ides from Porphyromonas
Table 1. Relevant bacterial evidence between periodontal disease and CVD.
Abbreviations: Aa, Aggregatibacter actinomycetemcomitans; Pg, Porphyromonas gingivalis; Cp, Chlamydia pneumoniae,; Bf, Bacteroides forsythus; Pi, Prevotella intermedia; Fn, Fusobacterium nucleatum; Pn, Prevotella nigrescens; Tf, Tannerella forsythia; HCMV, human cytomegalovirus; MI, myocardial infarction; MOMA-2, Monocyte/Macrophage marker; PCR, polymerase chain reaction; CVD, cardiovascular disease.
gingivalis and Prevotella intermedia profoundly stimulate the secretion of interleukins by human macrophages. Periodontal pathogens may increase the risk of CVD through mechanisms such as platelet activation and aggregation  .
3. Effects of Periodontal Intervention on Inflammatory Cytokines
Inflammatory cytokines include pro-inflammatory mediators, such as tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-12, chemokines (e.g. IL-8), and anti-inflammatory mediators (e.g. IL-10, IL-1 antagonist and IL-4), play distinct biological effects  . The chemokine mainly attracts and activates neutrophils, and is considered important mediators for granulocyte accumulation. IL-6 secreted by various cell types, such as fibroblast cells, monocyte macrophage cells, and epithelium cells, and its level is increased by bacterial lipopolysaccharide stimulated. IL-6 can promote coagulation and result in the development of atherosclerosis. The enhancement of IL-6 levels has been associated with both cardiovascular-risk and periodontal disease  . TNF-α stimulates the production of chemokines and cytokines, collagenase, prostaglandin E2  , cellular adhesion molecules and bone resorption-related factors. Based on the biological properties of pro-inflammatory cytokines, high levels of TNF-α and IL-6 in plasma have been associated with an increased morbidity and mortality of cardiovascular events  . Peripheral blood mononuclear cells from periodontitis subjects released higher levels of TNF-α and IL-6 than those from healthy subjects. In contrast, mononuclear cells obtained from healthy subjects presented higher amounts of IL-8 than those from periodontitis individuals  . In a prospective study of apparently healthy men, the IL-6 levels of those who subsequently had a myocardial infarction were higher than matched control without myocardial infarction during a 6-year follow-up  . IL-6 levels may be a predictor of risk of future myocardial infarction in apparently healthy men. Severe periodontitis can result in systemic inflammation characterized by elevated serum IL-6  . A recent study reported that subjects with both coronary artery disease and periodontitis had significantly higher serum IL-6 concentrations compared with subjects with coronary artery disease who had no periodontitis  . TNF-α is involved in the initiation and development of coronary artery disease  , and its levels increased in patients with periodontitis  . Conversely, IL-10 suppresses the inflammation reaction and minimizes tissue destruction  .
Periodontal therapy can reduce the levels of pro-inflammory cytokines at three months post-therapy, and thus may lower the CVD incidence. In addition, the current study concluded that periodontal therapy had minimal impact on levels of TNF-α and IL-1β  . The effects of periodontal intervention on serum IL-6 are not consistent. Some studies showed that periodontal therapy results in a decrease in IL-6 levels  , although others found no significant differences post-therapy  , In a recent study on coronary artery disease patients with periodontitis, periodontal therapy reduced serum concentrations of IL-6 at 6 months post-therapy  . Similar findings can be obtained in which periodontitis patients with coronary heart disease received mechanical periodontal therapy and control patients did not receive periodontal therapy. The serum IL-6 levels in periodontal therapeutic group decreased significantly than those in the control group at 3 months after periodontal therapy. The effect of periodontal therapy on circulating TNF-α levels is not consistent. An investigation showed that the TNF-α levels decreased significantly after periodontal therapy  . And others reported that no effect could be seen following periodontal intervention  .
4. Effect of Periodontal Intervention on C-Reactive Protein
CRP, an acute phase reactant protein, is responsible for the increase in the vascular inflammation. Its main function is thought to result in the activation of the complement system. In humans, the levels of CRP in plasma rise rapidly (as much as 1000 folds or more) after an acute inflammatory stimulus. This increase is mainly due to increased synthesis of this protein by hepatocytes that are stimulated by various cytokines, particularly IL-6  . CRP level measurement can provide a more sensitive means of detecting signs of inflammation and trauma. CRP concentration in serum is significantly increased in patients with coronary heart disease and myocardial infarction. Elevated plasma levels of CRP have been documented as a major risk factor for CVD, and may be used as an important indication of coronary artery disease and acute myocardial infarction  . In a cohort study, it was noted that increasing levels of serum high-sensitivity CRP were associated with the risk of cardiovascular events, and that CRP was the strongest univariate predictor of the risk of such events  . CRP can increase low density lipoprotein uptake into macrophages and inhibit endothelial nitric-oxide synthase expression in aortic endothelial cells. CRP can also induce adhesion molecule expression in human endothelial cells in serum and may contribute to the hypercoagulative state in coronary disease patients  . Recently, accumulated evidence has demonstrated the association between periodontitis and CRP. The serum CRP is increased in systemically healthy subjects with periodontitis  . It was reported that subjects with periodontitis had 1.65 mg/L higher serum CRP compared with individuals without periodontitis  . Studies have showed that periodontitis patients with CVD or hypertension had significantly higher serum sensitivity CRP concentrations than patients without periodontitis  . Periodontal diseases are associated with changes in serum components that are consistent with the increased circulation of IL-6 and elevated levels of high sensitivity CRP  . Recently, clinical trials have shown a significant reduction of CPR levels and other inflammatory markers in serum after periodontal therapy  . Furthermore, a multi-centered randomized control study showed that periodontal therapy can reduce the CRP levels from high to moderate in non-obese periodontal disease patients  . Similar results confirmed by a randomized controlled trial that the levels of CRP reduced after periodontal therapy  . Periodontal intervention and periodontal maintenance may contribute to the systemic inflammation and thereby decrease the incidence and morbidity of CVD  . But other studies have found that periodontal intervention, especially one that involves periodontal surgery and dental extraction, will increase the levels of inflammatory mediators immediately  . Therefore, full-mouth disinfection agent has been introduced as a short-term method to suppress periodontal pathogens within 24 h  .
5. Effects of Periodontal Procedures on CVD and Antibiotic Prophylaxis (Table 2)
Gingival inflammation is correlated positively with the prevalence of bacteraemia  .
Table 2. Effects of periodontal procedures on CVD and antibiotic prophylaxis.
Abbreviations: CHD, coronary heart disease; PD, peridontal pocket depth; CRP, C-reactive protein; RCT, randomized controlled trials; CAD, coronary artery disease; Pg, Porphyromonas gingivalis; S100A9, S100 calcium-binding protein A9; SMemb, embryonic isoform of myosin heavy chain; MIC, minimal inhibitory concentration.
Periodontal bleeding per se is a poor indicator of odontogenic bacteraemia. The certain periodontal procedures are associated with bacteraemia. The prevalence of bacteraemia arise from periodontal therapy and various oral hygiene practices. In many instances the prevalence of bacteraemia after such innocuous events is comparable with that occurring after periodontal procedures. It has been suggested that oral hygiene practices are responsible for spontaneous cases of bacteraemia. Such bacteraemias either from periodontal procedures or oral hygiene practices are of low-grade intensity (10 - 200 CFU/ml of blood) and of short duration  . Bacteremia induced by Porphyromonas gingivalis (Pg) leads to intimal hyperplasia associated with overexpressions of embryonic isoform of myosin heavy chain and oral hematogenous spreading of Pg is a causative event in the development of aortic hyperplasia in periodontitis patients  . Penicillin has been shown to reduce bacteraemia by 84% - 86% at 5 min and 95% - 97% at 30 min after bacteraemia induction. These results can be compared with a reduction of 24% - 42% and 49% - 76%, respectively, when no prophylaxis used  . By contrast, other workers have shown that single doses of 2 g penicillin and 3 g amoxicillin fail to reduce bacteraemia after dental extractions  . Although most attention has been focused on antibiotic prophylaxis, there is evidence that antiseptic mouthwashes such as chlorhexidine and povidone-iodine used prior to certain periodontal procedures may reduce the prevalence of bacteraemia  . Maharaj B  found that there were none of the significant treatments prevented post-extraction bacteraemia and confirmed earlier reports that bacteraemia was not completely eliminated by antibiotics. Recently, studies have showed that there is no obvious increase in the incidence of infective endocarditis cases or deaths in the two years after the guideline was introduced about the cessation prescribing antibiotic prophylaxis. The findings support the cessation of prescribing antibiotic prophylaxis  . Therefore further clinical trials should determine if periodontal intervention combined with drug therapy would reduce the incidence of CVD.
Periodontal inflammatory response could exacerbate vascular inflammation via secreted cytokines that ultimately modulate atherosclerosis and CVD. The inflammatory cytokine IL-6 and TNF-α, and CRP levels in serum increased are association with CVD and periodontal diseases. Periodontal intervention had a positive impact on the established risk factors for CVD to reduce inflammatory responses. Periodontal intervention studies have strengthened the evidence for an association between the periodontal disease and CVD, and have also indicated a causal link. As some periodontal procedures may increase bacteraemia temporarily, effective antibiotic prophylaxis is necessary to the prevention bacteraemia and the onset of CVD  . However, detailed mechanism of spontaneous periodontal disease induces bacteraemia and the influence of periodontal intervention procedures inducing bacteraemia leading to CVD is unknown. Because of these different research results, carefully designed randomized trials based on this concept with longer follow-up and clinical observation are required to prove if periodontal intervention combined with drug therapy would reduce the incidence of CVD.
This study was supported by Shanghai Health and Family Planning Commission Research Grants (No. 20134418 and General Logistics Department Research Grants of CPLA (No. CHJ13J035). The study was also supported by Shanghai Municipal Hong Kou District Health and Family Planning Commission Research Grants (No. 1503-31) and National Nature Science Foundation of China (No. 3870831). We also would like to thank all the contributors for the substantial information compiled in previously published papers that were cited in this manuscript. Their information was immensely helpful for preparing this manuscript.
Conflict of Interest Statement
The authors confirm no conflict of interest.
 Rosamond, W., Flegal, K., Friday, G., Furie, K., Go, A., Greenlund, K., et al. (2007) Heart Disease and Stroke Statistics—2007 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 115, e69-e171.
 Mattila, K.J., Asikainen, S., Wolf, J., Jousimies-Somer, H., Valtonen, V. and Nieminen, M. (2000) Age, Dental Infections, and Coronary Heart Disease. Journal of Dental Research, 79, 756-760.
 Emingil, G., Buduneli, E., Aliyev, A. and Atilla, G. (2000) Association between Periodontal Disease and Acute Myocardial Infarction. Journal of Periodontology, 71, 1882-1886.
 Ouyang, X.Y., Xiao, W.M., Chu, Y. and Zhou, S.Y. (2011) Influence of Periodontal Intervention Therapy on Risk of Cardiovascular Disease. Periodontology 2000, 56, 227-257.
 Geerts, S.O., Legrand, V., Charpentier, J., Albert, A. and Rompen, E.H. (2004) Further Evidence of the Association between Periodontal Conditions and Coronary Artery Disease. Journal of Periodontology, 75, 1274-1280.
 Hung, H.C., Joshipura, K.J., Colditz, G., Manson, J.E., Rimm, E.B, Speizer, F.E., et al. (2004) The Association between Tooth Loss and Coronary Heart Disease in Men and Women. Journal of Public Health Dentistry, 64, 209-215.
 Wu, T.J., Trevisan, M., Genco, R.J., Falkner, K.L., Dorn, J.P. and Christopher, T. (2000) Examination of the Relation between Periodontal Health Status and Cardiovascular Risk Factors: Serum Total and High Density Lipoproten Cholesterol, C-Reactive Protein, and Plasma Fibrinogen. American Journal of Epidemiology, 151, 273-282.
 Andriankaja, O.M., Genco, R.J., Dorn, J., Dmochowski, J., Hovey, K. and Falkner, K.L. (2007) Periodontal Disease and Risk of Myocardial Infarction: The Role of Gender and Smoking. European Journal of Epidemiology, 22, 699-705.
 Bahekar, A.A., Singh, S., Saha, S., Molnar, J. and Arora, R. (2007) The Prevalence and Incidence of Coronary Heart Disease Is Significantly Increased in Periodontitis: A Meta-Analysis. American Heart Journal, 154, 830-837.
 Brodala, N.M.E., Bellinger, D.A., Damrongsri, D. Offenbacher, S. and Beck, J. (2005) Porphyromonas gingivalis Bacteremia Induces Coronary and Aortic Atherosclerosis in Normocholesterolemic and Hypercholesterolemic Pigs. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 1446-1451.
 Meurman, J.H., Sanz, M. and Janket, S.J. (2004) Oral Health, Atherosclerosis and Cardiovascular Disease. Critical Reviews in Oral Biology & Medicine, 15, 403-413.
 Persson, G.R. and Persson, R.E. (2008) Cardiovascular Disease and Periodontitis: An Update on the Associations and Risk. Journal of Clinical Periodontology, 35, 362-379.
 Ioannidou, E., Malekzadeh, T. and Dongari-Bagtzoglou, A. (2006) Effect of Periodontal Treatment on Serum C-Reactive Protein Levels: A Systematic Review and Meta-Analysis. Journal of Periodontology, 77, 1635-1642.
 Roberts, G.J., Gardner, P. and Simmons, N.A. (1992) Optimum Sampling Time for Detection of Dental Bacteraemia in Children. International Journal of Cardiology, 35, 311-315.
 Strom, B.L., Abrutyn, E., Berlin, J.A., Kinman, J.L., Feldman, R.S., Stolley, P.D., et al. (1998) Dental and Cardiac Risk Factors for Infective Endocarditis. A Population-Based, Case-Control Study. Annals of Internal Medicine, 129, 761-769.
 Tzukert, A.A., Leviner, E. and Sela, M. (1986a) Prevention of Infective Endocarditis: Not by Antibiotics Alone. A 7-Year Follow-Up of 90 Dental Patients. Oral Surgery Oral Medicine and Oral Pathology, 62, 385-388.
 Seymour, R.A., Preshaw, P.M., Thomason, J.M., Ellis, J.S. and Steele, J.G. (2003) Cardiovascular Diseases and Periodontology. Journal of Clinical Periodontology, 30, 279-292.
 Hanatani, T., Suzuki, J. and Ogawa, M. (2012) The Periodontal Pathogen Aggregatibacter actinomycetemcomitans Deteriorates Ventricular Remodeling after Myocardial Infarction in Mice. International Heart Journal, 53, 253-256.
 Haraszthy, V.I., Zambon, J.J., Trevisan, M., Zeid, M. and Genco, R.J. (2000) Identification of Periodontal Pathogens in Atheromatous Plaques. Journal of Periodontology, 71, 1554-1560.
 Kebschull, M., Demmer, R.T. and Papapanou, P.N. (2010) Gum Bug, Leave My Heart Alone! Epidemiologic and Mechanistic Evidence Linking Periodontal Infections and Atherosclerosis. Journal of Dental Research, 89, 879-902.
 Gaetti-Jardim, E., Marcelino, S.L., Feitosa, A.C.R., Romito, G.A. and Avila-Campos, M.J. (2009) Quantitative Detection of Periodontopathic Bacteria in Atherosclerotic Plaques from Coronary Arteries. Journal of Medical Microbiology, 58, 1568-1575.
 Mattila, K., Nieminen, M., Valtonen, V., Rasi, V., Kesaniemi, Y. and Syrjala, S. (1989) Association between Dental Health and Acute Myocardial Infarction. British Medical Journal, 298, 779-782.
 Nakajima, T., Honda, T. and Domon, H. (2010) Periodontitis-Associated Up-Regulation of Systemic Inflammatory Mediator Level May Increase the Risk of Coronary Heart Disease. Journal of Periodontal Research, 45, 116-122.
 Boyce, B.F., Li, P., Yao, Z., Zhang, Q., Badell, I.R., Schwarz, E.M., et al. (2005) TNF-Alpha and Pathologic Bone Resorption. The Keio Journal of Medicine, 54, 127-131.
 Abeywardena, M.Y., Leifert, W.R., Warnes, K.E., Varghese, J.N. and Head, R.J. (2009) Cardiovascular Biology of Interleukin-6. Current Pharmaceutical Design, 15, 1809-1821.
 Goncalves, T.O., Costa, D., Brodskyn, C.I., et al. (2010) Release of Cytokines by Stimulated Peripheral Blood Mononuclear Cells in Chronic Periodontitis. Archives of Oral Biology, 55, 975-980.
 Ridker, P.M., Rifai, N., Stampfer, M.J. and Hennekens, C.H. (2000) Plasma Concentration of Interleukin-6 and the Risk of Future Myocardial Infarction among Apparently Healthy Men. Circulation, 101, 1767-1772.
 Loos, B.G., Craandijk, J., Hoek, F.J., Wertheim-van, D.P.M. and van der, V.U. (2000) Elevation of Systemic Markers Related to Cardiovascular Diseases in the Peripheral Blood of Periodontitis Patients. Journal of Periodontology, 71, 1528-1534.
 Higashi, Y., Goto, C., Hidaka, T., Soga, J., Nakamura, S., Fujii, Y., et al. (2009) Oral Infection-Inflammatory Pathway, Periodontitis, Is a Risk Factor for Endothelial Dysfunction in Patients with Coronary Artery Disease. Atherosclerosis, 206, 604-610.
 Czerniuk, M.R., Gorska, R., Filipiak, K.J. and Opolski, G. (2004) Inflammatory Response to Acute Coronary Syndrome in Patients with Coexistent Periodontal Disease. Journal of Periodontology, 75, 1020-1026.
 Go’rska, R., Gregorek, H., Kowalski, J., Laskus-Perendyk, A. and Syczewska, M. (2003) Relationship between Clinical Parameters and Cytokine Profiles in Inflamed Gingival Tissue and Serum Samples from Patients with Chronic Periodontitis. Journal of Clinical Periodontology, 30, 1046-1052.
 Maynard, C.L. and Weaver, C.T. (2008) Diversity in the Contribution of Interleukin-10 to T Cell Mediated Immune Regulation. Immunological Reviews, 226, 219-233.
 Buhlin, K., Hultin, M. and Norderyd, O. (2009) Periodontal Treatment Influences Risk Markers for Atherosclerosis in Patients with Severe Periodontitis. Atherosclerosis, 206, 518-522.
 Yamazaki, K., Honda, T., Oda, T., Ueki-Maruyama, K., Nakajima, T., Yoshie, H., et al. (2005) Effect of Periodontal Treatment on the C-Reactive Protein and Proinflammatory Cytokine Levels in Japanese Periodontitis Patients. Journal of Periodontal Research, 40, 53-58.
 D’Aiuto, F., Parkar, M., Andreou, G., Suvan, J., Brett, P.M., Ready, D., et al. (2004) Periodontitis and Systemic Inflammation: Control of the Local Infection Is Associated with a Reduction in Serum Inflammatory Markers. Journal of Dental Research, 83, 156-160.
 Iwamoto,Y., Nishimura, F., Soga, Y., Takeuchi, K., Kurihara, M., Takashiba, S., et al. (2003) Antimicrobial Periodontal Treatment Decreases Serum C-Reactive Protein, Tumor Necrosis Factor-Alpha, but Not Adiponection Levels in Patients with Chronic Periodontitis. Journal of Periodontology, 74, 1231-1236.
 Forner, L., Neilson, C.H., Bendtzen, K., Larsen, T. and Holmstrup, P. (2006) Increased Plasma Levels of IL-6 in Bacteremic Periodontis Patients after Scaling. Journal of Clinical Periodontology, 33, 724-729.
 Kaptoge, S., Di Angelantonio, E. and Lowe, G. (2010) C-Reactive Protein Concentration and Risk of Coronary Heart Disease, Stroke, and Mortality: An Individual Participant Meta-Analysis. The Lancet, 375, 132-140.
 Ridker, P.M., Hennekens, C.H., Buring, J.E. and Rifai, N. (2000) C-Reactive Protein and Other Markers of Inflammation in the Prediction of Cardiovascular Disease in Women. The New England Journal of Medicine, 342, 836-843.
 Pasceri, V., Willerson, J.T. and Yeh, E.T. (2000) Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells. Circulation, 102, 2165-2168.
 Sun, X.J., Meng, H.X., Shi, D., Xu, L., Zhang, L., Chen, Z.B., et al. (2009) Elevation of C-Reactive Protein and Interleukin-6 in Plasma of Patients with Aggressive Periodontitis. Journal of Periodontal Research, 44, 311-316.
 Paraskevas, S., Huizinga, J.D. and Loos, B.G. (2008) A Systematic Review and Meta-Analyses on C-Reactive Protein in Relation to Periodontitis. Journal of Clinical Periodontology, 35, 277-290.
 Tuter, G., Kurtis, B. and Serdar, M. (2007) Evaluation of Gingival Crevicular Fluid and Serum Levels of High-Sensitivity C-Reactive Protein in Chronic Periodontitis Patients with or without Coronary Artery Disease. Journal of Periodontology, 78, 2319-2324.
 Thakare, K.S., Deo, V. and Bhongade, M.L. (2010) Evaluation of the C-Reactive Protein Serum Levels in Periodontitis Patients with or without Atherosclerosis. Indian Journal of Dental Research, 21, 326-329.
 Vidal, F., Figueredo, C.M., Cordovil, I. and Fischer, R.G. (2009) Periodontal Therapy Reducesplasma Levels of Interleukin-6, C-Reactive Protein, and Fibrinogen in Patients with Severe Periodontitis and Refractory Arterial Hypertension. Journal of Periodontology, 80, 786-791.
 Offenbacher, S., Beck, J.D. and Moss, K. (2009) Results from the Periodontitis and Vascular Events (PAVE) Study: A Pilot Multi-Centered, Randomized, Controlled Trial to Study Effects of Periodontal Therapy in a Secondary Prevention Model of Cardiovascular Disease. Journal of Periodontology, 80, 190-201.
 Taylor, B., Tofler, G. and Morel-Kopp, M.C. (2010) The Effect of Initial Treatment of Periodontitis on Systemic Markers of Inflammation and Cardiovascular Risk: A Randomized Controlled Trial. European Journal of Oral Sciences, 118, 350-356.
 Acharya, A., Bhavsar, N., Jadav, B. and Parikh, H. (2010) Cardioprotective: Effect of Periodontal Therapy in Metabolic Syndrome: A Pilot Study in Indian Subjects. Metabolic Syndrome and Related Disorders, 8, 335-341.
 D’Aiuto, F., Nibali, L., Parkar, M., Suvan, J. and Tonetti, M.S. (2005) Short-Term Effects of Intensive Periodontal Therapy on Serum Inflammatory Markers and Cholesterol. Journal of Dental Research, 84, 269-273.
 Izumi, Y., Nagasawa, T. and Umeda, M. (2009) Periodontitis and Cardiovascular Diseases: The Link and Relevant Mechanisms. Japanese Dental Science Review, 45, 98-108.
 Hokamura, K. and Umemura, K. (2010) Roles of Oral Bacteria in Cardiovascular Diseases, from Molecular Mechanisms to Clinical Cases: Porphyromonas gingivalis is the Important Role of Intimal Hyperplasia in the Aorta. Journal of Pharmaceutical Sciences, 113, 110-114.
 Hall, G., Hedstrom, S.A., Heimdahl, A. and Nord, C.E. (1993) Prophylactic Administration of Penicillins for Endocarditis Does Not Reduce the Incidence of Postextraction Bacteremia. Clinical Infectious Diseases, 17, 188-194.
 Maharaj, B., Coovadia, Y. and Vayej, A.C. (2012) A Comparative Study of Amoxicillin, Clindamycin and Chlorhexidine in the Prevention of Post-Extraction Bacteraemia. Cardiovascular Journal of Africa, 23, 491-494.
 Thornhill, M.H., Dayer, M.J., Forde, J.M., Corey, G.R., Chu, V.H., Couper, D.J., et al. (2011) Impact of the NICE Guideline Recommending Cessation of Antibiotic Prophylaxis for Prevention of Infective Endocarditis: Before and after Study. BMJ, 342, d2392.
 Chen, T.L., Wang, S.F. and Zhang, X.H. (2012) Influence of Periodontitis and Nonsurgical Periodontal Intervention on Atherosclerosis Diseases. Advances in Bioscience and Biotechnology, 3, 531-537.