Indian Journal of Dental Research

: 2015  |  Volume : 26  |  Issue : 3  |  Page : 231--236

Role of cardiovascular disease markers in periodontal infection: Understanding the risk

Mili Gupta1, Rashi Chaturvedi2, Ashish Jain2,  
1 Department of Biochemistry, Dr. Harvansh Singh Judge Institute of Dental Sciences and Hospital, Panjab University, Chandigarh, India
2 Department of Periodontics, Dr. Harvansh Singh Judge Institute of Dental Sciences and Hospital, Panjab University, Chandigarh, India

Correspondence Address:
Rashi Chaturvedi
Department of Periodontics, Dr. Harvansh Singh Judge Institute of Dental Sciences and Hospital, Panjab University, Chandigarh


Context: Both periodontitis and cardiovascular diseases (CVD) represent chronic inflammatory conditions, and periodontal infections have been postulated to perpetuate the progression of CVD's. However, limited evidence is available to prove the causal relationship. Aim: An effort in exploring this interrelation has been made in this study. The role of two inflammatory mediators, soluble CD40 ligand (sCD40 L) and monocyte chemoattractant protein-1 (MCP-1) has been established in progression and acute precipitation of CVD's. Due to a close link between these two mediators, the present study was designed to correlate the levels of sCD40 L and MCP-1 in serum and gingival crevicular fluid (GCF) of patients with chronic periodontitis. Methods: Fifteen healthy and 30 patients of severe chronic periodontitis (diseased) participated in the study. Patients of the diseased group underwent scaling/root planning. The evaluation of plaque index, gingival index, probing depth, clinical attachment level, and a collection of serum and GCF samples was done at baseline and 6 weeks following periodontal therapy. The sCD40 L and MCP-1 levels were quantified using ELISA. Results: The sCD40 L levels correlated strongly with MCP-1 levels in both GCF (r = 0.888) and serum (r = 0.861) in patients of chronic periodontitis. The relationship between the levels of the two markers was maintained in GCF (r = 0.868) and serum (r = 0.750) after Phase I periodontal therapy. Conclusions:The positive correlation observed suggests this pathway as one of the mechanisms that may lead to increasing severity of periodontal disease and its systemic effects. Further research efforts should be made in designing appropriate clinical trials, starting at an early stage and monitoring the potential benefits of maintenance of oral hygiene on cardiovascular health.

How to cite this article:
Gupta M, Chaturvedi R, Jain A. Role of cardiovascular disease markers in periodontal infection: Understanding the risk.Indian J Dent Res 2015;26:231-236

How to cite this URL:
Gupta M, Chaturvedi R, Jain A. Role of cardiovascular disease markers in periodontal infection: Understanding the risk. Indian J Dent Res [serial online] 2015 [cited 2021 Mar 1 ];26:231-236
Available from:

Full Text

Periodontitis is initiated by the oral microbial biofilm and the response to this infection is predominantly mediated by activation of the intracellular signaling pathways leading to the production of numerous bio-molecules.[1] Research is ongoing to explore the role of these mediators for diagnostic, prognostic, and therapeutic purposes as these score over clinical indices in their potential to reflect the underlying etiology and identify mechanistics in disease pathogenesis. Localized site-specific assessment warrants, the evaluation of gingival crevicular fluid (GCF)[2] whereas for a more holistic patient assessment, biomarkers are usually sampled from peripheral blood, saliva, or pooled GCF from multiple sites.[3]

Bacteria and their virulence factors may enter the bloodstream and disseminate through the ulcerated pocket epithelium, which serve as portals of entry, thereby having a measurable systemic effect on vascular physiology.[4] Exposure to periodontal infections has been postulated to perpetuate various inflammatory events; one of the primary being those involved in cardiovascular diseases (CVDs).[5][6][7][8]

There is enough research backing the concept of inflammation as a hallmark of CVD, and numerous biomarkers have been identified to be associated with the increased risk for its development.[9] Among these, one of the critical mediators is monocyte chemoattractant protein-1 (MCP-1), a chemokine essentially involved in the up-regulation and migration of monocytes to the sites of atheromatous plaque formation.[10] These monocytes not only promote the release of various pro-inflammatory cytokines and growth factors but also amplify their own response thereby perpetuating atherosclerotic and thrombogenic events.[11],[12]

Another modulator of cardiovascular events is soluble CD40 ligand (sCD40 L), a co-stimulatory molecule for T-helper cell activation leading to the expression of a plethora of inflammatory and cell adhesion molecules.[13],[14] CD40 ligand exists in two forms; membrane-bound and soluble which have been identified on activated T-helper cells and in large numbers in platelets.[15] Engagement of CD40 L to CD40 receptor that is constitutively expressed on B cells, macrophages, endothelial cells, vascular smooth muscle cells, and platelets leads to induction of proinflammatory cytokines and chemokines, cell adhesion molecules, matrix metalloproteinases, and promotion of thrombotic activity through stimulating release of tissue factor, as well as direct pro-coagulant effects, on the endothelium.[14] The role of sCD40 L in mediating various forms of coronary artery diseases such as atherosclerosis, angina, acute coronary syndromes is being extensively studied and its elevated levels have been identified as a risk indicator in these CVD states.[16],[17]

Several epidemiological studies support an association between high levels of inflammatory biomarkers due to peri-odontopathic infections and increased risk and progression of CVD, however, enough evidence to provide a causal relationship between the two diseases is still lacking.[5],[18],[19] This association had prompted the authors to analyze the levels of these two key mediator molecules of CVD propagation; MCP-1 and sCD40 L in patients with severe periodontal disease.[20],[21] The levels of both these markers were found to be significantly raised not only in the localized periodontal microenvironment, but also in serum thereby enhancing the systemic inflammatory load and a possibility of widespread effects.

Further, it has been seen in a few studies that raised levels of circulating sCD40 L or recombinant ligands for CD40 receptors on monocytes activate circulating leukocytes thereby increasing platelet leukocyte and leukocyte endothelium interactions.[22] These interactions enhance the release of several cytokines with specific reference to up-regulation in the levels of MCP-1. This correlation has never been explored in a periodontal disease setting and through the present study, we explored the existence of any significant correlation between the levels of MCP-1 and sCD40 L in GCF and serum, in patients of severe chronic periodontitis.[22][23][24][25]

Periodontal therapy aims at eliminating the periodontopathogens, thereby minimizing the immune-mediated deleterious effects. Correlation if any, was also assessed between the levels of both these markers 6 weeks after Phase I periodontal therapy in the two biological fluids.


A total of 45 patients were enrolled for the present study from the Department of Periodontics at Dr. Harvansh Singh Judge Institute of Dental Sciences and Hospital, Panjab University, Chandigarh, India, which comprised of 30 patients of severe chronic periodontitis and 15 healthy controls. The ethical approval for conducting the study was obtained from the Institutional Ethical Committee of Panjab University, Chandigarh. Informed consent was obtained from the patients after explaining the research protocol, as well as sampling techniques to them, prior to conducting the study.

The criteria for selection included patients of severe chronic periodontitis with the presence of at least 20 natural teeth excluding third molars and healthy controls with no history of underlying periodontal disease. Patients with history of smoking, allergies, pregnancy, lactation, CVDs such as hypertension, angina, MI, any invasive cardiac treatment within last 6 months, presence of any history of or clinically evident chronic inflammatory disease states were excluded from the study. Patients who had undergone scaling in the last 3 months or consumed any antibiotic within the last month were also not included in the research.

Periodontal status assessment: Baseline clinical parameters assessed were a gingival index (GI), plaque index (PI), probing depth (PD), and clinical attachment level (CAL). Based on these findings, the patients were categorized into Group I (healthy) and Group II (diseased group). Healthy patients (n = 15) were characterized by the following readings: GI < 1, PD < 3 mm, CAL = 0. Severe periodontitis patients (n = 30) were patients with two or more inter-proximal sites with CAL ≥ 6 mm, not on the same tooth, and one or more inter-proximal sites with PD ≥ 5 mm.[26] The clinical assessment was done using UNC 15 probe (Hu-freidy®) by a single examiner who had been calibrated with a reliability ascertained to be 0.8 using Dahlberg's formula.

The second part of the study involved administration of Phase I periodontal therapy, which comprised of scaling and root planning and routine oral hygiene instructions to diseased patients (Group II). No adjunctive antibiotics or anti-inflammatory agents were prescribed. Posttherapy these patients were considered as Group III and were subsequently followed up for a period of 6 weeks at the end of which the evaluations were repeated.

Sample collection

A standardized volume of 2 µl of GCF was collected from each patient from the site most severely afflicted with periodontitis at baseline and following periodontal therapy. To prevent salivary contamination during sample collection, the site was isolated and cleaned of supragingival plaque and debris with a curette. 1–5 µl color coded Hirschmann's microcapillary pipettes (Sigma-Aldrich, St. Louis, MO, USA) were placed gently, extra-crevicularly at the gingival margin without penetration into the gingival crevice. GCF collection was done on a separate appointment from clinical assessment to avoid spontaneous bleeding and contamination at the collection sites. In healthy patients, to accumulate the requisite quantity, pooled GCF sample was collected from various sites. The samples were dispensed into previously sterilized, airtight 0.5 ml Eppendorfs containing 398 µl of sample diluent, using a blast of air through the microcapillary pipettes to enable complete removal. Serum was separated from two milliliter of peripheral venous blood and immediately transferred to storage vials. All samples were stored at −80°C until analysis. Samples were thawed only once for the assay.

MCP-1 and sCD40 L levels in GCF and serum obtained from the study participants were measured using a solid phase sandwich enzyme-linked immunosorbent assay, using ELISA kits (Cat # ELH-MCP-1-001, Ray Biotech, Inc. and Cat# CSB-E04716 h, Cusabio Biotech Co., LTD, China) as per manufacturer's instructions.[20]

Statistical analysis

The statistical analysis was carried out using statistical package for social sciences (SPSS version 15.0 for Windows, Inc., Chicago, IL, USA). In this study for the sample size enrolled, the power of the correlations came out to be 90% at 95% confidence interval. All quantitative variables were estimated using measures of central location (mean, median) and measures of dispersion (standard deviation). Normality of data was checked for measures of skewness by the application of one-sample Kolmogorov-Smirnov tests of normality. The parametric evaluations were done by applying the one-way ANOVA using Bonferroni post-hoc tests. For the comparison of the readings of various parameters between the diseased and treated group, paired t-test was applied. All statistical tests were two-sided and performed at a significance level of α = 0.05. Since the data were normally distributed, Karl Pearson's correlation was done to assess the correlation between the levels of MCP-1 and sCD40 L in GCF and serum.


Regarding age (P = 0.157) and gender (P = 0.395), the patients were equally matched in both groups. The pre- and post-treatment mean values of all the clinical parameters and levels of MCP-1 and sCD40 L in GCF and serum and their comparatives have been tabulated [Table 1].{Table 1}

The correlation studies among the levels of these markers showed that sCD40 L levels correlated strongly with the levels of MCP-1 in GCF (r = 0.888), as well as in serum (r = 0.861) [Figure 1].{Figure 1}

Following scaling and root planning, the diseased patients were longitudinally assessed after 6 weeks and represented a posttreatment group. Correlation studies revealed that both these markers demonstrated a strong correlation among each other in the two fluids after therapy also [Figure 2].{Figure 2}


Chronic inflammatory periodontal diseases are among the most common human infections with 10–15% of the population afflicted with advanced forms of the disease.[27] The presence of periodontal infection further evokes a generalized inflammatory response thereby posing a risk for numerous systemic disease states, one of them being a higher risk of CVD.

There exists a clear evidence of an epidemiological association between oral infections and CVD. A few studies have even demonstrated a correlation between the subgingival microbiota and the pathogens detected in the vascular lesions.[28],[29] Most of the studies concluded that the levels of mediators like CRP found in individuals, with both CVD and periodontitis were additive relative to levels found in patients with either condition.[30] Individuals suffering from periodontitis on average presented with 14–15% greater risk of developing CVD from prospective trials while the odds increased to more than 100% when analyzing case-control studies compared to healthy individuals.[31] Links between periodontitis and atherosclerosis have been predicted based on inflammatory mechanisms initiated by bacteria associated with periodontal lesions. Invasive periodontopathic bacteria like Porphyromonasgingivalis and their byproducts reach systemic circulation.[4] The adaptive immune response to the presence of these bacteria exacerbates the expression of pro-inflammatory cells which in turn up-regulate the endothelial cell activation, promote infiltration of activated leukocytes, and influence the propagation of the atherosclerotic lesions.[30]

Thus, the mainstay of the pathogenesis is the involvement of bio-molecules in the inflammatory and immune cascade which has prompted several authors to analyze their levels in GCF and serum of periodontitis afflicting the population. MCP-1 and sCD40 L are two such mediator molecules that have been researched to not only initiate and propagate an atherosclerotic state but also be involved in the progression of periodontal disease. The increase in concentrations of both these mediators has been independently documented both locally in GCF, as well as systemically in patients with severe periodontitis vis-a-vis healthy controls in few studies.[20],21,[32][33][34][35] The findings of these studies substantiated the probable pathogenic role played by the two markers in causing severe periodontal disease and increasing the systemic inflammatory load.

Due to the suggestion of a link between inductions of MCP-1 by high levels of sCD40 L, the present study was designed to correlate the affiliation between the levels of these mediators in GCF and serum. A significant association was seen that is, an increase in the quantity of sCD40 L corresponded with an increase in levels of MCP-1 in both GCF and serum. To the best of our knowledge, this is thefirst study documenting such interrelationship between the two markers in patients with periodontal disease.

Kiener et al. in their study documented sCD40 L to be a potent monocytes activator. The results suggested that ligation of CD40 on human monocytes induces phenotypic changes that would influence T-cell activation by the monocytes and also enhance or prolong their inflammatory response.[36] Aukrust et al. have further specifically proved in their exvivo study that sCD40 L induces dose-dependent and specific release of MCP-1 from peripheral blood mononuclear cells.[23] Another promising study has documented that repeated injections of thrombin activated platelets from Cd40l+/+ but not from Cd40l−/− Apoe−/− mice in Apoe−/− mice caused a significant increase in the expression of plasma, as well as endothelial deposition of monocytes CCL2.[22] Giannini et al. in their in vivo model documented that level of MCP-1 and not of interleukin-8 and soluble vascular cell adhesion molecule-1 significantly correlated with the levels of CD40 L expressed by platelets.[24] The explanation proposed is that increased sCD40 interacts with its receptor on monocytes and enhances the release of CC-chemokine, MCP-1 from mononuclear cells. MCP-1 further promotes the infiltration of these activated leukocytes into the atherosclerotic lesion, and these in turn may directly activate smooth muscle cells, macrophages, and T cells inside the vessel wall, promoting atherogenesis. The authors concluded that platelet CD40 L plays a pivotal role in atherosclerosis by increasing platelet-leukocyte and leukocyte-endothelium interactions, and increase in MCP-1 through CD40 ligand seems to be a crucial phenomenon in acerbating atherosclerosis.[23],[37]

Our present study also aimed at highlighting the existence of this correlation between the levels of MCP-1 and sCD40 L in GCF of patients with severe chronic periodontitis. As the pathogenesis of severe periodontitis is still being explored, this pathway could be one key mechanistic in causing severe oral disease in prone patients. Further, dissemination of these dental plaque bacteria in the circulation can induce platelet activation leading to increased expression of both surface and soluble CD40 L, which can interact with CD40 receptor on endothelial cells, macrophages, and fibroblasts to promote a wide array of functions causing progressive atherosclerosis and its destabilization.[38] A positive correlation observed between sCD40 L and MCP-1 levels suggest this phenomenon as one of the pathways that may lead to the propagation of cardiovascular events in patients with periodontal disease.

Various studies have assessed the impact of treatment of periodontal disease on systemic inflammatory mediators of CVD. Levels of many of these markers have been found to decrease after periodontal therapy, comprising of scaling and root planing with or without the adjunctive antibiotic regime.[39][40][41] A similar proportionate decrease was observed in the levels of sCD40 and MCP-1 both in the oral fluid and plasma in this study, which again indicates the periodontium as a source of systemic inflammation. If subsequent research confirms a causal relationship between periodontal disease and atherosclerosis, then periodontal therapy could be suggested as an additional measure in reducing the progression of the latter.


Recent research is documenting that improvement in oral health is important in preventing progression of various systemic illnesses. Thus, treatment, as well as prevention of periodontal disease, should not be considered in isolation, but as an integral part of the maintenance of general health of the patients. For this, a collaborative effort is needed between medical and dental practitioners with the former becoming more aware of clinical presentations of periodontal disease in their patients and their early referral to dentists, thus, minimizing chances of any systemic effects. Similarly, dentists should not only render treatment for periodontal disease, but also look for any confounding risk factors for periodontitis and CVD (overweight, hypertension, diabetes) and help in their management along with their medical counterparts.


We sincerely thank Mrs. Kusum Chopra, who helped us with the statistical analysis of the data and Mr. Mahender Mehra who helped us with the preparation of the graphs.

Financial support and sponsorship

The project was funded by DST under Promotion of University Research and Scientific Excellence (PURSE) grant, Panjab University.

Conflicts of interest

There are no conflicts of interest.


1Van Dyke TE, van Winkelhoff AJ. Infection and inflammatory mechanisms. J Periodontol 2013;84 4 Suppl: S1-7.
2Champagne CM, Buchanan W, Reddy MS, Preisser JS, Beck JD, Offenbacher S. Potential for gingival crevice fluid measures as predictors of risk for periodontal diseases. Periodontol 2000 2003;31:167-80.
3Kinane DF, Preshaw PM, Loos BG; Working Group of Seventh European Workshop on Periodontology. Host-response: Understanding the cellular and molecular mechanisms of host-microbial interactions – Consensus of the Seventh European Workshop on Periodontology. J Clin Periodontol 2011;38 Suppl 11:44-8.
4Takeuchi H, Furuta N, Morisaki I, Amano A. Exit of intracellular Porphyromonas gingivalisfrom gingival epithelial cells is mediated by endocytic recycling pathway. Cell Microbiol 2011;13:677-91.
5Dietrich T, Sharma P, Walter C, Weston P, Beck J. The epidemiological evidence behind the association between periodontitis and incident atherosclerotic cardiovascular disease. J Clin Periodontol 2013;40 Suppl 14:S70-84.
6Ide M, Papapanou PN. Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes – Systematic review. J Clin Periodontol 2013;40 Suppl 14:S181-94.
7Borgnakke WS, Ylöstalo PV, Taylor GW, Genco RJ. Effect of periodontal disease on diabetes: Systematic review of epidemiologic observational evidence. J Clin Periodontol 2013;40 Suppl 14:S135-52.
8Linden GJ, Lyons A, Scannapieco FA. Periodontal systemic associations: Review of the evidence. J Periodontol 2013;84 4 Suppl: S8-19.
9Schenkein HA, Loos BG. Inflammatory mechanisms linking periodontal diseases to cardiovascular diseases. J Periodontol 2013;84 4 Suppl: S51-69.
10Namiki M, Kawashima S, Yamashita T, Ozaki M, Hirase T, Ishida T, et al.Local overexpression of monocyte chemoattractant protein-1 at vessel wall induces infiltration of macrophages and formation of atherosclerotic lesion: Synergism with hypercholesterolemia. Arterioscler Thromb Vasc Biol 2002;22:115-20.
11Tanaka T, Nakamura Y, Nasuno A, Mezaki T, Higuchi K, Fukunaga H, et al.Plasma concentrations of monocyte chemoattractant protein 1 (MCP-1) and neopterin in the coronary circulation of patients with coronary artery disease. Circ J 2004;68:114-20.
12Gonzalez-Quesada C, Frangogiannis NG. Monocyte chemoattractant protein-1/CCL2 as a biomarker in acute coronary syndromes. Curr Atheroscler Rep 2009;11:131-8.
13Schönbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci 2001;58:4-43.
14Phipps RP. Atherosclerosis: The emerging role of inflammation and the CD40-CD40 ligand system. Proc Natl Acad Sci U S A 2000;97:6930-2.
15André P, Nannizzi-Alaimo L, Prasad SK, Phillips DR. Platelet-derived CD40L: The switch-hitting player of cardiovascular disease. Circulation 2002;106:896-9.
16Heeschen C, Dimmeler S, Hamm CW, van den Brand MJ, Boersma E, Zeiher AM, et al.Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003;348:1104-11.
17Schönbeck U, Varo N, Libby P, Buring J, Ridker PM. Soluble CD40L and cardiovascular risk in women. Circulation 2001;104:2266-8.
18Amar S, Gokce N, Morgan S, Loukideli M, Van Dyke TE, Vita JA. Periodontal disease is associated with brachial artery endothelial dysfunction and systemic inflammation. Arterioscler Thromb Vasc Biol 2003;23:1245-9.
19Nakajima T, Honda T, Domon H, Okui T, Kajita K, Ito H, et al.Periodontitis-associated up-regulation of systemic inflammatory mediator level may increase the risk of coronary heart disease. J Periodontal Res 2010;45:116-22.
20Gupta M, Chaturvedi R, Jain A. Role of monocyte chemoattractant protein-1 (MCP-1) as an immune-diagnostic biomarker in the pathogenesis of chronic periodontal disease. Cytokine 2013;61:892-7.
21Chaturvedi R, Gupta M, Jain A, Das T, Prashar S. Soluble CD40 ligand: A novel biomarker in the pathogenesis of periodontal disease. Clin Oral Investig 2015;19:45-52.
22Lievens D, Zernecke A, Seijkens T, Soehnlein O, Beckers L, Munnix IC, et al.Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 2010;116:4317-27.
23Aukrust P, Müller F, Ueland T, Berget T, Aaser E, Brunsvig A, et al.Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999;100:614-20.
24Giannini S, Falcinelli E, Bury L, Guglielmini G, Rossi R, Momi S, et al.Interaction with damaged vessel wall in vivo in humans induces platelets to express CD40L resulting in endothelial activation with no effect of aspirin intake. Am J Physiol Heart Circ Physiol 2011;300:H2072-9.
25Davì G, Tuttolomondo A, Santilli F, Basili S, Ferrante E, Di Raimondo D, et al.CD40 ligand and MCP-1 as predictors of cardiovascular events in diabetic patients with stroke. J Atheroscler Thromb 2009;16:707-13.
26Page RC, Eke PI. Case definitions for use in population-based surveillance of periodontitis. J Periodontol 2007;78 7 Suppl: 1387-99.
27Leishman SJ, Do HL, Ford PJ. Cardiovascular disease and the role of oral bacteria. J Oral Microbiol 2010;2:5781-93.
28Kozarov EV, Dorn BR, Shelburne CE, Dunn WA Jr, Progulske-Fox A. Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitansand Porphyromonas gingivalis. Arterioscler Thromb Vasc Biol 2005;25:e17-8.
29Mahendra J, Mahendra L, Kurian VM, Jaishankar K, Mythilli R. 16S rRNA-based detection of oral pathogens in coronary atherosclerotic plaque. Indian J Dent Res 2010;21:248-52.
30Packard RR, Libby P. Inflammation in atherosclerosis: From vascular biology to biomarker discovery and risk prediction. Clin Chem 2008;54:24-38.
31Bahekar AA, Singh S, Saha S, Molnar J, Arora R. The prevalence and incidence of coronary heart disease is significantly increased in periodontitis: A meta-analysis. Am Heart J 2007;154:830-7.
32Marcaccini AM, Meschiari CA, Sorgi CA, Saraiva MC, de Souza AM, Faccioli LH, et al.Circulating interleukin-6 and high-sensitivity C-reactive protein decrease after periodontal therapy in otherwise healthy subjects. J Periodontol 2009;80:594-602.
33Pradeep AR, Daisy H, Hadge P. Gingival crevicular fluid levels of monocyte chemoattractant protein-1 in periodontal health and disease. Arch Oral Biol 2009;54:503-9.
34Papapanagiotou D, Nicu EA, Bizzarro S, Gerdes VE, Meijers JC, Nieuwland R, et al.Periodontitis is associated with platelet activation. Atherosclerosis 2009;202:605-11.
35Pradeep AR, Daisy H, Hadge P. Serum levels of monocyte chemoattractant protein-1 in periodontal health and disease. Cytokine 2009;47:77-81.
36Kiener PA, Moran-Davis P, Rankin BM, Wahl AF, Aruffo A, Hollenbaugh D. Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. J Immunol 1995;155:4917-25.
37Stumpf C, Lehner C, Raaz D, Yilmaz A, Anger T, Daniel WG, et al.Platelets contribute to enhanced MCP-1 levels in patients with chronic heart failure. Heart 2008;94:65-9.
38Imamura T, Travis J, Potempa J. The biphasic virulence activities of gingipains: Activation and inactivation of host proteins. Curr Protein Pept Sci 2003;4:443-50.
39D'Aiuto F, Parkar M, Nibali L, Suvan J, Lessem J, Tonetti MS. Periodontal infections cause changes in traditional and novel cardiovascular risk factors: Results from a randomized controlled clinical trial. Am Heart J 2006;151:977-84.
40Tonetti MS, D'Aiuto F, Nibali L, Donald A, Storry C, Parkar M, et al.Treatment of periodontitis and endothelial function. N Engl J Med 2007;356:911-20.
41D'Aiuto F, Orlandi M, Gunsolley JC. Evidence that periodontal treatment improves biomarkers and CVD outcomes. J Periodontol 2013;84 4 Suppl: S85-105.