Over the past four decades, implant restoration has become one of the most popular approaches for replacing missing teeth [1]. With the goal of promoting early and effective osseointegration, dental implants are superior in terms of patient comfort and longevity, with a long-term survival rate of over 90% [2]. After implant placement, osseointegration with surrounding tissue is required and this is the basis for long-term stability of the implant [3]. However, in the course of clinical practice, there are still technical and biological complications that arise [4], and these can destroy osseointegration and threaten the survival of the implant.

Peri-implantitis, similar to periodontitis, occurring in the tissue surrounding the implant, is believed to be a pathological condition principally associated with dental plaque [5]. The main characteristics of peri-implantitis is the inflammation of the peri-implant mucosa and subsequent progressive loss of supporting bone. Studies have shown that the incidence of peri-implantitis can be as high as 22% (range: 1%–47%) [6], and the control of disease requires early diagnosis and early prevention. According to the third working group of the World Dental Federation Consensus Conference in 2018, Renvert et al. [7] summarized the diagnosis of peri-implantitis as follows: (i) Bleeding and/or suppuration on light probing; (ii) increased probing depth compared to baseline; and (iii) bone loss due to initial bone remodeling that exceeds changes at the crest bone level. The occurrence of peri-implantitis is related to many factors. Several studies [8, 9] concluded that history of chronic periodontitis, poor plaque control, and smoking are all risk factors for peri-implantitis. In addition, others [10] have shown that the presence of systemic diseases may have an impact on osseointegration, which is detrimental to the health of implants. However, Diz et al. [11] have stated opposing opinions on the existence of systemic diseases. Specifically, these investigators argue that for implant surgery, absolute contraindications are rare, and for systemic diseases, good control is more important than the nature of the disease itself. Recent observations [12] have found that diabetes will result in an increased incidence of peri-implantitis, however, there is no conclusive relationship between cardiovascular disease and peri-implantitis.

Cardiovascular disease (CVD), a class of diseases that occur in the heart and blood vessels, include hypertension, coronary heart disease, and atherosclerosis. From a global perspective, CVD is the leading cause of disease burden [13] and the major reason for mortality, although the survival rates affected by CVD have improved significantly over the past few decades [14]. Domestically, between 1990 and 2016, the age-standardized prevalence of CVD in China increased by 14.7%, and the number of deaths from CVD increased from 2.51 to 3.97 million [15].

More than a century ago, oral sepsis and tooth extraction were considered to be causes of infective endocarditis, and connecting local oral infection with systemic diseases [16]. Furthermore, others have reported that there are certain commonalities between CVD and periodontal disease. For example, periodontitis will lead to the damage of circulating progenitor cells, the number and function of which are markers of endothelial damage related to CVD and are used to evaluate the ability of vascular repair following CVD [17]. At the transcriptional level, periodontitis and periodontal inflamed surface area can predict the level of micro RNAs (miRNAs) associated with subclinical cardiovascular disease risk [18]. More importantly, several studies [19, 20] have shown that patients with CVD with previously diagnosed periodontitis have a significantly increased risk of death. As to the relationship between CVD and peri-implantitis, an inflammatory disease that also occurs in periodontal/peri-implant tissue, a study [21] found that there was a correlation between the risk markers of CVD and peri-implantitis and that high levels of triglycerides and uric acid are not only biochemical markers of CVD but also risk parameters for peri-implantitis. Further examination of the correlation between cardiovascular disease and peri-implant inflammation may prompt clinicians to employ relevant measures prior to the implant operation to improve the success rate of implant and alleviate patient pain. Moreover, this correlation may further support an association between local inflammation and systemic diseases and promote research into this process. Therefore, the present systematic review and meta-analysis aims to augment existing knowledge by including observational studies, such as retrospective and case-control studies to examine the relationship between peri-implantitis and cardiovascular disease.

This systematic review was performed to summarize the relationship between peri-implant pathology and CVD. Rigorous evaluation of this correlation required a strict definition of peri-implantitis. As outlined above, peri-implantitis was defined as an inflammatory reaction with concomitant loss of supporting bone in tissues surrounding implant. To further improve data reliability, only studies that evaluated the risk of peri-implantitis with and without CVD were included in this meta-analysis. Starting with an initial 272 studies selected using automated approach, the by enforcing outlined inclusion criteria and in-depth analysis of these reports led to the selection of 5 articles for inclusion in this review. Moreover, these included studies had no less than a score of 5 using the NOS scale. The results show that peri-implant inflammation is more likely to occur in patients with CVD.

To our knowledge, this study is the first systematic review and meta-analysis to examine the relationship between peri-implantitis and CVD from the point of view of clinical incidence. However, some comparable information regarding this area is available from other reports. For example, studies have shown a common relationship between CVD and periodontitis [29]. Periodontal disease may have a negative impact on CVD [30], which appears to be linked to the level of circulating progenitor cells. Specifically, other studies determined that circulating endothelial progenitor cells play a significant role in the etiology of periodontitis, and the level of circulating endothelial progenitor cells is inversely correlated with the severity of periodontitis and periodontal disease [17]. In some respects, peri-implantitis is similar to periodontitis, and may share key pathogens such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Tannerella forsythia [31, 32, 33]. Others [2] showed that in patients with hypertension who underwent implant restoration that although there was no impact on implant survival during the study, there was some adverse effect on clinical parameters of the peri-implant tissue. Such effects included probing depth and the differences were found to be statistically significant. In addition, Wang et al. [34] reported the differences between patients with and without CVD and found that the levels of some systemic pro-inflammatory factors such as IL-1$\beta$, TNF-$\alpha$, and MMP-8 were significantly higher in the patients with CVD than those without CVD. Finally, others [35] showed that MMP-8 is an important predictor of periodontitis and peri-implantitis, thus further supporting the relationship between peri-implantitis and CVD.

In a retrospective study by Saaby et al. [36], 26% of patients with peri-implantitis, as defined as bone resorption of $\ge$2 mm and with bleeding or pus on probing, had CVD. In addition, 27.3% of patients with peri-implantitis in the study by Revent et al. [24] had CVD, with an OR value of 8.7. These findings indicate that patients with CVD have a significantly higher risk of developing peri-implantitis after implant restoration compared with non-CVD patients. Moreover, these findings are consistent with the results of our study.

In this review, results obtained show an association between peri-implantitis and CVD (RR = 1.12, p = 0.02), and that this supports a correlation between local inflammation and the whole-body burden caused by systemic disease. However, our study has some limitations. First, there is a high degree of heterogeneity between selected studies, which may be due to uncontrolled treatment-related factors, such as the number of missing teeth, the three-dimensional position of implantation, and the type of superstructures. Second, none of the five included studies reported the statistical impact on their findings due to lost patient follow-up. Third, potential publication bias stemming from only analyzing studies published in English is possible. Therefore, to obtain firmer conclusions, clinical trials with larger sample sizes, longer follow-up periods, and well-controlled confounders are required.

The conclusion of this systematic review and meta-analysis clearly indicates that the presence of CVD increases the risk of peri-implantitis. Clinicians need to control CVD as much as possible before implant surgery to reduce the possibility of postoperative complications such as peri-implantitis. Since relevant studies are still limited, additional clinical studies are needed to further refine these conclusions.

CVD, Cardiovascular diseases; CS, case-control study; RC, Retrospective cohort study; NR, Not Reported; PD, Probing depth; BOP, Bleeding on probing; RBL, Radiological bone loss.

DC and ZF have contributed to the development of the research question and study design. DC and RW developed the literature search, performed the study selection, analysed the data and interpreted the results. DC wrote the manuscript. ZF edited the article. RW revised the final manuscript with DC. All authors reviewed and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

Not applicable.

2021 Key Special Project of National Key R&D Plan (2021YFC2400400). Scientific research project of Shanghai Municipal Health Commission (202040094).

The authors declare no conflict of interest.