common risk factors with MI, such as diabetes and smoking (Kjellström et al., 2016). In addition, growing literature indicates that local/systemic inflammation caused by periodontitis contributes to the risk of CVD, including MI events (De Nardin, 2001; Shrihari, 2012). An in vivo study showed that the periodontal pathogens could induce myocarditis and/or myocardial infarction in mice (Akamatsu et al., 2011).

Despite rapid growth in the number of studies on the possible etiological role of periodontal disease in the pathology of MI, this issue has not been resolved, and the findings of these studies have been inconsistent (Hujoel et al., 2000; Andriankaja et al., 2006; Dietrich et al., 2008; Sidhu, 2016). While the majority of publications have suggested an association between periodontitis and MI, several epidemiologic studies have found no such relationship (Hujoel et al., 2000; Howell et al., 2001). One systematic review (Sidhu, 2016) concluded that no relationship between these two conditions had been precisely replicated or verified, and therefore insufficient evidence was available to justify the hypothesis that periodontal interventions could prevent the onset or progression of MI events; the conclusion of that review was similar to that of the American Heart Association (AHA) (Lockhart et al., 2012). In addition, despite the existence of several systematic reviews and meta-analyses evaluating the association between periodontitis and CVD (Janket et al., 2003; Blaizot et al., 2009), specialized meta-analyses that quantitatively assess the presence and strength of the association between MI and periodontitis are still lacking.

Several different types of studies have been used to investigate the association between periodontitis and MI, including cross-sectional studies, case-control studies, and prospective and retrospective cohort studies. The pooling of data from studies using different designs has led to significant structural and methodological variation in published system reviews and meta-analysis and, therefore, increased heterogeneity (Kelly et al., 2013). To facilitate the determination of uniform statistical indicators and obtain more accurate and credible results, it is preferable to collect and merge data from the same type of research study. Therefore, the goal of this meta-analysis was to identify all related case-control studies investigating the association between periodontitis and MI and critically evaluate them to assess the strength of the association between MI and periodontitis. These results will provide clinicians and patients with better evidence-based evaluations and recommendations.

At present, the majority of studies focusing on the association between periodontitis and MI have been observational studies. Despite the fact that is has been suggested that randomized control trials (RCT) provide a higher-quality of evidence, this type of study cannot be used to answer all clinical questions for ethical, methodological, or logistic reasons (Guyatt et al., 2008; Blaizot et al., 2009). In this meta-analysis, to reduce structural and methodological variation and obtain more accurate results, the included studies were confined to those using a case-control methodology. Analysis of data from the 17 case-control studies included in our meta-analysis revealed that compared with the control subjects, MI patients had higher odds of periodontitis and more serious periodontitis, indicating there was a significant association between MI and periodontitis. Moreover, the MI patients suffered from worse periodontal status and more tooth loss.

The pooled OR was 2.531 (95% CI: 1.927–3.324), indicating that periodontitis was significantly associated with MI. Our results were similar to the findings of another meta-analysis that focused on the association between periodontal diseases and cardiovascular events; in that study, the pooled OR calculated using data from the 22 case-control and cross-sectional studies were 2.35 (Blaizot et al., 2009). Both their and our meta-analysis showed high statistical heterogeneity among included studies. In this research, the I²-value was 79.385, and a random effects model was adopted. However, the sensitivity analysis performed by sequentially removing individual studies did not change the results (Figure 3). Furthermore, the cumulative analysis performed by the order of publication date revealed stable and statistically significant results (Figure 4). In the subgroup analyses, the included studies were grouped according to quality, region, method of periodontal assessment, and number of confounding factors adjusted for in the models. Those results of all the subgroup analyses revealed significant associations between MI and periodontitis (Table 2). Moreover, analysis performed within each subgroup also revealed high levels of heterogeneity.

Based on the current literature, the observed heterogeneity may have resulted from the following aspects. First, different diagnostic criteria and methods of periodontitis assessment were used. However, some researchers found that the association between periodontitis and MI was consistent regardless of the different measurements and case definitions of periodontitis used (Andriankaja et al., 2006; Kodovazenitis et al., 2014). It is undeniable that different criteria and methods will lead to variation in the outcome measures. Second, different types of control subjects were included. Among the included studies, healthy subjects (Kodovazenitis et al., 2014; Willershausen et al., 2014), trauma patients (Cueto et al., 2005), or the CVD patients without MI (Kaisare et al., 2007; Wożakowska-Kapłon et al., 2013) were recruited as control subjects. Third, incomplete and differential adjustment for confounding factors may have played a role. Some factors can affect both MI and periodontitis independently, such as tobacco, diabetes, and age (Guiglia et al., 2008; Blaizot et al., 2009; Kodovazenitis et al., 2014). The included studies matched or adjusted for different types and numbers of the confounding factors. In this meta-analysis, the number of the confounding factors considered in the included studies ranged from 0 to 8. Forth, myocardial infarction is a medical emergency, and only the patients who survived an MI event (excluding those patients died of MI) had been included in these studies. These factors are not all of the reasons that heterogeneity was observed; however, they may have played a critical role in contributing to the high level heterogeneity identified among these observational studies.

Through comprehensive analysis of the periodontal parameters, the overall effects showed that periodontal status and oral hygiene were worse in MI patients compared to control subjects. The periodontal measurements CAL and PD have been well established as reflections of periodontal disease in both clinical research and clinical practice (Machtei et al., 1993; Andriankaja et al., 2006; Kodovazenitis et al., 2014). In addition, these two factors reflect both past periodontitis and recent inflammation in patients. This meta-analysis found that MI patients had more attachment loss and deeper periodontal pockets. The differences in the means values of CAL and PD between MI and control subjects were 1.000 and 1.209 mm, respectively. Moreover, in the MI patients, a significantly higher level of plaque and BOP were identified compared with control subjects, indicating poor oral hygiene in MI patients. However, the reason that MI patients had a higher level of BOP and dental plaque might also be that they had longer stays in the intensive care unit and hospital during which they may not or could not have maintained their daily oral hygiene (Rutger Persson et al., 2003; Renvert et al., 2004). Furthermore, the overall effect revealed that the MI patients had lost more than 4 teeth (difference in means: 4.122, 95% CI: 2.012–6.232, P = 0.000) more than the control subjects. While tooth loss can be caused by many reasons, the greater extent of tooth loss in this population somewhat reflects a previous accumulation of oral inflammation, (Liljestrand et al., 2015) and many studies have determined there to be an association between MI status and the number of missing teeth (Andriankaja et al., 2006; Stein et al., 2009; Kodovazenitis et al., 2011, 2014).

This meta-analysis showed that there was a significant association between MI and periodontitis. While there is still a lack of relevant evidence for the causal relationship between MI and periodontitis (Blaizot et al., 2009; Stewart and West, 2016), it is undeniable that this associations is of great importance because of the potential effect that preventing or treating periodontal disease could have on reducing the risk of MI. In the long-term, the achievement of a sustained improvement in periodontal health and reduction in the risk of MI or relevant complications, rather than a single treatment, have been recommended (Stewart and West, 2016). However, the AHA has noted that although periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction in short-term studies, there is no evidence that they prevent atherosclerotic vascular disease or modify its outcomes (Lockhart et al., 2012). In addition, some researchers have concluded that insufficient evidence is available to justify the hypothesis that periodontal interventions can prevent the onset or progression of acute myocardial events (Li et al., 2014; Henschel and Keenan, 2015; Sidhu, 2016). Therefore, more clinical research to evaluate the effectiveness of interventions for periodontitis on the reduction of MI events is needed in future.

To our knowledge, this is the first meta-analysis to specifically estimate the association between MI and periodontitis using quantitative analysis. We included only case-control studies to reduce structural and methodological variation. We not only assessed the association between MI and periodontitis by pooling the OR values reported by each study but also examined relevant periodontal parameters to evaluate periodontal and oral hygiene status. Moreover, sensitivity and cumulative analyses were performed to determine the stability of the pooled results. However, our meta-analysis has three limitations. First, heterogeneity among the included studies was high, both in the overall effect analysis and the subgroup analyses. Second, the search strategy was confined to English-language studies, which might have introduced a selection bias into this meta-analysis. Third, due to the limited number of studies analyzing each of the periodontal parameters, sensitivity, cumulative and subgroup analyses were not performed.

In summary and in consideration of the strengths and limitations of this study, the pooled data evaluated in this meta-analysis support the conclusion that MI patients had higher odds of periodontitis and more serious periodontitis than did controls, and there was a significant association between MI and periodontitis. At the same time, MI patients had worse periodontal and oral hygiene status and fewer teeth than did control subjects. More importantly, more high-quality and well-designed studies focused on the casual relationship between MI and periodontitis should be conducted. In addition, studies focused on the effect of interventions for periodontitis on the reduction of MI events are also needed in the future.

The sections on literature research, study selection and data extraction were completed by QS and BZ; the section on risk of bias evaluation and data analysis were completed by NH and CC; QS drafted the manuscript and BZ, JX helped to revise the manuscript. HL and JX are the corresponding authors, and they undertook the work of designing this meta-analysis, coordinating and helping to draft the manuscript. All authors read and approved the final manuscript.

This study was supported in part by grants from the National High Technology Research and Development Program (“863” Program) of China (2015AA033502) and the National Natural Science Foundation of China (NO. 81271180, 81500861).