Cardiovascular disease (CVD) is a class of diseases involving the heart and blood vessels. It is also commonly known as heart and vascular disease (1). CVD encompasses a range of conditions that can affect the heart and blood vessels, including coronary artery disease, stroke, heart failure, arrhythmias, valvular heart disease, etc. However, periodontitis (PD), a severe form of gum disease, has been found to affect cardiovascular disease potentially. The link between periodontitis and cardiovascular disease has been explored through various studies and research efforts (2, 3). Both periodontitis and CVD share common risk factors such as smoking, diabetes, obesity and age. Moreover, periodontitis was found to be significantly correlated with heart failure, myocardial infarction, endocarditis, acute coronary syndrome, and atherosclerosis.

While more compelling and indicative evidence has come forth, emphasizing a potential causal association between these two pathologies, further research is imperative to definitively establish PD as an independent risk factor for CVD (4). Furthermore, an array of potential mechanisms have been explored in previous studies. Endothelial dysfunction, systemic inflammation and immune response, including C-reactive protein, interleukins, thrombotic markers and antibodies, have all been observedin patients with PD and CVD. Nonetheless, no study has definitively elucidated the precise mechanism that directly links PD to CVD. Periodontal pathogens (Porphyromonas gingivalis Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Fusobacterium nucleatum and Treponema denticola) and their byproducts such as hemagglutinins, lipopolysaccharides (LPS), and gingipains were also found to contribute to the development of CVD (5). However, it is difficult to determine what kind of pathogens' byproducts play a vital role in the process. LPS, released by periodontal pathogens could activate TLR4/NF-κB inflammatory pathway which is associated with CVD, could also derive from the large intestine (6). Based on the above issues, a better understanding of the PD and CVD relationship and a well-designed method are needed to clarify the complex network.

Bibliometrics, the quantitative study of scientific literature and research output, can play a valuable role to provide with visual representation of impact and influence of the current research. Compared with literature reviews and systematic reviews, bibliometrics offers objective data analysis with scalability and efficiency. It reduces the potential bias introduced by subjective decision-making. By analyzing publication trends over time, bibliometrics can identify emerging research areas and hot topics in specific fields. This can be particularly useful for researchers to stay updated with the latest developments and plan their strategies accordingly. As far as we know, there have been no Bibliometric analyses that can specifically on the associations between periodontal disease and various cardiovascular diseases. This bibliometric analysis is to analyze the overall features, research hotspots, and future research trends of the links between PD and CVD. Combining bibliometrics, experimental studies, clinical trials, and other research methods can contribute to a more comprehensive understanding of the relationship between periodontitis and cardiovascular disease.

This study presents a visualized analysis of the association between periodontitis and CVD, identifying several characteristic qualities of this research field. The examination is based on articles and reviews published within this field up to May 15, 2023. Data were sourced from the Web of Science Core Collection (WOSCC) and analyzed using CiteSpace, VOSviewer, and Bibliometrix to evaluate the current research landscape and emerging trends. The surge in published content indicates an escalating interest in the interplay between these two diseases, with dentistry emerging as the primary research domain. While periodontal disease-related journals represent the main platforms for publication, several highly-cited articles have also found their place in general scientific research journals. Analysis of countries, institutions, and authors suggests limited global collaboration, with the United States outpacing other nations in terms of research output.

In a paper, the judicious use of keywords enables accurate and rapid identification of a study's themes and topics. This principle is equally applicable to bibliometrics, where keyword analysis provides insights into research trends in a specific field. Table 5 exhibits the top 20 most frequent keywords, predominantly focusing on PD, cardiovascular diseases, disease mechanisms, periodontal pathogens, among others. Prominent keywords such as “inflammation”, “C-reactive protein”, “Porphyromonas gingivalis”, and “infection”, suggest that inflammation and oral infection are critical links between periodontitis and CVD, defining prevalent research directions. Our study incorporates a co-occurrence analysis of 86 keywords that appeared more than 20 times. As illustrated in Figure 9A, these keywords, represented as nodes, form a complex network where the size of a node corresponds to the keyword's frequency and indicates the primary discussion topics linking periodontitis and CVD. Furthermore, the emergence of four distinct clusters from these keywords reaffirms the aforementioned inference that both inflammation and oral infection are significant factors in the interplay between these two diseases.

Figure 8A indicates that the latest burst references are Sanz M (8) and Aguilera EM (9), with Hajishengallis G (10) yielding the highest burst citation strength of 15.49. The latter review discusses two potential mechanisms connecting periodontitis to cardiovascular disease. Initially, gingival ulceration within the periodontal pocket allows bacteria to enter systemic circulation, leading to bacteremia, a condition frequently observed in periodontitis patients that may provide an atherogenic stimulus. Alternatively, a mice study suggested that the bacteria Porphyromonas gingivalis could alter gut microbiota, indirectly inducing systemic inflammation (11). Sanz M's paper, the most recent reference to exhibit a strong citation burst in our study, is a consensus report on the PD-CVD connection. The paper concludes that the robust epidemiological evidence linking periodontitis to an increased risk of future atherosclerotic cardiovascular disease, affirms the biological plausibility of periodontitis's impact on CVD.

Regarding the keyword thematic map produced by R-Bibliometrix (Figure 10B), two clusters are prominent in the upper right quadrant, including “oral microbiota”, “Porphyromonas gingivalis”, and “biofilm”. These terms, distinguished by their high density and centrality, signal well-established and core research themes within the periodontitis and CVD interplay. Meanwhile, keywords like “saliva” and “peri-implantitis” situated in the third quadrant represent burgeoning topics that are yet to be fully explored, thus likely to be focal points in future research. Notably, a cluster straddling the right and left upper quadrants includes “COVID-19”, “microbiome”, and “comorbidities”, terms that have garnered increasing attention in recent years.

The top 20 most frequent keywords included“Porphyromonas gingivalis” and “infection”, while the top 50 keywords included “Actinobacillus actinomycetemcomitans”, “pathogens”, “bacteria”, “bacteremia”, “dental infections”, and “plaque”. As shown in the keyword thematic map, “oral microbiota”, “Porphyromonas gingivalis”, and “biofilm” were well-established and core research themes. Considering the above results, periodontal pathogens, especially Porphyromonas gingivalis, are likely potential initial factors for the connection to cardiovascular disease. The Porphyromonas gingivalis, a significant pathogen of periodontal diseases, has been implicated in the development and progression of several cardiovascular diseases. Here are some cardiovascular conditions that may be affected by Porphyromonas gingivalis, such as atherosclerosis, myocardial infarction, stroke and endocarditis. Porphyromonas gingivalis, can potentially affect cardiovascular diseases through various mechanisms (12, 13). First of all, Porphyromonas gingivalis can induce a localized inflammatory response in the gum tissues affected by periodontal diseases. The release of bacterial toxins and pro-inflammatory molecules by Porphyromonas gingivalis can lead to the production of inflammatory mediators such as cytokines and acute-phase proteins, including Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8) and Interleukin-17 (IL-17) (5, 14). These inflammatory mediators can enter the bloodstream and promote systemic inflammation throughout the body, including the blood vessels and arterial walls. Systemic inflammation can contribute to the development of atherosclerosis, plaque destabilization, and increased risk of cardiovascular events. Widen et al. found out that serum levels of Interleukin-8 had increased significantly in acute coronary syndrome (15). Furthermore, Porphyromonas gingivalis induced inflammation can negatively impact the endothelial cells that line the blood vessels, leading to endothelial dysfunction (16). Endothelial dysfunction is a crucial early step in the development of atherosclerosis, acute coronary syndrome and myocardial infarction. The bacterial toxins released by Porphyromonas gingivalis can impair the normal functioning of endothelial cells, affecting their ability to regulate vascular tone, promote vasodilation, and maintain proper blood flow (17). Belanger's study (18) showed that Porphyromonas gingivalis expressing hemagglutinin A, had an increased capability to adhere to and invade human coronary artery endothelial cells. Lastly, the immune response triggered by Porphyromonas gingivalis and its byproducts can contribute to the formation of atherosclerotic plaques (19). The bacterium can activate immune cells leading to their recruitment to the arterial walls affected by atherosclerosis. Peptidoglycan, one kind of byproduct of P. gingivalis, could elevate intercellular adhesion molecule-1 production to promote monocyte migration to the cardiac endothelium (20). These immune cells, along with Porphyromonas gingivalis-induced inflammation, promote the uptake of modified low-density lipoprotein (LDL) by macrophages, resulting in the formation of foam cells (21, 22). P. gingivalis promotes lipid accumulation in macrophages by upregulating CD36 and inhibiting cholesterol efflux from macrophages by promoting lysosomal integral membrane protein 2 (23, 24). By interfering with lipid metabolism, P. gingivalis promotes macrophages to covert to foam cells. Foam cells accumulate in the arterial walls and are a hallmark of early atherosclerotic lesions (25).

Furthermore, some interventional studies have investigated the impact of controlling periodontal pathogens on cardiovascular outcomes by periodontal treatment. While the results are mixed, some studies have shown that periodontal treatment, such as scaling and root planning, can lead to improvements in cardiovascular measures, including endothelial function and arterial stiffness. Caúla's research (26) showed that periodontal treatment was effective in reducing inflammatory markers related to the risk for cardiovascular disease in 6 months, such as C-reactive protein, cholesterol, and triglycerides. D'Aiuto et al. had similar conclusions in their studies (27). Periodontal treatment reduced inflammatory plasma levels, including C-reactive protein, interleukin-6 and tumor necrosis factor-alpha. Interestingly, Graziani et al. had found that full-mouth scaling and root planning were more effective in systemic inflammation reduction than multiple quadrant scaling and root plannings (28). Based on one of the most cited articles in our study, the American Heart Association supported an independent association between periodontitis and atherosclerotic cardiovascular disease (29). Therefore, substantial evidence has supported that periodontal bacteria could contribute to cardiovascular disease as an important potential independent risk factor.

The relationship between periodontal pathogens and cardiovascular disease is a complex and evolving area of research. While the exact mechanisms are not fully understood, several hypotheses have been proposed to explain how periodontal pathogens may influence the development and progression of cardiovascular disease, such as inflammation, bacteremia, endothelial dysfunction, immune response and autoimmunity, platelet activation, and clot formation, among others (4, 30). According to our study, the most frequent keywords related to the mechanisms were “inflammation” and “C-reactive protein,” whose appearance ratios in our 1,116 articles as keywords were 28.94% and 22.22%, respectively. These ratios were significantly higher than those of other keywords, such as “endothelial dysfunction” (6.36%), “oxidative stress” (3.76%), “lipopolysaccharide” (2.42%), and “antibodies” (2.15%). In general, the appearance ratios of keywords related to inflammation, including various inflammation mediators, were remarkably higher than those of other mechanism-related keywords. A growing body of literature suggests that inflammation might be the more likely way for periodontal pathogens to affect cardiovascular disease.

The role of inflammation is crucial in understanding the associations between periodontitis and cardiovascular disease. When periodontal tissues become inflamed, pro-inflammatory cytokines and other inflammatory mediators are released into the bloodstream (31). These inflammatory markers can directly affect the vascular endothelium. The systemic mediators of inflammation released from inflammatory periodontal tissues included C-reactive protein, interleukins and matrix metalloproteinases (32, 33). Besides inflammatory cytokines, antibodies could also mediate system inflammation. Antibodies can stimulate the immune response and trigger an inflammatory cascade (34). Hajishengallis' article summarized that, when antibodies recognize and bind to periodontal antigen, they can activate immune cells such as macrophages, neutrophils, and T cells to release pro-inflammatory molecules into blood vessels, promoting the development of atherosclerosis and contribute to cardiovascular risk (10). Pussinen, who had the most publications in our study, found that serum antibodies to Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis were associated with coronary heart disease in a study containing 1,000 samples (35). Some studies suggested that antibodies produced against periodontal pathogens can cross-react with proteins present in cardiovascular tissues (36, 37). IgG anti–beta-1-adrenorecepters extracted from periodontal patients could work against rat cardiac membranes in vitro. Those patients with periodontitis who had IgG anti–beta-1-adrenorecepters had showed lower heart rate variability, which means impaired contractility of the heart (38, 39). When antibodies mistakenly recognize and target cardiovascular proteins due to their similarity to periodontal antigens, they can trigger an autoimmune-like response. This response can lead to chronic inflammation and contribute to the development of CVD. To sum up, studying how periodontal pathogens mediate the impact on cardiovascular disease through inflammation and inflammatory mediators is currently a research hotspot, and it holds great potential as a future research direction.

Moreover, certain genetic background can predispose patients to suffer from periodontitis and cardiovascular disease more easily than others. Teeuw WJ et al. (40) demonstrated a significant association between ANRIL and periodontitis, as well as an association between ANRIL variations and C reactive protein levels in periodontitis patients, further proving that genes are risk factors in both periodontitis and systemic inflammation.

Regarding the various cardiovascular diseases related to PD, the top 5 keywords included “atherosclerosis,” “coronary heart disease,” “myocardial infarction,” “coronary artery disease,” and “acute myocardial infarction” in our study. Atherosclerosis is the most common type of cardiovascular disease and a major cause of coronary heart disease, myocardial infarction, and other related complications. Epidemiologic studies have strongly associated periodontitis with atherosclerotic disease (41, 42). At least, 11 studies have reported positive associations between periodontitis and atherosclerotic cardiovascular disease (41, 42). Hayashida et al. reported a dose-dependent association between periodontal pocket depth and markers of atherosclerosis in 2013 (43). In Beukers' study, which included 60,174 cases, periodontitis was linked with acute cardiovascular disease with an odds ratio of 2.52. In another study, periodontitis was found significantly associated with the incident of acute myocardial infarction, with an odds ratio of 2.4 (2). Moreover, Górski et al. found that the extent of periodontitis was more strongly associated with acute myocardial infarction than the severity (44).

In addition to the previously mentioned epidemiological investigations, a multitude of biological plausibilities have been put forth to elucidate the connection between periodontal diseases and atherosclerosis (30). It is hypothesized that these bacteria may contribute to the formation and progression of atherosclerotic lesions. Available evidence has been presented and evaluated. The incidence rate of bacteremia can reach 49.4% after periodontal treatments (45). At the same time, the bacteria associated with periodontal diseases, such as Porphyromonas gingivalis, have been found in atherosclerotic plaques with new approaches to target periodontal bacteria's DNA, RNA and antigens (46). Furthermore, some scholars have found live P. gingivalis in atheroma or isolated P. gingivalis from cultured atheromatous tissue (5). To further demonstrate the role of periodontal infections in cardiovascular diseases, periodontal pathogens have been colonized on different animal models and proven to induce or promote atherosclerotic lesions. On the contrary, the noninvasive mutant of P. gingivalis did not promote atherosclerosis and induced fewer pro-inflammatory mediators than the wild type (47, 48).

Besides atherosclerosis, endocarditis is also believed to be associated with periodontitis (49). The bacteria present in the periodontal pockets can travel through the bloodstream and reach other parts of the body, including the heart (50, 51). The bacteria can form clumps or colonies on the valves, leading to the formation of infective endocarditis lesions. These lesions can cause inflammation and damage to the heart tissues. According to Herbert Deppe's study, 10% of bacterial sources of infective endocarditis are from oral pathogens (52). Furthermore, Rinaldo et al. also reported that infective endocarditis in patients with heart valve prostheses was mainly caused by oral bacteria in young male adults in Brazil and 77% of infective endocarditis cases were at high or moderate risk for periodontal disease (53).

Apart from the extensively studied roles, certain prominent subjects have significantly contributed to the interplay between periodontitis and CVD. However, those topics need further research to clarify their roles, such as COVID-19 and peri-implantitis.

In the aftermath of the COVID-19 pandemic, numerous studies (3) (54–56) have surfaced suggesting a potential connection between periodontitis and COVID-19, both of which appear to induce and exacerbate various cardiometabolic complications (57). The nexus between COVID-19 and PD is intricate and multifaceted, with evidence implying a shared inflammatory pathophysiology (58). This inflammation can instigate endothelial dysfunction, oxidative stress, and coagulation irregularities, thereby fostering the onset of cardiometabolic complications (59), including cardiovascular disease, type 2 diabetes, and metabolic syndrome. Several researchers have highlighted the possible role of oral bacteria and their byproducts in triggering systemic inflammation, thereby contributing to the progression of COVID-19 and associated cardiometabolic complications (35). Recent findings further underscore that individuals with periodontal disease (60) or cardiovascular disease (61) exhibit a higher susceptibility to severe COVID-19 infection. Therefore, in the current scenario of coexistence between humans and the COVID-19 virus, it is crucial to manage these underlying conditions to reduce the risk of severe outcomes in the event of a COVID-19 infection.

Peri-implantitis is characterized by inflammation, bleeding, bone loss, and potential implant failure which is deeply related to periodontal tissue. Some studies have indicated that there might be a correlation between the presence of peri-implantitis and an increased risk of cardiovascular disease (62, 63). It has been proposed that the chronic inflammation associated with peri-implantitis could contribute to the development or progression of cardiovascular conditions (64). Hom-Lay Wang's studies showed that 64.6% of peri-implantitis was found in CVD patients, while only 56.5% of peri-implantitis was found in the controls (65). Moreover, IL-1β and TNF-α were significantly higher in CVD patients, which were significant markers for peri-implantitis (66). Inflammation plays a crucial role in the pathogenesis of atherosclerosis, the underlying cause of many cardiovascular diseases. The theory suggests that the systemic inflammatory response triggered by peri-implantitis could potentially contribute to the development or worsening of cardiovascular problems.

While the exact nature of the relationship between periodontitis and cardiovascular disease is still being explored, research studies have shown an association between the two. It is important to note that association does not necessarily imply causation, and more research is needed to establish a definitive cause-and-effect relationship. Nevertheless, the current bibliometric studies above not only help us to understand the relationship between periodontitis and cardiovascular disease by analyzing the keyword trends in recent years, but also show us potential general directions for future research. Given that our study's primary recommendations encompass periodontal pathogens (notably Porphyromonas gingivalis), inflammation, and atherosclerosis, we propose that future research endeavors focus on these three trajectories. The exigency for research in these three dimensions becomes particularly evident in the concluding lines of our article.

This study provides a systematic summary of global publication trends, aiding scholars in identifying essential authors, institutions, and journals within the field of interest. Moreover, through keyword and co-citation clustering analysis, this study offers valuable guidance to researchers in selecting promising research directions within the subject area. Future research in this domain should aim to conduct longitudinal studies with larger sample sizes to provide more robust evidence of the relationship between periodontitis and CVD. Rigorous clinical trials will help determine whether treating periodontal disease has a tangible impact on cardiovascular health and vice versa. Positive findings from such trials could revolutionize treatment approaches, leading to integrated management plans that address both diseases simultaneously. This holistic approach has the potential to yield improved patient outcomes and quality of life. Additionally, fostering multidisciplinary collaboration among dental practitioners, cardiovascular specialists, immunologists, and researchers from related fields can foster a robust exchange of knowledge and innovative ideas. The collective expertise and resources can accelerate the pace of research, driving forward novel discoveries and therapeutic breakthroughs. Anticipated future collaborations among authors, institutions, and countries are likely to expedite the development of research in the realm of periodontitis and CVD.

The study is not without limitations. First, due to constraints in the currently utilized scientometric software, combining multiple databases for analysis proves challenging. Consequently, this study relied solely on the WoSCC database for literature screening, potentially leading to the omission of relevant publications. To address this limitation, future efforts will involve the inclusion of additional databases for analysis. Second, the inclusion of only English articles in this article resulted in a reduced pool of retrieved articles. Third, certain recently published literature updates were regrettably omitted. Furthermore, the lack of a unified standard for configuring CiteSpace, VOSviewer, and Bibliometrix settings introduces the possibility of deviations in the visual analysis. Additionally, the uneven quality of the collected literature data can compromise the credibility of the generated atlas.

In conclusion, the results of the visual analysis provide a comprehensive overview of the current landscape of research on periodontitis and CVD, offering valuable insights for future research directions. The highest number of articles originated from the USA, Japan, and Sweden; the University of Helsinki and Karolinska Institute emerged as the leading publishers; and eminent scholars include professors D'Aiuto, Francesco and Beck, James D. Current research targets the periodontitis-CVD mechanism, highlighting microbial co-initiators like Porphyromonas gingivalis and the key shared mechanism of inflammation. The strong association between atherosclerosis and periodontitis is well-established. However, it requires more research for a definitive cause-and-effect relationship between PD and CVD. Furthermore, it is crucial for future research to explore the development of therapeutic management strategies for both two diseases that effectively balance systemic and oral health care. Additionally, fostering collaborative relationships among authors and regions to establish standardized industry-recognized guidelines and consensus are highly necessary.