Periodontal Diseases and Heart Diseases: A Systemic Review

ABSTRACT

Introduction:

Up to 50% of people worldwide are affected by periodontal disease (PD); cardiovascular diseases are a serious concern for the major portion of the world’s population. Observational data have shown a connection between PD and CVD. The current systemic review investigates the incidence of the CVD in individuals with PD through various designs of the previous research.

Materials and Methods:

An extensive online search in the various databanks of EMBASE, Medline, Pubmed, and Scopus was conducted. The keywords searched were: “PD, CVD, myocardial infarction, coronary heart disease (CHD), and stroke; technique of diagnosis and the degree of PD were assessed clinically or by self-report.” The studies selected were longitudinal research design and randomized trials. To ascertain the risk of mortality due to cardiac issues in periodontal diseases, meta-analysis, and meta-regression were carried out. The diagnosis techniques for periodontal diseases, severity, and impact of gender, were also examined.

Results:

After full-text screening, 32 longitudinal cohort studies were included. PD patients had a significantly greater risk of CVD than non-PD patients (RR: 1.20). Clinical and self-reported PD diagnoses did not differ in CVD risk (RR = 0.97). Men were at increased risk for both severe PD (RR: 1.25), and CVD (RR: 1.16). The risk of stroke was the highest among all forms of CVD (RR = 1.24), and the risk of CHD was significantly elevated (RR = 1.14).

Conclusion:

Current review showed that populations with PD consistently and modestly have an elevated risk of CVD. Men and those with severe PD are at higher CVD risk, which suggests population-targeted therapies may be helpful.

INTRODUCTION

Cardiac diseases remain a major concern for world population due to their higher mortality. These may be seen as associated with many other health conditions; one among them is periodontal disease. Over half the world population is suffering from “Periodontal disease (PD)” and cardiovascular illnesses have been linked in observational studies. For instance, a significant cross-sectional investigation of a cohort of >50000 individuals in Europe revealed that people with periodontitis are a 2.52 times increased chance of developing atherosclerotic diseases. Similarly, among middle-aged men with severe PD, the chance of having a cardiovascular event is twice as more for periodontal issues in this population. It was also noted that men with periodontal issues had considerably higher levels of inflammatory markers than men without PD.[1-5]

Previous theories have proposed causal connections between PD and CVD. These findings frequently point to infections and inflammatory pathways associated with PD-related bacteria like Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans as the culprit. According to Socransky SS, et al., endotoxins of the pathogens found in the mouth can spread disease to other parts of the body, while other research suggests that these pathogens may be carried by erythrocytes as it circulates in the body.[4] Patients who underwent oral operations also experienced pathogenic and systemic symptoms of bacteremia, supporting yet another potential causative relationship. The data collected from the medical departments allows for finding the links between CVD and other diseases. Nevertheless, there is still much to understand about the exact mechanism of oral diseases and later CVD.[6-10]

The connection between PD and CVD problems has been discussed in earlier reviews. Liccardo et al., qualitative analysis of the proof for links between PD and CVD was published in 2019.[9] In addition, recent research by M. Aguilera et al. showed that those with PD have a 1.6-fold higher risk of developing hypertension.[10] Additionally, it has been discovered that PD is linked to stroke, peripheral artery disease, and coronary heart disease. Most of the studies have been designed as cross-sectional studies that have only evaluated the incidence of the disease rather than finding out the cause of CVD in the PD subjects.

A meta-analytical study of longitudinal cohort research that would have quantified the risk of cardiac diseases in periodontal disease populations in comparison to those who don’t have periodontitis subjects is missing from the body of research. Additionally, because observational studies can be extremely heterogeneous, a meta-analysis combined with meta-regression could enable the investigation of study features, risk factors, and the relationship between CVD risks.

The present study was piloted as a systematic review to assess the risk of incidence of cardiac events in patients with and without periodontal disease. To achieve this goal, a meta-analysis that estimated the risk of cardiac events in PD subjects was conducted, together with a meta-regression to assess the significance of major risk factors. The prognosis for people with periodontal disease will be better understood with the full assessment of the data quantifying this directional link, which will also emphasize the need for good oral health practices and directed chronic CVD preventive measures.

MATERIALS AND METHODS

Study design

A thorough analysis of longitudinal cohort studies and randomized controlled trials that compare the risk of incidence of cardiac events in patients with and without periodontal disease was done. Analysis was made on the basis of the PRISMA standards.

Search technique

The manual and electronic literature searches up to 2020 in the databanks of the EMBASE, MEDLINE, PUBMED, and SCOPUS were conducted. The search terms were: “(periodontal OR tooth loss OR missing teeth) AND (atrial fibrillation OR heart failure OR cerebrovascular accident OR stroke OR angina OR acute coronary syndrome OR myocardial infarction OR peripheral vascular disease OR hypertension OR cardiovascular disease) AND (incidence) AND (cohort OR longitudinal OR randomised controlled trial OR RCT).”

Selection standard

Two reviewers independently read, evaluated, and screened articles, and the differences were resolved with discussion. Articles that didn’t meet the requirements for inclusion were excluded.

Selection and scrutinizing

Titles and abstracts of publications were independently evaluated for eligibility. Relevant articles were picked for full-text screening. The paper screening process and eligibility assessment were carried out independently by two authors. In the event of a disagreement amongst the authors, the judgment was decided by an independent third author. Titles were screened first followed by the abstracts. When the abstracts didn’t fulfill the criteria of selecting the studies were excluded. Figure 1 in accordance with PRISMA recommendations is shown for the selected studies.[19]

Figure 1.

Flowchart exhibiting the study selection

Obtaining data and evaluating its quality

Independently, two researchers evaluated search results, chose studies, and extracted data. For additional review, the full documents were retrieved. The following criteria were gathered to create a customized Microsoft Excel spreadsheet, and the succeeding information was acquired from the inclusion criteria: “the name of the author and the year it was published, study design, patient age, country, and periodontal outcome variables.”

Eligibility requirements

Strict eligibility standards served as the search’s guide to assure the inclusion of relevant studies, minimize heterogeneity, and boost the power of the findings. The following were listed as the inclusion criteria:

• Design: prospective trials were included that were properly randomized.

• Subjects: periodontal disease subjects of >10 sample size;

• Follow-up: the evaluation of the results after at least 24 weeks of articles that are only available in English.

• Randomized controlled trials and longitudinal retrospective/prospective cohort study designs.

• A minimum follow-up time of one year.

• PD method of diagnosis.

• The classification of CVDs is clearly stated.

The study was asked to be excluded from the evaluation if it met one of the following standards:

• A cross-sectional, case-series, or case-control study.

• Research on animals or groups known to have a systemic disease before follow-up.

• Conference proceedings, abstracts, reviews, or protocols.

• The absence of a recognized or precisely defined PD diagnosis.

• Lack of or ambiguous definition of CVD.

• Inaccessible CVD risk.

Statistic evaluation

The information gathered was entered into an excel spreadsheet and analyzed (Microsoft, Redmond, Washington, USA). The analysis was valued at 95 percent significance levels. The “Newcastle-Ottawa Scale (NOS) for Quality Assessment” was used to appraise the value of the studies. The “Cochran test (Test Q)” and “Inconsistency test” (I² 50 percent) were used to assess study heterogeneity. Values above 75% (in both tests) were regarded to indicate significant heterogeneity, preventing the use of a fixed-effect analytic approach. The “standard deviation (SD)” number was utilized to construct the “confidence interval (CI)” because the “confidence interval (CI)” was not provided. In addition, linear regression was used. RRs were created using ORs and HRs to enhance the size of the study (Shor et al., 2017). Key confounders, including demographics and smoking, were adjusted for respective trials and pooled with the adjusted RRs for the meta-analysis. The severity and the demographics as well as the follow-up time were all noted for the periodontal groups. In order to compare the subgroups’ CVD risk, meta-regression was used.

RESULTS

The original search returned a total of 1,563 studies. After screening, 129 studies underwent comprehensive content screening, of which 32 research were included.[11-42] 2 studies were left out of the meta-analysis because it was impossible to retrieve the raw data on sample sizes.[31,42] The included studies were conducted between the years 1993-2019 The majority of investigations (n = 16) were piloted in the US, and the remaining studies employed data from industrialized nations in Asia, Europe, and Australia. The mean follow-up period was 14.5 years. Of the 32 studies that were included, 22 were prospective cohort studies and they used cohorts with clinically confirmed PD in 21 of the studies [Table 1].

Table 1.

Study characteristics of the included studies

Study	Study design	Sample size	Method of evaluation	Results	Follow-up	ROB
Yu et al., 2015	Prospective	39,863	Self-report	Stroke + MI	16	Critical
Wu et al., 2000	Prospective	9,962	Clinical	Stroke	22	Serious
Tu et al., 2007	Prospective	12,631	Clinical	CHD + stroke	57	Serious
Sen et al., 2018	Retrospective	6,736	Clinical	Stroke	15	Serious
Rivas-Tumanyan, et al., 2012	Prospective	31,543	Self-report	Hypertension	20	Critical
Noguchi et al., 2014	Prospective	3,081	Self-report	MI	5	Serious
Mucci et al., 2009	Prospective	15,273	Self-report	CHD + stroke	37	Serious
Morrison, Ellison, and Taylor, 1999	Retrospective	9,331	Clinical	CHD + stroke	23	Serious
Lin et al., 2019	Retrospective	161,923	Clinical	Stroke	10	Critical
Lee, Hu, Chou, and Chu, 2015a	Retrospective	720,343	Clinical	MI	10	Critical
Lee et al., 2017	Retrospective	354,850	Clinical	Stroke + MI	12	Critical
Lee et al., 2013a	Retrospective	719,436	Clinical	Stroke	10	Critical
LaMonte et al., 2017	Prospective	57,001	Self-report	CHD + stroke	12	Critical
Joshy et al., 2016	Prospective	172,630	Self-report	CHD + stroke	5	Serious
Joshipura 2003	Prospective	41,380	Self-report	Stroke	12	Critical
Joshipura 1996b	Prospective	44,119	Self-report	CHD	6	Critical
Jimenez et al., 2009	Prospective	1,231	Clinical	Stroke	34	Critical
Hung et al., 2004	Retrospective	100,381	Self-report	CHD	12	Critical
Hung et al., 2003	Prospective	45,094	Self-report	PAD	12	Critical
Hujoel, Drangsholt, Spiekerman, and DeRouen, 2001	Prospective	8,032	Clinical	CHD	20	Serious
Howell, Ridker, Ajani, Hennekens, and Christen, 2001	RCT	22,037	Self-report	Stroke + MI	13	Critical
Holmlund et al., 2017b	Prospective	8,999	Clinical	Any CVD	34	Critical
Heitmann and Gambourg, 2008	Prospective	2,932	Clinical	CHD	7	Serious
Hansen, Egeberg, Holmstrup, and Hansen, 2016	Prospective	100,694	Clinical	Stroke + MI	15	Critical
Dietrich et al., 2008	Prospective	1,203	Clinical	CHD	35	Critical
DeStefano, Anda, Kahn, Williamson, and Russell, 1993a	Prospective	9,760	Clinical	CHD	16	Serious
Chou et al., 2015a	Retrospective	27,146	Clinical	Any CVD	9	Critical
Choe et al., 2009	Prospective	679,170	Clinical	Stroke	14	Critical
Chen, Lin, Chen, and Chen, 2016	Retrospective	787,490	Clinical	AF	10	Critical
Beck et al., 1996	Prospective	1,147	Clinical	CHD + stroke	18	Critical
Batty et al., 2018	Prospective	626,106	Clinical	CHD	21	Serious
Abnet et al., 2005b	Prospective	29,584	Clinical	Stroke	15	Critical

Six types researches looked at the risk of cardiovascular diseases in women, while 14 studies looked evaluated in men. Although five studies did not account for smoking, all studies showed age-adjusted CVD risk. For more information, see Table 2.

Table 2.

Results from meta-regression models demonstrating between-group difference of PD diagnosis, gender, PD severity and region as independent variables

Variable	n	Risk ratio (95% CI)
Diagnosis method
Clinical	19	1
Self-reported	11	0.97 (0.87-1.07)
Gender
Female	6	1
Male	14	1.04 (0.92-1.17)
PD severity
Mild	12	1
Moderate	15	1.10 (0.99-1.22)
Severe	18	1.11 (1.00-1.22)
Region
Asia/Australia	10	1
Europe	4	1.18 (1.03-1.35)
North America	16	1.03 (0.93-1.13)

21 studies had a critical risk of bias by the ROBINS-I assessment, and 11 had a significant risk. Egger’s test showed a significant probability of publication bias (Egger’s test: = 2.91, P = .004).

In general, random effects meta-analysis shows that the risk of CVD is significantly higher in the population with PD than in the general population (RR = 1.20). Due to the large sample sizes used in most investigations, there was a significant amount of heterogeneity (I2 = 97.3%). The risk of stroke increased by 24% in PD (RR = 1.24) and the risk of CHD increased by 14% (RR = 1.14) for individual CVD events with more than six reporting studies. The accuracy of the estimate based on the confidence interval boundaries was not significant, despite the fact that the risk of MI was raised (RR = 1.12).

In studies using clinical PD diagnosis, the risk of all incident CVD was 22% higher in PD and in self-reported diagnosis, it was 17% higher in PD compared with non-PD. Compared to non-PD, men with PD had an incident CVD risk that was 16% higher and women with PD had an incident CVD risk that was 11% higher. However, there was no significant difference in CVD risk between the two genders.

According to the severity of the PD, the risk of incident CVD rose from 9% for mild PD to 23% for moderate PD and 25% for severe. In contrast to moderate PD, severe PD significantly increased the incidence of incident CVD [Table 2].

DISCUSSION

Using longitudinal cohort studies, current research investigated the risk of cardiac events in individuals with periodontitis. The results show that people with periodontitis have a greater risk of all incident CVD events than populations without PD and that this risk is constant regardless of the method used to diagnose PD, the severity of the PD, the gender, or the study locations. The risk of cardiac events is not different between the genders, clinical and self-reported diagnoses, or study regions, although it is related to the severity of PD and those regions.

The meta-analysis calculated the incident cardiovascular risk in PD patients versus non-PD patients. Our findings confirm the qualitative findings of other reviews. Dietrich et al. (2013) reported a considerably higher risk of cardiovascular across 11 out of 12 investigations, but no attempt was made at a meta-analysis.[43] In a narrative analysis Scannapieco, et al., similarly identified a moderately positive correlation between PD and CVD prevalence.[44]

Besides quantifying the risk of total incident CVD, the current study also took incident CHD, stroke, and MI risks into account. Previous evaluations have taken note of the elevated risk of stroke and CHD. The accuracy of the calculation based on confidence intervals shows that the current review did not find a substantial rise in the risk of MI. This may be a result of sample size restrictions and also echoes findings from other reviews.

Although the correlation between the two diseases was not assessed, more recent research on the causal link suggests that the two conditions are related through common inflammatory pathways. Both raised levels of C-reactive protein and platelet counts have been found to represent signs of systemic inflammation. Inflammation-induced cell signaling disruption may lead to cell death and systemic symptoms similar to those seen in circumstances associated with cardiovascular disease (CVD). Additionally, research has shown that PD management may reduce CVD symptoms, and the relationship between the two disorders may be reciprocal.

The current research showed that men with PD had a greater risk of CVD than females did. Despite meta-conclusion regression that gender has no impact on CVD risk, earlier studies have shown that hormonal sex variations may cause dissimilar systemic diseases in the two. To explore this link, the next study should examine gender as an independent risk factor for PD.

Other systematic reviews have confirmed our conclusion that severe PD patients had the highest CVD risk. The current review has shown that there is a gradient between PD severity and CVD risk. Due to the higher CVD risk in the population with severe PD, focused interventions may be more successful in lowering the CVD risk in these groups.

It is debatable if a proxy, like self-reported data, is useful in supporting a PD diagnosis. The current review shows that utilizing clinical PD criteria does not significantly alter the risk of CVD. Earlier research presented that communities underreport the prevalence of self-reported PD, with evidence that the validity of self-reported PD may be biased or error-prone.

Smoking, a significant adjustable risk factor, was not adjusted for in a number of the included studies. Along with amplified PD severity, smoking is also strongly linked to all CVD outcomes. Stress is yet another factor that may interact with PD and CVD because it has both systemic and oral deleterious consequences.

Strengths and weaknesses

Since this meta-analysis is the first of its sort in this field of study, there are certain notable advantages. This review investigated the impact of periodontal disease identification technique, gender, and PD severity on cardiovascular events and specific cardiac diseases using subgroup and meta-regression meta-analysis. This study was also able to infer causation because this systematic evaluation only included longitudinal and RCT trials. The trustworthiness of our findings is strengthened by the thorough adherence to PRISMA principles used in this review.

This study has certain restrictions as well. Due to the observational nature of the eligible studies, there was a high likelihood of confounding factors, bias, and heterogeneity in the pooled findings. Only a small portion of the observed heterogeneity was explained by these studies. Age, for example, could not be measured since complete data for all included research was not accessible. Strong correlations between older individuals with PD and CVD have been shown in cross-sectional studies in the past.

This review attempted to take this into account by classifying observations according to the kind of PD diagnosis (clinical/self-report), although the clinical methods employed for PD diagnosis still have some limitations. For instance, CAL could not be a good indicator of early clinical classification because it is a sign of moderate to severe PD. A full mouth examination is suggested. Since there is evidence that radiography significantly underestimates actual alveolar bone level, it may also not be a valid method for diagnosing PD.

The results of this systematic study support earlier findings that PD and CVD are significantly correlated. Future CVD morbidity and death may be significantly reduced by early therapies that focus on these risk factors and PD therapy, which eliminates the bacterial pathogens that cause CVD.

This evaluation has also uncovered a number of directions for more study. A general case definition for PD is crucial in the near future. By using a common definition, researchers may maintain consistency in their studies of dental health while minimizing bias. To enable reliable meta-analyses in the future, further studies investigating the risk of CVD outcomes in PD, with adjustments for major variables, are needed. Recent studies have shown a solid link between using electronic cigarettes and periodontitis, with e-cigarette users having a higher risk of the disease than smokers of traditional cigarettes. Future analyses should account for smoking, and stress to ensure that confounding effects are kept to a minimum.

CONCLUSION

The findings of the current systematic review show that persons with periodontitis have a higher chance of developing CVD. The highest risk of getting CVD is shown in men and among those with periodontal diseases, suggesting potential objective populations for further public health initiatives. To understand the reason for the results’ heterogeneity and to draw firm conclusions, more investigation is necessary. Future cohort studies should also establish a common clinical case definition for PD to take into account any heterogeneity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.