There was an association between coronary heart disease and poor periodontal status in the middle-aged males investigated. This association was independent of diabetes and all other cardiovascular risk factors investigated.

Briggs JE, McKeown PP, J Periodontol 2006.77.1.95.
http://www.joponline.org/doi/abs/10.1902/jop.2006.77.1.95? prevSearch=keywordsfield%3ACreactive_ protein

A historical perspective on atherosclerosis allows us to reflect on the once controversial hypotheses in the field. Plaque formation was once thought to be dependent upon hypercholesterolemia alone, or solely in response to injury. More recently, inflammatory cascades were thought to be at the root of lesion development. A more realistic view may be that atherosclerosis is neither exclusively an inflammatory disease nor solely a lipid disorder: it is both.

Daniel Steinberg, Nature Medicine 8, 1211 - 1217 (2002),
http://www.nature.com/nm/journal/v8/n11/full/nm1102-1211.html

Background and Objective: Certain types of chronic infection increase the plasma level of very-low-density lipoprotein, leading to formation of the particularly atherogenic low-density lipoprotein subclass, small dense low-density lipoprotein. In the present study, we examined whether aggressive forms of periodontis are associated with these atherogenic lipoprotein parameters. Conclusion: These results indicate that periodontal infection is associated with elevated plasma levels of atherogenic lipoprotein species. This association may account for the increased risk of periodontitis patients for cardiovascular disease.

Rufail ML, Schenkein HA, et al., Journal of Periodontal Research Volume 42 Issue 6 Page 495-502, December 2007. http://www.blackwellsynergy. com/doi/abs/10.1111/j.1600-0765.2007.00973.x

Dental health was significantly worse in patients with acute myocardial infarction than in controls.

Mattila KJ, Nieminen MS, et.al., Brit Med J 189; 298:779-81.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=2496855&dopt=Abstract

Because NB can be identified by using culture, monoclonal antibodies, and electron microscopy techniques, and because they were detected in both dental pulp stones and CA, NB should be considered a potential causative agent to be screened in related diseases. We propose that NB may provide a potential bridge between periodontal diseases and peripheral artery disease.

Çiftçio lu N, McKay DS, Circulation. 2003;108:e58.
http://circ.ahajournals.org/cgi/content/full/108/8/e58

Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.(Inflammation and infection are factors that induce or promote inflammation and artherogenesis.)

Ross R, NEJM Vol.340:115-126 Jan 14, 1999 1999.
http://content.nejm.org/cgi/content/short/340/2/115

Scientists now agree that inflammation fuels the development and progression of atherosclerosis. The old view - that fat builds up on passive arterial walls- does not fit recent evidence. Inflammation can also cause certain plaques to rupture. Blood clots tend to form over ruptured plaques and can then occlude arteries, leading to such atherosclerotic complications as heart attack and stroke. Excess LDL can trigger arterial inflammation. The presence of CRP in the blood signifies that inflammation is present somewhere in the body.

Peter Libby MD, Scientific American, May 2002,p50-59.
http://www.ahs.uwaterloo.ca/~kh346/pdf/libby.pdf

Inflammation and coagulation play pivotal roles in the pathogenesis of vascular disease. Increasing evidence points to extensive cross-talk between these two systems, whereby inflammation leads not only to activation of coagulation, but coagulation also considerably affects inflammatory activity. Activation of coagulation and fibrin deposition as a consequence of inflammation is well known and can be viewed as an essential part of the host defense of the body against, for example, infectious agents or nonidentical cells, in an effort to contain the invading entity and the consequent inflammatory response to a limited area. An exaggerated or insufficiently controlled response may, however, lead to a situation in which coagulation and thrombosis contribute to disease, as illustrated by the fact that thrombus formation on a ruptured atherosclerotic plaque, containing abundant inflammatory cells, is the pathological basis of acute arterial thrombotic events such as myocardial infarction or unstable angina.1 Expression of procoagulant material by inflammatory cells in the unstable plaque (in particular tissue factor) may initiate activation of coagulation, and the thrombin generated will both activate platelets and result in the formation of a platelet-fibrin thrombus (Figure 1). Another example is the occurrence of systemic coagulation activation in combination with microvascular failure that results from the systemic inflammatory response to severe infection or sepsis and that contributes to multiple organ dysfunction.2 However, rather than this being a 1-way process with inflammation leading to coagulation, both systems closely interact, whereby coagulation can also substantially modulate inflammatory activity.

Levi, M, van der Poll, T, et al. Circulation. 2004;109:2698-2704.
http://www.circ.ahajournals.org/cgi/content/ extract/109/22/2698

CRP and blood pressure are independent determinants of cardiovascular risk, and their predictive value is additive. CRP showed a linear relationship with blood pressure across all categories of blood pressure. Both CRP and blood pressure were independent determinants of cardiovascular risk, and in combination, each parameter had additional predictive value. data suggest that increasing levels of blood pressure may stimulate a proinflammatory response and that endothelial inflammation may also herald the changes in arterial wall that characterize the hypertensive state. Inflammatory processes are now recognized to play a fundamental role in atherogenesis. C-reactive protein (CRP) has been found to be a robust predictor of incident cardiovascular disease. In this regard, the American Heart Association and the Centers for Disease Control and Prevention have recently issued a class IIa recommendation for the measurement of CRP in primary prevention among those at intermediate risk.

Blake GJ, Rifai N. et. al., Circulation. 2003;108:2993.
http://circ.ahajournals.org/cgi/content/full/108/24/2993

C-reactive protein levels are associated with future development of hypertension, which suggests that hypertension is in part an inflammatory disorder.

Sesso HD, Buring JE, et. al., JAMA. 2003;290:2945-2951.
http://jama.ama-assn.org/cgi/content/abstract/290/22/2945

High Creactive protein (CRP) levels are associated with an increased risk of cardiovascular events, even in apparently healthy individuals. It has not been established whether elevated CRP reflects an increased burden of subclinical coronary atherosclerosis. . Conclusions- High CRP levels are associated with increased coronary calcification. Among individuals with elevated CRP, subclinical atherosclerosis may contribute to an increased risk for future cardiovascular events.

Wang TJ, Larson MG, et al. Circulation. 2002;106:1189.
http://circ.ahajournals.org/cgi/content/ abstract/106/10/1189

The goal of this study was to assess the presence of systemic inflammation in degenerative aortic valvular stenosis. Local inflammatory changes, resembling those observed in atherosclerosis, have been recently reported in degenerative aortic valvular stenosis. It is presently unknown whether systemic signs of inflammation, similar to those observed in atherosclerosis, may be present in this disorder. C-reactive protein (CRP) was measured by enzyme immunoassay in 141 subjects: 62 with trileaflet degenerative valvular aortic stenosis and 79 volunteers with similar demographic and clinical characteristics. IgG antibodies against Helicobacter pylori (enzyme-linked immunosorbant assay) and Chlamydia pneumoniae (microimmunofluorescence assay) were also measured. Systemic signs of inflammation, similar to those found in atherosclerosis, are present in patients with degenerative aortic valve stenosis. They do not seem to be linked to C. pneumoniae or H. pylori infection.

Galante A, Pietroiusti A, et.al. J Am Coll Cardiol, 2001; 38:1078-1082.
http://content.onlinejacc.org/cgi/ content/abstract/38/4/1078 1078.

These findings suggest that CRP may promote matrix degradation and thus contribute to plaque vulnerability.

Williams TN, et.al., Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:61.
http://atvb.ahajournals.org/cgi/content/ abstract/24/1/61

Inflammation has long been known to be part of the body's response to infection. Evidence is accumulating that coagulation is part of that response as well..Aside from their usual role in hemostasis, platelets have other previously unrecognized abilities that closely link them to inflammation. . Platelets themselves release and display on their surfaces a variety of inflammatory mediators. Among those mediators are cytokines, such as interleukin 1b, and members of the CC and CXC chemokine family. Degranulation and secretion of preformed mediators is a critical and rapid innate hemostatic and inflammatory response.

Pulmonary Reviews.com, Vol.8, No.6.
http://www.pulmonaryreviews.com/jun03/ pr_jun03_coagulate.html

By initiating a procoagulant response, infectious agents can indirectly trigger a prothrombotic response. Alternatively, some microbes can directly trigger platelet aggregation in vitro and in animal models, suggesting direct prothrombotic potential in human cardiovascular disease. Activation of coagulation and thrombosis characterizes the pathological response to infectious agents in human disseminated intravascular coagulation and infective endocarditis. Given the underlying biological plausibility, the cumulative lifetime burden of chronic pathogens may be expected to create risk of atherosclerosis and thrombosis, and, indirectly, signs of cardiovascular disease.

Herzberg MC, Annals of Periodontology, 2001, Vol. 6, No. 1, Pages 16-19. http://www.joponline.org/doi/abs/10.1902/annals.2001.6.1.16

There is increasing evidence that chronic inflammation is tightly linked to diseases associated with endothelial dysfunction, including the induction of aberrant angiogenesis. While leukocytes have been described as mediators of inflammation-associated angiogenesis, the effects of direct chronic endothelial activation have not been addressed in this context. Using an uncleavable mutant of the transmembrane form of tumor necrosis factor- (TNF- ), we have established models of stable TNF- expression in endothelial cells in vitro and in transgenic mice in vivo. In the in vitro model, continuous endothelial activation leads to increased leukocyte cellular adhesion molecule expression and intracellular reactive oxygen species, hallmarks of a proinflammatory and dysfunctional endothelium. In addition, stable expression of TNF- in endothelial cells increased angiogenic sprout formation in the presence but also in the absence of angiogenic growth factors. The partial neutralization of this effect by TNF- antibodies and the inability of conditioned media from stable TNF- -expressing endothelial cells to induce angiogenic activities in control endothelial cells suggest that this effect does not require expression of additional autocrine factors, but is an autonomous effect of the transmembrane TNF on the endothelial cells. Furthermore, using the Matrigel plug assay in vivo, increased angiogenesis was observed in endothelial TNF- -expressing transgenic versus control mice. In conclusion, chronic inflammatory changes mediated by TNF- can induce angiogenesis in vitro and in vivo, suggesting endothelial cell activation as a direct link between inflammation and angiogenesis.

Rajashekhar G, Willuweit A, et al. J Vasc Res 2006;43:193-204. http://content.karger.com/ProdukteDB/produkte.asp?doi=10.1159/000090949

These various findings all highlight the central role of inflammation as a determinant of the biology underlying the acute thrombotic complications of atherosclerosis. Inflammation has emerged as a leading pathophysiologic mechanism (for thrombosis and acute myocardial infarction). In addition to local effects of inflammation at the level of the atherosclerotic lesion itself, systemic aspects of the inflammatory response may alter thrombotic risk. Inflammation upsets the prevailing homeostatic balance. Increased fibrinogen and plasminogen activator inhibitor circulate at higher concentrations in inflammatory states. A given plaque disruption could have a greater chance to produce an occlusive thrombus under such conditions.

Libby P. Circulation. 2001;104:365.
http://circ.ahajournals.org/cgi/content/full/104/3/365

Patients with deep periodontal pockets have an increased risk for electrocardiographic abnormalities, suggesting a heightened risk of cardiovascular disease. Elevated levels of the inflammatory compounds C-reactive protein, interleukin-6 and neutrophils associated with periodontitis may cause inflammatory changes to atherosclerotic lesions, increasing the risk of cardiac events, the researchers concluded.

ADA News Release.
http://www.ada.org/prof/resources/pubs/adanews/adanewsarticle.asp?articleid=956

Inflammatory dental disease may be a determinant of fibrinogen level and white cell count in the general population, and that fibrinogen and white cell count may be two mediators of the link between dental disease and myocardial infarction.

Kweider M, Lowe GD, et. al, Scott med J. 1993 Jun;38(3):73-4. Department of Oral Surgery, Dental Hospital & School, Glasgow. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=8356427&dopt=Abstract

In addition to "classical" risk factors for coronary heart disease (CHD) and stroke, "emerging" risk predictors (which may also play roles in pathogenesis) include measures of chronic infections and of chronic, low-grade activation of inflammation and of hemostasis. As all dental healthcare professionals know (but probably fewer medical practitioners and their patients), the oral cavity is a major site of chronic infection and inflammation, particularly periodontal disease. In recent years there has been increasing interest in the www.MDReferrals.net 18 "periodontal-systemic connection" between dental health parameters and the risks of cardiovascular disease, respiratory disease, diabetes mellitus, osteoporosis, and adverse pregnancy outcomes.

Lowe G, Circulation 2004;109:1076-1078.
http://circ.ahajournals.org/cgi/content/full/109/9/1076 .

Background: Periodontopathogens may play a role in the etiology of cardiovascular disease. The aim of the present study was to investigate biopsies of aortic tissue for the presence of periodontopathogens. Methods: Samples taken from the aortas of 26 patients connected to a heart-lung machine during open-heart surgery were analyzed in a gene-diagnostics laboratory by polymerase chain reaction. Immediately after biopsy, the samples were transferred into liquid nitrogen and stored at -80°C. 16S rRNA gene gene- directed primers were used for general detection of bacterial cells, and specific primers for detection of Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans actinomycetemcomitans. Questionable amplificons were verified by Southern hybridization using . DNA probes. Results: Bacterial DNA was found in 23 of 26 (88.5%) samples, in most cases only in concentrations around the detection limit. Four samples were clearly positive for P. gingivalis; A. actinomycetemcomitans was not detected. Conclusion: These results might indicate a link between periodontopathogens entering the cardiovascular system and cardiovascular disease.

Journal of Periodontology, 2002, Vol. 73, No. 8, Pages 868-870. Stelzel M, Conrads G, et al. http://www.joponline.org/doi/abs/10.1902/jop.2002.73.8.868

Background and Purpose- There is growing experimental evidence implicating chronic inflammation/infection as an atherosclerotic risk factor. In this study, the involvement of periodontal disease in the development of early atherosclerotic vascular lesions has been evaluated. Methods- In randomly chosen 82 patients with periodontal disease and 31 periodontally healthy individuals subjected to a clinical oral examination in 1985, atherosclerotic risk factor analysis and carotid ultrasonography was performed during reexamination 16 years later. Common carotid artery intima-media thickness (IMT) and lumen diameter were measured and intima-media area (cIMA) was calculated. The relationship between IMT and cIMA as dependent variables and periodontal disease, age, gender, body mass index, heredity for atherosclerosis, diabetes mellitus, hypertension, plasma cholesterol, smoking, and education as independent variables was evaluated in a multiple logistic regression model. . Conclusions- The present results indicate that periodontal disease is associated with the development of early atherosclerotic carotid lesions.] Soder P, Soder B. Stroke. 2005;36:1195. http://stroke.ahajournals.org/cgi/content/full/36/6/1195 100. Effect of aortic valve replacement on c-reactive protein in nonrheumatic aortic stenosis. [Plasma levels of Creactive protein were higher in 20 patients with bicuspid or trileaflet degenerative aortic stenosis than in 31 normal controls and in 19 patients with pure aortic regurgitation. C-reactive protein decreased from before to 6 months after aortic valve replacement for aortic stenosis. These observations suggest that aortic stenosis is an inflammatory disease.

Gerber IL, Stewart RA, et.al. Am J Cardiol. 2003 Nov 1;92(9):1129-32.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=14583374&dopt=Abstract Abstract.

Objective- In periodontitis, overgrowth of Gram- Gramnegative bacteria may cause negative endotoxemia and systemic inflammation leading to cardiovascular diseases (CVD). We investigated in a prospective study the associations of serum endotoxin, antibodies to periodontal pathogens, and inflammation markers with the risk of incident CVD.

Methods and Results- The FINRISK 1992 cohort of 6051 individuals was followed up for 10 years. We examined 185 incident CVD events and a control cohort of 320 individuals using a prospective case-cohort design. High antibody response to periodontal pathogens independently predicted incident CVD events with hazard ratios (HR, quartile 4 versus quartiles 1 to 3, 95% CI) of 1.87 (1.13 to 3.08). The subjects with a high antibody response and high CRP or interleukin (IL)- 6 had multivariate-adjusted HRs of 3.01 (1.27 to 7.09) and 3.11 (1.42 to 6.83) compared with low- lowresponders, respectively. responders, The corresponding HRs for high endotoxin concentration were 1.82 (1.22 to 2.73, alone), 3.92 (1.99 to 7.74, with CRP), 3.54 (1.78 to 7.03, with IL-6), and 2.26 (1.13 to 4.52, with tumor necrosis factor (TNF)- ) after adjusting for age and gender. These associations were abolished after adjusting for serum lipids. High endotoxin/HDL ratio, however, had a multivariateadjusted HR of 1.92 (1.19 to 3.08) for CVD events.

Conclusions- Our results suggest that the exposure to periodontal pathogens or endotoxin induces systemic inflammation leading to increased risk for CVD.

Pussinen PJ, Tuomisto K, et al. Arteriosclerosis, Thrombosis, and Vascular Biology, 2007;27:1433.
http://atvb.ahajournals.org/ cgi/content/abstract/27/6/1433

Unstable atherosclerotic plaque is a dangerous clinical condition, possibly leading to acute coronary deficiency resulting in cardiac infarction. Questions about the role of inflammatory factors in the formation of pathological lesions in the endothelium of coronary vessels have often been raised. This condition may be caused by bacteria that are able to initiate clot formation in a blood vessel, destabilizing an atherosclerotic plaque that is already present. The sources of these pathogens are chronic inflammatory processes occurring in the host, including periodontal disease, which is one of the most frequent conditions. The aim of this study was to evaluate the incidence of selected anaerobic bacteria in subgingival and atherosclerotic plaque in patients treated surgically because of coronary vessel obliteration. .In patients with the severe form of chronic periodontitis, it seems that clinical attachment loss is not associated with bacterial permeability into coronary vessels. What is important is the presence of an active inflammatory process expressed by a significantly higher bleeding index in those patients in whom the examined bacterial species were found in atherosclerotic plaque.

Zaremba M, Górska R, et.al. Journal of Periodontology 2007, Vol. 78, No. 2, Pages 322-327 327.http://www.joponline.org/doi/abs/10.1902/jop.2006.060081

Researchers have found that people with periodontal disease are almost twice as likely to suffer from coronary artery disease as those without periodontal disease. Additional studies have pointed to a relationship between periodontal disease and stroke. In one study that looked at the causal relationship of oral infection as a risk factor for stroke, people diagnosed with acute cerebrovascular ischemia were found more likely to have an oral infection when compared to those in the control group.

http://www.perio.org/consumer/mbc.heart.htm

Detection of periodontal pathogens in atherosclerotic plaques by PCR does not provide evidence as to the bacteria's viability within the plaque. This is the first report to provide evidence for the presence of invasive periodontal pathogens at the sites of atherosclerotic disease. In addition, their presence was demonstrated at the DNA levels. The intracellular bacteria must have been viable because only viable P gingivalis and A actinomycetemcomitans can invade host cells.8,9 Notably, the images presented here are all from the same patient. The patient apparently harbors periodontal organisms, judging from his oral health (partial dentition only). Further investigative work needs to be performed to determine whether periodontal pathogens truly have a role in the pathogenesis of atherosclerotic disease and, if so, how the bacteria contribute to the progression of this disease. Nevertheless, establishing such an unequivocal physical link between these two prevalent conditions will certainly support the notion of periodontitis as an exacerbating factor in cardiovascular pathologies. Identifying the inflammatory bacteria associated with vascular pathogenesis will be beneficial to understanding the epidemiological link between periodontal disease and CVD as well as in developing novel therapies for CVD..

Kozarov et al. Arteriosclerosis, Thrombosis, and Vascular Biology Biology. 2005;25:e17. . http://atvb.ahajournals.org/cgi/reprint/25/3/e17? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1=kozarov &andorexacttitle=and&andorexacttitleabs=and&andorexactfulltext=and&searchid=1&FIRSTIND EX=0&sortspec=relevance &volume=25&resourcetype=HWCIT

BACKGROUND: Recent studies suggest that chronic infections including those associated with periodontitis increase the risk for coronary vascular disease (CVD) and stroke. We hypothesize that oral microorganisms including periodontal bacterial pathogens enter the blood stream during transient bacteremias where they may play a role in the development and progression of atherosclerosis leading to CVD.

METHODS: To test this hypothesis, 50 human specimens obtained during carotid endarterectomy were examined for the presence of Chlamydia pneumoniae, human cytomegalovirus, and bacterial 16S ribosomal RNA using specific oligonucleotide primers in polymerase chain reaction (PCR) assays. Approximately 100 ng of chromosomal DNA was extracted from each specimen and then amplified using standard conditions (30 cycles of 30 seconds at 95 degrees C, 30 seconds at 55 degrees C, and 30 seconds at 72 degrees C). Bacterial 16S rDNA was amplified using 2 synthetic oligonucleotide primers specific for eubacteria. The PCR product generated with the eubacterial primers was transferred to a charged nylon membrane and probed with digoxigenin-labeled synthetic oligonucleotides specific for Actinobacillus actinomycetemcomitans, Bacteroides forsythus, Porphyromonas gingivalis, and Prevotella intermedia.

RESULTS: Eighty percent of the 50 endarterectomy specimens were positive in 1 or more of the PCR assays. Thirty- Thirtyeight percent were positive eight for HCMV and 18% percent were positive for C. pneumoniae. PCR assays for bacterial 16S rDNA also indicated the presence of bacteria in 72% of the surgical specimens. Subsequent hybridization of the bacterial 16S rDNA positive specimens with species-specific oligonucleotide probes revealed that 44% of the 50 atheromas were positive for at least one of the target periodontal pathogens. Thirty percent of the surgical specimens were positive for B. forsythus, 26% were positive for P. gingivalis, 18% were positive for A. actinomycetemcomitans, and 14% were positive for P. intermedia. In the surgical specimens positive for periodontal pathogens, more than 1 species was most often detected. Thirteen (59%) of the 22 periodontal pathogen-positive surgical specimens were positive for 2 or more of the target species.

CONCLUSIONS: Periodontal pathogens are present in atherosclerotic plaques where, like other infectious microorganisms such as C. pneumoniae, they may play a role in the development and progression of atherosclerosis leading to coronary vascular disease and other clinical sequelae.

Haraszthy V.I., Zambon J.J., et al. J Periodontol. 2000 Oct;71 (10):1554-60
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? db=PubMed&cmd=Retrieve&list_uids=11063387&dopt=Abstract

Infectious agents may play a role in the pathogenesis of atherosclerosis by several mechanisms of action and at different stages. Microorganisms could infect vascular endothelial cells directly, initiating the inflammatory response needed for the initial process of inducing atherosclerosis. Furthermore, even if the induction or initial injury to the endothelium was caused by another inciting agent or factor (for example, hypercholesterolemia or hypertension), infectious agents could accelerate or enhance the process through several mechanisms of action. They include further recruitment and stimulation of proinflammatory cytokines and tissue growth factors in the arterial wall, as well as enhancement of lipid (low-density lipoprotein, or LDL) accumulation through stimulation of macrophage scavenger or LDL-receptors. Microbes could indirectly influence the development and progression of atherosclerosis by a systemic effect without directly invading the arterial endothelium. Release of endotoxin or lipopolysaccharide into the circulation could indirectly damage vascular endothelium or the immune response, and systemic cytokine release could result in lipid profile predisposing to atherosclerosis or could predispose the arterial environment to a procoagulant state, resulting in acute thrombus on a pre-existent unstable or critical plaque, thus causing an acute ischemic event. Infectious agents may play an important role in atherogenesis, but the jury is not in. Further studies are needed to prove causality of atherogenesis from C. pneumoniae and to establish an association between cardiovascular disease and periodontitis. There is, however, sufficient evidence from biological mechanisms and animal models to warrant interventional studies on periodontitis and development of cardiovascular events.

Fong IW, J Am Dent Assoc, Vol 133, No suppl_1, 7S- 13S.
http://jada.ada.org/cgi/content/full/133/suppl_1/7S

Atherothrombosis of the coronary and cerebral vessels is understood to be a disorder of inflammation and innate immunity, as well as a disorder of lipid accumulation. From a vascular biology perspective, the processes of cellular adhesion, monocyte and macrophage attachment, and transmigration of immune cells across the endothelium are crucial steps in early atherogenesis and in the later stages of mature plaque rupture, particularly the transition of unstable plaque at the time of acute thrombosis. There is abundant clinical evidence demonstrating that many biomarkers of inflammation are elevated years in advance of first ever myocardial infarction (MI) or thrombotic stroke and that these same biomarkers are highly predictive of recurrent MI, recurrent stroke, diabetes, and cardiovascular death. In daily practice, the inflammatory biomarker in widest use is high- highsensitivity C-reactive protein sensitivity (hsCRP); when interpreted within the context of usual risk factors, levels of hsCRP <1, 1 to 3, and >3 mg/l denote lower, average, and higher relative risk for future vascular events. Risk-prediction models that incorporate hsCRP, such as the Reynolds Risk Score, have been developed that improve risk classification and the accuracy for global risk prediction, particularly for those deemed at "intermediate risk" by usual algorithms, such as the Framingham Risk Score. With regard to cerebral vessels, increased biomarkers of inflammation, including hsCRP, have been associated with increased stroke risk as well as an increased rate of atherosclerosis progression in the carotid vessels. Although the proportion of variation in hsCRP explained by genetic factors may be as large as 20% to 40%, diet, exercise, and smoking cessation remain critical tools for risk reduction and CRP reduction. Statin therapy reduces hsCRP in a largely low-density lipoprotein (LDL)-independent manner, and the "anti-inflammatory" properties of these agents have been suggested as a potential mechanism beyond LDL reduction for the efficacy of these agents. The ongoing multinational Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of 17,802 initially healthy men and women with low levels of LDL cholesterol but increased levels of hsCRP will help to define whether vascular protection can be achieved with statin therapy, even in the absence of hyperlipidemia. Targeted anti-inflammatory therapies are being developed that may provide a direct method of translating the biology of inflammation into new clinical treatments across multiple vascular beds. This article summarizes data supporting a role for inflammation in cardiovascular disease and offers the possibility that other disorders characterized by inflammation, such as periodontal disease, may have an indirect role by influencing the risk, manifestation, and progression of vascular events.

Ridker PM, Silvertown JD. Journal of Periodontology, 2008, Vol. 79, No. 8s, Pages 1544-1551. http://www.joponline.org/doi/full/10.1902/jop.2008.080249

Background: Inflammation is a significant component of atherosclerosis lesions. Bacteria, including periodontopathogens, have been demonstrated in atherosclerotic plaques and cross-reactivity of the immune response to bacterial GroEL with human heat shock protein 60 has been suggested as a link between infections and atherosclerosis.

Methods: In this study, the nature of the inflammatory infiltrate and the presence of human heat shock protein 60 and GroEL were examined in 31 carotid endarterectomy specimens. Additionally, monoclonal antibodies were used to detect the presence of six bacteria, including those implicated in periodontal disease.

Results: The inflammatory cell infiltrate of the lesions was dominated by CD14+ macrophages and CD4+ T cells. Most cells of the infiltrate as well as the endothelium were HLA-DR+ DR+, indicating , activation; however, there was an absence of CD25 expression, demonstrating that the activated T cells were not proliferating. Few CD1a+ and CD83+ cells were noted. Human heat shock protein 60 expression was evident on endothelial cells and cells with the appearance of smooth muscle cells and lymphocytes. GroEL and bacteria were detected within intimal cells. Chlamydia pneumoniae, Porphyromonas gingivalis, Fusobacterium nucleatum, Tannerella forsythia, Prevotella intermedia, and Actinobacillus actinomycetemcomitans were found in 21%, 52%, 34%, 34%, 41%, and 17% of arteries, respectively.

Conclusion: These results give evidence for a specific immune response associated with atherosclerosis. Whether bacteria initiate the observed inflammation in atherosclerotic lesions is not clear; however, the present study shows that maintenance of inflammation may be enhanced by the presence of periodontopathic bacteria.

Ford PJ, Gemmell E, et al. Oral Microbiology and Immunology, Volume 21 Issue 4 Page 206-211, August 2006.
http://www. blackwellsynergy. com/doi/abs/10.1111/j.1399-302X.2006.00276.x

Invasion of host cells is believed to be an important strategy utilized by a number of pathogens, which affords them protection from the host immune system. The connective tissues of the periodontium are extremely well vascularized, which allows invading microorganisms, such as the periodontal pathogen Porphyromonas gingivalis gingivalis, to readily enter the bloodstream. These , results indicate that P. gingivalis can actively invade endothelial cells and that fimbriae are required for this process. P. gingivalis invasion of endothelial cells may represent another strategy utilized by this pathogen to thwart the host immune response.

http://intliai. asm.org/cgi/content/abstract/66/11/5337

There are live periodontal bacteria in human atherosclerotic tissue.

March 22, 2005 Ann Progulske-Fox, chief investigator, U of FL College of Dentistry. http://www.napa.ufl.edu/2005news/plaque.htm

Recent meta-analyses reported a weak association between periodontal disease (PD) on clinical examination and cardiovascular disease (CVD). Systemic bacterial exposure from periodontitis, which correlates poorly with the clinical examination, has been proposed as the more biologically pertinent risk factor. The purpose of this study was to review and analyze the association between PD with elevated systemic bacterial exposure and CVD. Periodontal disease with elevated bacterial exposure is associated with CHD events and early atherogenesis (CIMT), suggesting that the level of systemic bacterial exposure from periodontitis is the biologically pertinent exposure with regard to atherosclerotic risk.

Mustapha IZ, Debrey S, et al. Journal of Periodontology, 2007, Vol. 78, No. 12, Pages 2289-2302
http://www.joponline.org/doi/abs/10.1902/jop.2007.070140 2007.070140.

Objective: The objective of the study was to assess the association between periodontitis and the metabolic syndrome in a cross-sectional survey of a nationally representative sample of the noninstitutionalized civilians in the United States.

Design, Setting, and Participants: Data analysis from the Third National Health and Nutrition Examination Survey on 13,994 men and women aged 17 yr or older who received periodontal examination were studied.

Main Outcome Measures: Association of diagnosis and extent of periodontitis (gingival bleeding, probing pocket depths) with the metabolic syndrome and its individual component conditions (central obesity, hypertriglyceridemia, low high-density lipoprotein-cholesterol, hypertension, and insulin resistance) were measured. Adjustment for age, sex, years of education, poverty to income ratio, ethnicity, general conditions, and smoking were considered.

Results: The prevalence of the metabolic syndrome was 18% [95% confidence interval (CI) 16-19], 34% (95% CI 29-38), and 37% (95% CI 28-48) among individuals with no-mild, moderate, and severe periodontitis, respectively. After adjusting for confounders, participants aged older than 45 yr suffering from severe periodontitis were 2.31 times (95% CI 1.13-4.73) more likely to have the metabolic syndrome than unaffected individuals. Diagnosis of metabolic syndrome increased by 1.12 times (95% CI 1.07-1.18) per 10% increase in gingival bleeding and 1.13 times (95% CI 1.03-1.24) per 10% increase in the proportion of periodontal pockets.

Conclusions: Severe periodontitis is associated with metabolic syndrome in middle-aged individuals. Further studies are required to test whether improvements in oral health lead to reductions in cardiometabolic traits and the risk of metabolic syndrome or vice versa.

D'Aiuto F, Sabbah W, et al., Journal of Clinical Endocrinology & Metabolism Metabolism, Vol. 93, No.10, , 3989-3994. http://jcem.endojournals.org/cgi/content/abstract/93/10/3989

The endpoint of clinical therapy is the elimination of inflammation. To achieve this, open debridement may be required in addition to scaling and root planing, and treatment may be aided by chemotherapeutic agents. Scaling and root planing results in systemic effects (including bacteremia) and local effects which include decreases in the levels of calculus, pathogenic microorganisms and clinical inflammation. Additional therapy may be required to achieve clinical health.

Haake SK, Isaacs D. (Note: http://www.dent.ucla.edu/pic/members/microscaling/

Heart attack survivors who suffer advanced gum disease show significantly higher levels of C-reactive protein in their blood than patients without gum disease, new University of North Carolina at Chapel Hill research indicates.

UNC News Services,
http://www.unc.edu/news/archives/nov00/deliar111300.htm ;
http://www.sciencedaily.com/releases/2000/11/001113071724.htm

Objectives: To investigate a possible link between valvular incompetence in primary varicose veins and chronic infection of periodontal disease by assessing the presence of oral bacteria in the great saphenous vein from patients with varicose veins and control subjects.

Material and methods: Forty-four primary varicose vein patients were enrolled in the study. 12 control saphenous veins were obtained from patients undergoing peripheral arterial bypass without clinical evidence of venous reflux. In total, 56 saphenous vein specimen (44 varicose veins and 12 control veins) were examined for 7 periodontal bacteria using a polymerase chain reaction (PCR) method.

Results: Of the 44 primary varicose vein patients, 31 patients were women and mean age was 59 years (range, 39-79 years). PCR examination of the diseased vein specimens showed that 48% were positive for at least one of 7 periodontal bacterial DNA. No bacteria were detected in the control specimens.

Conclusion: Bacterial colonisation or infection of varicose veins is a frequent event although we were not able to establish whether this is a cause or consequence of the development of varices but this could be considered a risk factor for the development of varices.

Kurihara N, Inoue Y, et al. European Journal of Vascular and Endovascular Surgery , Volume 34 , Issue 1 , Pages 102 - 106. http://linkinghub.elsevier.com/retrieve/pii/S1078588407001499

Many systemic diseases and conditions have oral manifestations that may be the initial signs of clinical disease. The mouth is a portal of entry as well as the site of disease for microbial infections that affect general health status. Sufficient evidence exists to conclude that oral lesions, especially advanced periodontic pathogies, place certain patients at increased risk of developing cardiovascular disease and stroke.

Rose LF, Mealey B. J Am Dent Assoc, Vol 133, No suppl_1, 37S-44S.
http://jada.ada.org/cgi/ content/full/133/suppl_1/37S

Evidence continues to support an association among periodontal infections, atherosclerosis and vascular disease. Most studies reported positive associations between periodontal disease and cardiovascular disease after accounting for the effects of multiple risk factors such as age, sex, diabetes, cholesterol levels, blood pressure, obesity, smoking status, dietary patterns, race/ ethnicity, education and socioeconomic status. Carotid atherosclerosis as measured by intima-media thickening increased with higher levels of the periodontal bacteria. The mounting evidence points to an association of periodontal disease at th eibological, clinical, radiographic and microbiological levels in relation to clinical and subclinical vascular disease. The emergence of periodontal infections as a potential risk factor for CVD is leading to a convergence in oral and medical care that can only benefit the patients and public health.

Demmer RT, Desvarlieux M., JADA, Vol.137, Oct 2006 Supplement, pp.15s-20s. http://jada.ada.org/content/vol137/suppl_2/index.dtl

These findings indicate that gingival tissues may be a port of entry for previously unrecognized invasive spirochetes in humans.

Infect Immuno 59:3377-80, 1991. Riviere GR et al.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=1894352&dopt=Abstract

Mild forms of periodontal disease affect 75 percent of adults in the United States, and more severe forms affect 20 to 30 percent of adults. Because periodontal disease is common in the population, it may account for a significant portion of the proposed infectionassociated risk of cardiovascular disease.

Genco R, Offenbacher S. J Am Dent Assoc Assoc, Vol 133, No suppl_1, , 14S-22S. http://jada.ada.org/cgi/content/full/133/suppl_1/14S

According to the American Academy of Periodontology, people with periodontal disease are almost twice as likely to have coronary artery disease (also called heart disease). And one study found that the presence of common problems in the mouth, including gum disease (gingivitis), cavities, and missing teeth, were as good at predicting heart disease as cholesterol levels.

April, 2005, WebMD.
http://www.webmd.com/content/Article/104/107270.htm?printing=true

Periodontal disease is an important risk factor for total CVA and, in particular, nonhemorrhagic stroke.

Wu T, Trevisan M, et al. Arch Intern Med. 2000;160:2749-2755.
http://archinte.ama-assn.org/cgi/content/abstract/160/18/2749

People with periodontal disease are more likely to have thickened carotid arteries, which can lead to stroke, according to a study released at the American Academy of Neurology's 51st annual meeting in Toronto.

American Academy of Neurology 51st annual meeting Toronto CA, 4/21/1999, Mitchell Elkind, MD, Columbia Univ, New York.
http://www.pslgroup.com/dg/f896a.htm

The influence of periodontitis on lipoprotein metabolism has emerged as a new, important factor. Recent studies provide experimental proof that periodontitis may predispose to atherosclerosis.

Pussien PJ et al. Current Opinion in Lipidology Lipidology. 15(5):583-588, Oct . 2004. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=15361795&dopt=Abstract

Chronic inflammation from any source is associated with increased cardiovascular risk. Periodontitis is a possible trigger of chronic inflammation. We investigated the possible association between periodontitis and coronary heart disease (CHD), focusing on microbiological aspects. Our findings suggest an association between periodontitis and presence of CHD. Periodontal pathogen burden, and particularly infection with A actinomycetemcomitans, may be of special importance.

Spahr A, Klein E, et. al., Arch Intern Med. 2006;166:554- 559.
http://archinte.ama-assn.org/cgi/content/short/166/5/554

New findings are presented which indicate that the extent of the periodontal infection, a measure reflecting microbial burden, also is related to onset of new CHD events. Our previously published model describing the potential biological mechanisms underlying the associations found is reviewed. This model places the associations into a context of an intrinsic or acquired hyperinflammatory monocyte trait that results in a more intense inflammatory response to lipopolysaccharide (LPS) challenges, such as periodontal infections. This hyperinflammatory response may promote atheroma formation and thromboembolic events. finally, new findings from ongoing animal studies are presented, indicating that high fat diets in atherosclerotic-susceptible mice induce greater inflammatory responses to Porphyromonas gingivalis challenges. We conclude that the available evidence does allow an interpretation of periodontitis being a risk factor for atherosclerosis/CHD. Current findings regarding the associations between oral conditions and atherosclerosis/CHD imply that the criteria for causality may be met in the not-too-distant future.

Beck JD, Offenbacher S. Ann Periodontol. 1998 Jul;3(1):127-41.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=9722697&dopt=Citation

C-reactive protein (CRP) is a marker of inflammation and predicts outcome in apparently healthy subjects and patients with coronary artery disease. Systemic inflammation is present in patients with aortic valve stenosis (AS). The aim of this prospective study was to assess whether CRP levels predict the progression of AS severity. Blood samples for high-sensitivity CRP measurements and echocardiographic data were obtained in 43 patients (70% men; mean age 73 +/- 8 years) with asymptomatic degenerative AS at study entry. On the basis of repeat echocardiographic assessment at 6 months, patients were grouped as (1) slow progressors (a decrease in aortic valve area [AVA] <0.05 cm2 and/or an increase in aortic peak velocity <0.15 m/s) and (2) rapid progressors (a decrease in AVA > or =0.05 cm2 and/or an increase in aortic peak velocity > or =0.15 m/s). Plasma CRP levels were significantly higher in rapid progressors than slow progressors (median 5.1 [range 2.3 to 11.3] vs 2.1 [range 1.0 to 3.1] mg/L, p = 0.007). In multivariate analysis, CRP levels >3 mg/L were independently associated with rapid AS progression (odds ratio 9.1, 95% confidence interval 2.2 to 37.3). In conclusion, CRP levels are higher in patients with degenerative AS who show rapid valve disease progression. These findings suggest that inflammation may have a pathogenic role in degenerative AS.

Sanchez Pl, Santos JL, et.al. Am J Cardiol. 2006 Jan 1;97(1):90-3. Epub 2005 Nov 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=16377290&dopt=Abstract

Periodontitis has been linked to clinical cardiovascular disease but not to subclinical atherosclerosis. The purpose of this study was to determine whether periodontitis is associated with carotid artery intima-media wall thickness. These results provide the first indication that periodontitis may play a role in the pathogenesis of atheroma formation, as well as in cardiovascular events.

http://atvb.ahajournals.org/cgi/content/abstract/atvbaha;21/11/1816

Patients with periodontal disease are more likely to suffer from atherosclerosis than their counterparts with healthy gums, researchers from Columbia University Medical Center report. Bacteria that cause periodontal disease can migrate throughout the body via the bloodstream and stimulate the immune system, causing inflammation that results in the build up of deposits in the arteries.

ADA News Release.
http://www.ada.org/prof/resources/pubs/adanews/adanewsarticle.asp?articleid=1267

P. gingivalis exhibits several properties which could play a role in CVD as mediators of LDL oxidation, foam cell formation, and rupture of atherosclerotic plaque.

Kuramitsu HK, Annals of Periodontology, 2001, Vol. 6, No. 1, Pages 41-47. http://www.joponline.org/doi/abs/10.1902/annals.2001.6.1.41

Subjects under 55 with markers for periodontal disease showed a two- to four-times greater risk of having a heart attack, regardless of tobacco use.

ADA News Release.
http://www.ada.org/prof/resources/pubs/adanews/adanewsarticle.asp?articleid=939

Based on the results of this study, there is evidence of an association between cumulative periodontal disease, based on PHS, and a history of stroke. However, it is unclear whether cumulative periodontal disease is an independent risk factor for stroke or a risk marker for the disease.

Lee HJ, Garcia RI, Journal of Periodontology, 2006, Vol. 77, No. 10, Pages 1744-1754. http://www.joponline.org/doi/abs/10.1902/jop.2006.050339?journalCode=jop

Studies to date suggest that oral conditions may be associated with increased risk of ischemic stroke and peripheral vascular disease.

Joshipura K. J Am Dent Assoc, Vol 133, No suppl_1, 23S-30S.
http://jada.ada.org/cgi/content/ full/133/suppl_1/23S

Oral pathogens and inflammatory mediators (such as interleukin [IL]-1 and tumor necrosis factor [TNF]-a a) from periodontal ) lesions intermittently reach the bloodstream inducing systemic inflammatory reactants such as acute-phase proteins, and immune effectors including systemic antibodies to periodontal bacteria.

DeNardin E, Annals of Periodontology, 2001, Vol. 6, No. 1, Pages 30-40. http://www.joponline.org/doi/abs/10.1902/annals.2001.6.1.30

Introduction: Cardiovascular disease is predicted to be the most common cause of death worldwide by the year 2020. Half of heart disease patients lack established risk factors such as elevated lipids, hypertension, tobacco abuse, and positive family history. Additionally, these risk factors are generally associated with the disease, and the exact mechanism by which they may contribute to the development of atherosclerosis is not clear. However, previous and recent studies point to a linkage between infection with different bacteria and heart disease in the other 50% of observed incidences. Moreover, pathogenesis of the disease induced by infectious agents is described by three different mechanisms of action: induction of inflammation, release of toxins or superantigens, and molecular mimicry or cross-reactivity. This may result in plaque formation or antimyosin cellular and humoral immunity and subsequently, to myocarditis or other autoimmune diseases.

Infectious Agents: Through the years many reports have incriminated various infectious agents in the pathogenesis of autoimmune disease. Beta-hemolytic streptococcus has been implicated in rheumatic fever, Epstein-Barr virus in rheumatoid arthritis, Coxsackie virus B4 in diabetes, Herpes type-6 and measles virus in multiple sclerosis, cytomegalovirus, chlamydia pneumoniae and many other infectious agents in coronary artery disease. In addition, evidence has accumulated to suggest that chronic dental infection may be another factor for the development of atherosclerotic heart disease. Patients with poor dentition, especially those with periodontal disease are noted to have frequent recurrent episodes of bacteremia. The infectious agents involved are usually anaerobic proteolytic bacteria. These studies indicate that the most common strain of bacteria in dental plaque may cause blood clots. When blood clots escape into the bloodstream, they may increase the risk of heart attack and other heart illnesses. The plausible cause was further strengthened by the study of Dr. Beck and his associates published in The Journal of Periodontology, October 1996. In this study, the severity of periodontal disease during a three-year period in the 1970's was determined in 1147 men who were followed for 20 years. For those men with significant periodontal disease, the odds ratios for fatal coronary disease or stroke were 1.9 and 2.8, respectively. An association between periodontal disease and atherosclerotic or thrombotic events could arise from underlying inflammatory response or prothrombotic traits that place some people at high risk for both periodontal disease and atherosclerosis or thrombosis. It may also be that the chronic inflammation induced by the periodontal disease contributes to the pathogenesis of atherosclerosis.

Vojdani A. Immunosciences Lab, Inc.
http://www.immuno-sci-lab.com/ theroleofperiodontal.html

Background Systemic inflammation may impair vascular function, and epidemiologic data suggest a possible link between periodontitis and cardiovascular disease. Methods We randomly assigned 120 patients with severe periodontitis to community-based periodontal care (59 patients) or intensive periodontal treatment (61). Endothelial function, as assessed by measurement of the diameter of the brachial artery during flow (flow-mediated dilatation), and inflammatory biomarkers and markers of coagulation and endothelial activation were evaluated before treatment and 1, 7, 30, 60, and 180 days after treatment. Conclusions Intensive periodontal treatment resulted in acute, short-term systemic inflammation and endothelial dysfunction. However, 6 months after therapy, the benefits in oral health were associated with improvement in endothelial function.

Tonetti MS, D'Aiuto F, et.al. New England Journal of Medicine Vol 356:911-920, March 1, 2007, No.9. http://content.nejm.org/cgi/content/ abstract/356/9/911

Scientists have discovered how C-reactive protein, or CRP, is able to access endothelial cells. CRP is a known risk marker for heart disease. This is the first time that anyone has shown how CRP is able to get into the human aortic endothelial cells.

http://www.eurekalert.org/pub_releases/2005-06/uocd-udr062105.php

A new study by UC Davis physicians is the first to conclusively link C-reactive proteins (CRP) to formation of blood clots, a major cause of heart attacks, strokes and other vascular disease. Until now, CRP had been recognized mainly as a risk marker of heart disease disease. CRP causes cells in the arteries, endothelial cells, to produce higher levels of an enzyme that inhibits the breakdown of clots. The enzyme, plasminogen activator inhibitor-1 (PAI-1) is also a strong risk marker for heart disease, especially in diabetics.

http://www.ucdmc.ucdavis.edu/news/CRP_study.html

Increased levels of high- highsensitivity C-reactive sensitivity Protein (hsCRP) are associated with incident hypertension as well as cardiovascular events, and angiotensionII is a potent proinflammatory mediator.

Ridker PM, Danielson E, et. al., Hypertension Hypertension. 2006;48:1-7. . http://hyper.ahajournals.org/cgi/content/abstract/01.HYP.0000226046.58883.32v1? maxtoshow=&HITS=10&hits=10&RESU LTFORMAT=&fulltext=valsartan&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

Virginia Commonwealth University researchers have found that changes in the plasma lipoprotein profile of patients with severe periodontitis - a condition characterized by chronic infection and inflammation of the gums - may contribute to these patients' elevated risk for heart disease and stroke. Patients with periodontitis had elevated plasma levels of a particularly bad subclass of the low density lipoprotein (LDL) called small-dense LDL. Also the decrease of LDL associated PAF-AH activity in patients with severe periodontitis may increase cardiovascular risk in these patients.

RICHMOND, Va. (Dec. 1, 2005)
http://www.vcu.edu/uns/Releases/2005/dec/120105.html