|Year : 2016 | Volume
| Issue : 1 | Page : 4-11
Endothelial dysfunction and periodontitis: The role of inflammatory serum biomarkers
Reila Tainá Mendes1, Daniel Fernandes2
1 Department of Dentistry, Universidade Estadual de Ponta Grossa PR, Paraná, Brazil
2 Department of Pharmaceutical Sciences, Universidade Estadual de Ponta Grossa PR, Paraná, Brazil
|Date of Web Publication||24-Feb-2016|
Reila Tainá Mendes
Department of Dentistry, Room 94, Block M, Ponta Grossa State University, Ponta Grossa, Paraná
Source of Support: None, Conflict of Interest: None
Introduction: Periodontitis is a local chronic inflammation with systemic consequences. Many disorders are associated with periodontitis such as diabetes, high-serum low-density lipoprotein (LDL), and premature birth. Cardiovascular disease does not correspond to a classic risk factor for periodontitis but evidence suggests that endothelial dysfunction due to systemic inflammation may be the link between both pathologies. The aim of this study was to review the literature regarding endothelial dysfunction and periodontitis and to establish a possible link through systemic inflammatory biomarkers. Methods: We searched the terms "periodontitis and endothelial dysfunction" and "periodontal disease and endothelial dysfunction" in the following four databases: PubMed, Cochrane, Bibliografia Brasileira de Odontologia-Brazilian Bibliography in Dentistry (BBO), and Embase. Results: Both diseases share same systemic biomarkers. Conclusion: Endothelial dysfunction may be the link between periodontitis and other diseases such as cardiovascular ones.
Keywords: Biomarkers, cardiovascular diseases (CVDs), endothelial cells, inflammation, periodontitis
|How to cite this article:|
Mendes RT, Fernandes D. Endothelial dysfunction and periodontitis: The role of inflammatory serum biomarkers. Dent Hypotheses 2016;7:4-11
| Introduction|| |
Cardiovascular diseases (CVDs) are the main cause of death in Western countries.  CVDs have a complex and multifactorial etiology, which is determined by risk factors such as genetics and environmental conditions. These risk factors are smoking, sedentary lifestyle, age, and gender. Despite these, in the past two decades inflammation has been considered to be a potential risk factor for CVDs. Inflammation may participate in all stages of the disease, from the beginning until its progression. Important examples of these inflammatory conditions are oral infections such as periodontitis. The first stage of periodontitis is gum inflammation, which is called gingivitis. It is caused by aerobic gram-positive bacteria and its main clinical sign is bleeding of the gums. If left untreated, gingivitis may progress to periodontitis, a condition in which anaerobic gram-negative bacteria are uppermost and which is characterized by alveolar bone resorption and the loss of the clinical attachment level.
Although the relationship between periodontitis and CVDs has not yet been fully established,  it seems that systemic inflammation due to periodontitis leads to a vascular inflammation, which compromises the endothelial cells. Endothelial cells cover the vascular tree of all organs and are the first cells to be in contact with bacteria and their products. Thus, these cells are easily affected by inflammatory/infectious processes.  Moreover, many studies have shown the presence of endothelial dysfunction in patients with periodontitis. ,,,,, The hallmark of endothelial dysfunction is impairment of endothelial-dependent vascular reactivity, which is considered as the first stage in the development of CVDs such as hypertension and atherosclerosis.  Additionally, endothelial dysfunction may be one of the possible links between periodontitis and CVD. However, the true association between both the pathologies has not yet been established.
The main objectives of this review are:
- To clarify the association between endothelial dysfunction and periodontal disease;
- To clarify the improvement in systemic inflammation due to periodontal therapy through assessment of the serum level of specific biomarkers;
- And to clarify the most common biomarkers related to both pathologies.
| Methods|| |
Search strategy and inclusion
The terms "periodontitis and endothelial dysfunction" and "periodontal disease and endothelial dysfunction" were searched in the following four databases: PubMed/Medline, Cochrane, and Bibliografia Brasileira de Odontologia - Brazilian Bibliography in Dentistry (BBO). No limits for date, journal, or any other criterion were performed. The search was performed on October 16, 2015.
Criteria for including studies in this review
The articles obtained in the search were analyzed by titles and abstracts and were selected (or not) for potential inclusion in this review. Publications in English and Portuguese were included.
Original studies were included if they met the following criteria:
- Randomized controlled trials involving patients with periodontitis and endothelial dysfunction without any other risk factor for CVD; and
- Observational studies involving patients with periodontitis and endothelial dysfunction without any other risk factor for CVD.
Review articles, animal studies, in vitro studies, pilot studies, studies that included patients with other systemic diseases, studies that included patients with aggressive periodontitis, and studies that analyzed periapical periodontitis were excluded.
PICO was defined such as P (patient): Patients affected by periodontitis; I (intervention): Periodontal therapy; C (comparison): Before and after the therapy or the presence or absence of periodontitis; and O (outcome): Biomarker levels.
| Results|| |
The method used to select the studies is shown in [Figure 1]. Our search of PubMed/Medline, Embase, Bibliografia Brasileira de Odontologia - Brazilian Bibliography in Dentistry (BBO), and Cochrane Library initially retrieved 151 publications. One hundred and twenty eight of these were excluded because they were review articles or because they did not match our review focus. Fifty-four of them were duplicated and were excluded as well. We obtained and reviewed the full text of the remaining 23 articles. Out of these, four were excluded because they consisted of review articles (in these four cases, the title and abstract were not sufficient to rate them as review articles) and one was an in vitro study. Three others had diabetes as the main focus of the study, two concerned patients with other cardiovascular risk factors, one concerned patients with aggressive periodontitis, and another was also excluded because it was a pilot study. Finally, 11 studies were included in this review: Eight randomized controlled trials, one cross-sectional study, one case-control study, and one longitudinal study.
The characteristics of these 11 studies are shown in [Table 1].
We included seven randomized controlled clinical trials, ,,,,,, one case-control study,  one longitudinal study,  and two cross-sectional studies. , All the studies included patients with chronic periodontitis and all of them analyzed the serum levels of specific biomarkers. Three studies ,, compared two groups (healthy and periodontitis) before and after periodontal therapy. Five studies ,,,, compared the same group before and after therapy. Three studies ,, performed no treatment and the comparisons were made between two groups: Periodontitis group and the control group. Taking all the data together, the studies included patients aged 22-80 years.
Outcome of the studies
The selected studies analyzed the serum level of polymerase chain reaction (PCR), tissue plasminogen activator (t-PA), low-density lipoprotein cholesterol (LDL-C), tumor necrosis factor-alpha (TNF-α), von Willebrand factor, fibrinogen, cluster of differentiation 14 (CD14)+, CD36+, CD14+, toll-like receptor (TLR)2+, CD14+, TLR4+, endothelial progenitor cell (EPC), and/or circulating progenitor cell (CPC). All of these biomarkers were associated with endothelial dysfunction. PCR was the most common biomarker related to both periodontitis and endothelial dysfunction. Among the selected studies, PCR was associated with periodontitis and endothelial dysfunction in five studies. ,,,, LDL was associated with both pathologies in only one study  among the five studies that investigated that biomarker. ,,,, Only one study  investigated t-PA and found it to be related either to periodontitis or to endothelial dysfunction. TNF-α was evaluated in two studies , but only one  found it to be associated with both pathologies. TNF-α receptors were associated with endothelial dysfunction but not with periodontitis.  Fibrinogen was analyzed by two studies, , which found it to be associated with endothelial dysfunction. Only one  study associated fibrinogen with both periodontitis and endothelial dysfunction.
| Discussion|| |
The concept that focal infection could be a cause of systemic disorders was first established by Billings in 1912.  At that time, there was great interest concerning the idea of oral infection as the first stage of disorders in distant organs. The study of oral infection/inflammation as a risk factor for other diseases started in 1989, in a Finnish study about the association between tooth loss and CVDs.  At present, the association between periodontal disease and CVDs is well-established; however, the relevance, as well as the nature of this association, remain unknown. 
Many inflammatory conditions are associated with endothelial dysfunction. Endothelial dysfunction is characterized by a lack of nitric oxide bioavailability, which compromises the endothelium function and leads to cardiovascular complications.  Nitric oxide is an important vasodilatory agent and a regulator of vascular tone and platelets aggregation. Consequently, this might be one of the links between periodontitis and CVDs because periodontitis is a chronic inflammatory condition that can possibly lead to endothelial dysfunction. However, this association remains unclear.
Aiming to clarify this association, some researchers have investigated the relationship between both conditions. In this review, we pooled and analyzed data from seven randomized controlled trials, two cross-sectional studies, one case-control and one longitudinal study that compared the effects of periodontitis on endothelial function and inflammatory serum biomarkers. The results of our analyses showed that periodontal disease has a strong association with endothelial dysfunction, which is restored after periodontal therapy. The improvement of endothelial function due to periodontal therapy may be confirmed by the reduction in some serum biomarkers of CVD and endothelial dysfunction that are upregulated during periodontitis and return to normal levels after periodontal therapy [Table 2] and [Figure 2]. The present review addressed the following question: Which is the association between each specific systemic biomarker (also present during endothelial dysfunction) with periodontitis?
|Figure 2: Role of periodontitis and systemic inflammation. Periodontitis may generate endothelial dysfunction, which in turn is the first step of cardiovascular diseases. Although the exact mechanisms are not yet defined, some serum biomarkers are identified and may be used as a sign of the disease|
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|Table 2: Studies that investigated the biomarkers related to periodontitis, CVD and endothelial dysfunction|
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Is periodontal disease associated with C-reactive protein?
C-reactive protein (CRP), which is an acute-phase reactant, is a nonspecific marker of inflammation.  Many conditions can be related to its overexpression such as diabetes mellitus,  CVDs and endothelial dysfunction.  CRP directly impairs the endothelium both in vitro and in vivo. In vitro studies have associated CRP treatment with a reduction in endothelial nitric oxide synthase (eNOS) activity in endothelial cells.  Clinical studies have shown that patients with high levels of serum CRP presented a reduced capacity to activate eNOS and produce NO  : NO reduction is a specific feature of endothelial dysfunction. Additionally, evidence has shown a relation between CRP and periodontitis. 
In the past decade, some studies have attempted to elucidate the relationship between periodontitis and CRP overexpression. The cross-sectional study by Joshipura et al. in 2004  showed an expressive association between periodontal disease and elevation in serum CRP. The study enrolled 468 men without any other risk factors for CVD.  This association was also demonstrated in a longitudinal study by Piconi et al. in 2009,  which reported that periodontal disease per se may lead to cardiovascular disorders. The authors reported an increase in CRP in atherosclerosis as well as in periodontitis, and also indicated that periodontal therapy was associated with a reduction in this biomarker.  This was also confirmed in a study by Tonetti et al. in 2007.  A similar result was obtained by Amar et al. in 2003  who showed that 26 patients with severe periodontitis presented a higher level of CRP than the 29 healthy patients who were the control. 
In another study, the authors postulated that endothelial dysfunction, which is a critical element in the pathogenesis of atherosclerosis, would be present in patients with periodontitis. The study enrolled 61 patients. Those with periodontitis not only presented a compromised flow-mediated dilatation but they also presented high levels of CRP, which were restored to normal levels after periodontal therapy.  These results are in agreement with the study by Tsioufis et al. in 2011,  which investigated the relationship between periodontitis and endothelial dysfunction in hypertensive individuals.
However, the relationship between periodontitis and CRP is controversial. Li et al. in a cross-sectional investigation in 2009  did not observe such an association. There were no differences between healthy patients and those with mild periodontitis or those with moderate to severe periodontitis that were related to this biomarker.  Despite this deviation, most of the studies suggest that periodontal therapy may decrease the serum CRP level, thereby reducing the risk of CVD. 
Is periodontal disease associated with EPC, CD34, and CD133 KDR?
Based on emerging evidence that periodontal disease is associated with endothelial dysfunction, many studies have investigated the association between periodontitis and circulating endothelial progenitor cells (EPCs). ,,, EPC is a subtype of bone marrow-derived stem cells. , It can express antigens of both hematopoietic stem cells and endothelial stem cells,  and it participates in the endothelial repair of vasculature and the maintenance of vascular integrity.  The commonly used markers for EPC identification include CD34, CD133, and kinase insert domain receptor (KDR).  EPC has been suggested as a marker of endothelial dysfunction and the cumulative risk of cardiovascular disorders. 
In the Chinese cross-sectional study of Li et al. in 2009,  patients with periodontitis presented high levels of EPC, which also presented a positive relation to serum CRP. Furthermore, changes in EPC levels suggested endothelial dysfunction.  Li et al. in 2011  showed that periodontal treatment decreased the level of circulation of CD34+. Moreover, it has been suggested that such therapy may improve endothelial function.  Similar results were observed in a longitudinal study by Piconi et al. in 2009.  The authors observed a reduction in CD44- and CD49d-expressing CD4+ T cells after the resolution of the periodontal inflammation. 
Is periodontal disease associated with plasmatic levels of tissue plasminogen activator?
t-PA plays a key role on the lysis of blood clots; it is possibly a marker of endothelial dysfunction and is related to a high risk of CVD.  Meroni et al. in 2004  showed that patients with inflammatory disorders presented high levels of t-PA although the authors did not observe statistical differences.  Furthermore, a systematic review of blood markers and strokes associated increased the levels of t-PA with strokes. 
In a cross-sectional study by Joshipura et al.,  the authors showed that patients with periodontitis presented 11% higher levels of t-PA, which were also associated with endothelial dysfunction and might possibly have been a link between periodontitis and CVD. 
Is periodontal disease associated with von Willebrand factor?
Von Willebrand factor is released by platelets and mediates early homeostasis. Some authors have argued that it is the gold standard marker for endothelial dysfunction.
In their longitudinal study in 2009,  Piconi et al. observed no differences in von Willebrand factor due to periodontal therapy.  However, Joshipura et al. in 2004  showed that patients free of periodontitis presented 11% lower von Willebrand factor although without statistical significance.  Therefore, the results suggested that markers of systemic inflammation and endothelial dysfunction sustained the relation between periodontitis and this last condition. 
Is periodontal disease associated with tumor necrosis factor?
TNF-α, which is an early inflammatory marker, plays a key role in early inflammatory response.  TNF-α has been associated with risk factors linked with CVD  and the acute release of cytokines such as TNF-α in serum has been reported to occur as early as 60 min following periodontal therapy. ,
D`Aiuto et al. in 2007  showed a significant increase in TNF-α release 24 h after periodontal therapy, which returned to normal levels after 1 week and 1 month.  On the other hand, Joshipura et al. in 2004  showed no difference in serum TNF-α between healthy (control) and periodontal disease groups.  Therefore, these studies showed an acute increase in serum TNF due to periodontal treatment but not due to the disease itself. Because of its association with the early phase of inflammation, it may not be a good marker for diagnosis since patients often come for medical attention relatively late in the development of disease. 
Is periodontal disease associated with low-density lipoprotein?
High-serum/low-density lipoprotein cholesterol (LDL-C) is an established CVD risk factor , and it is also associated with endothelial dysfunction. LDL may induce endothelial damage, such as apoptosis, and it also modulates the gene expression involved in the cellular function of endothelial cells and smooth muscle cells in the vessel walls.  However, it is still unclear whether there is a causal relationship between periodontitis and hyperlipidemia. Preclinical studies have demonstrated a positive relationship between periodontitis and high LDL serum levels.  Clinical studies have shown an improvement in serum lipid profiles after periodontal treatment, which may indicate an association between periodontits and hyperlipidemia, and may suggest the possibility of reducing the risk of coronary heart disease by effective periodontal intervention.  Consequently, if periodontitis is also associated with LDL levels this may be one of the potential mediators for the association between periodontal disease and CVD. 
In a cross-sectional study by Joshipura et al. in 2004,  the population with periodontitis presented serum levels of LDL that were 11% higher than the population free of periodontitis.  No difference in serum LDL was observed among the individuals who participated in the studies by Amar et al. in 2003,  Mercanoglu et al. in 2004,  Seinost et al. in 2005,  and Li et al. in 2009.  However, even though some studies did not show differences in LDL levels among patients with periodontitis, it consists of a simple exam and it gives information regarding the systemic condition and the cardiovascular risk of the patient.
Is periodontal disease associated with fibrinogen?
Fibrinogen, which is a coagulation protein in plasma, is a cofactor for platelet aggregation and is an acute-phase reactant. Some studies have associated elevated plasma fibrinogen levels with coronary heart diseases. , Moreover, elevated plasma fibrinogen levels are known to be independently associated with CVDs. 
Endothelial damage is also related to high levels of fibrinogen. During systemic inflammation, coagulation is partly activated. Evidence is emerging, which shows that fibrin degradation products also trigger inflammation.  Even fibrinogen and fibrin monomers are able to bind to intercellular adhesion molecule 1 (ICAM-1) in endothelial cells and promote the attachment of leukocytes  and strong vasoconstriction.  Furthermore, a high concentration of fibrin degradation products in plasma has been associated with gram-negative infection. 
Recent studies have reported a relationship between elevated fibrinogen and periodontitis but the relevant data are controversial. In a study by Piconi et al. in 2009,  patients with periodontitis presented an abnormal elevated concentration of fibrinogen, which reduced to normal levels after periodontal therapy, suggesting that periodontal disease may increase the risk of CVD.  However, in a study by Joshipura et al. in 2004,  no association was observed between periodontal disease and increased levels of fibrinogen. 
| Conclusion|| |
Periodontitis has been associated with endothelial dysfunction, which in turn is a risk factor for CVDs. However, the role of the biomarkers that may be the link between periodontitis and endothelial dysfunction are still not perfectly defined. The studies presented above show a strong and unquestionable relationship between periodontitis and systemic inflammation. This relationship is sustained by the expression of several serum biomarkers, which are common in periodontitis, cardiovascular disorders, and endothelial dysfunction [Figure 2]. The exact association between periodontitis and CVDs is neither fully established and nor is there a gold standard biomarker for both conditions. However, the entire set of markers presented above may be very enlightening.
Based on the limited number of studies included in the review, the following can be outlined:
- There are insufficient studies to adequately state that periodontitis may lead to CVDs; however, the data presented above show that periodontitis is associated with endothelial dysfunction.
- Periodontitis is associated with higher levels of inflammatory serum biomarkers, such as PCR, t-PA, LDL, TNF, von Willebrand factor, fibrinogen, and endothelial progenitors cells, which are reduced after periodontal therapy.
Financial support and sponsorship
Capes and Fundação Araucária.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]
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