• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Cardiovascular disease, inflammation, and periodontal infection
 

Cardiovascular disease, inflammation, and periodontal infection

on

  • 1,843 views

 

Statistics

Views

Total Views
1,843
Views on SlideShare
1,057
Embed Views
786

Actions

Likes
0
Downloads
42
Comments
0

1 Embed 786

http://dentosca.wordpress.com 786

Accessibility

Categories

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    Cardiovascular disease, inflammation, and periodontal infection Cardiovascular disease, inflammation, and periodontal infection Document Transcript

    • Periodontology 2000, Vol. 44, 2007, 113–126 Ó 2007 The Authors.Printed in Singapore. All rights reserved Journal compilation Ó 2007 Blackwell Munksgaard PERIODONTOLOGY 2000Cardiovascular disease,inflammation, and periodontalinfectionD A V I D W. P A Q U E T T E , N A D I N E B R O D A L A & T I M O T H Y C. N I C H O L SCardiovascular and periodontal diseases are common infarction, and stroke. Traditional risk factors relatedinflammatory conditions in the human population. to behaviors, diet, lifestyle, and family history doIn atherogenesis, inflammation plays a continuous not appear to fully account for the developmentrole from endothelial cell expression of adhesion of atherosclerosis. Furthermore, despite continuedmolecules to the development of the fatty streak, preventive efforts addressing modifiable risk factors,established plaque, and finally plaque rupture. mortality rates from cardiovascular disease have re-Exposures to infections like periodontal disease have mained virtually unchanged over the past decadebeen postulated to perpetuate inflammatory events in developed countries. Clinicians and investigatorsin atherogenesis. Recent observational studies and currently appreciate that inflammation appears tometa-analyses continue to demonstrate a modest but play a pivotal role in the development of athero-statistically significant increased risk for cardiovas- sclerosis. This appreciation has intensified the searchcular disease among persons exposed to periodontal for chronic exposures or infections that potentiallydisease or infection. Experiments with animal models cause inflammation in vessels. Putative infectionsfurther indicate that periodontal infection can in- that may at least exacerbate atherosclerosis includecrease atherosclerosis in the presence or absence of cytomegalovirus, herpes simplex virus, Chlamydiahypercholesterolemia. While the available pilot data pneumoniae, Helicobacter pylori, and periodontalin patients suggest that periodontal interventions can disease (71). The major objective of this review is toimprove surrogate serum biomarkers and vascular provide the reader with a strong fundamentalresponses associated with cardiovascular disease, the understanding of the pathogenesis, risk factors, andeffect of these interventions on true outcomes of current interventions for cardiovascular disease. Thiscardiovascular diseases like myocardial infarction review will also present the latest relevant researchand stroke is presently unknown. Nevertheless, data implicating a relationship between cardiovas-clinicians and patients should be aware of the con- cular and periodontal diseases.sistent association between cardiovascular and peri-odontal diseases along with the potential preventivebenefits of periodontal interventions. Inflammation and the Cardiovascular disease accounts for 29% of deaths pathogenesis of cardiovascularworldwide and ranks as the second leading cause of diseasedeath after infectious and parasitic diseases (100).Atherosclerosis, which is a major component of car- Inflammation plays a central and continuous role indiovascular disease, affects one in four persons and the pathogenesis of atherosclerosis from its initiationcontributes to 39% of deaths annually in the United to the development of clinical complicationsStates (4). In atherosclerosis, large to medium-sized (Table 1) (58, 60). Normally, endothelial cells, whichmuscular and large elastic arteries become occluded form the innermost surface of the artery wall, resistwith fibro-lipid lesions called atheromas. End-stage adhesion by circulating leukocytes. Several exposurescomplications or events associated with atheroscler- or risk factors for atherosclerosis upset this homeo-osis include coronary thrombosis, acute myocardial stasis. Factors, such as a smoking, hypertension, 113
    • Paquette et al. Table 1. Summary of inflammatory signals and events in atherogenesis. Modified from Ref. (58) Stages of Endothelial Development of fatty Progression to Plaque rupture atherogenesis expression of streak complex plaque adhesion molecules Cellular and • Endothelial • Diapedesis and • Smooth muscle • Physical disruption vascular permeability migration of migration from of atherosclerotic changes • Rolling and monocytes from the media to intima lesion binding of vessel lumen to • Production and • Thinning and monocytes to intima accumulation of fibrous fracture of fibrous endothelial cells • Maturation to tissue in the intima cap macrophages (fibro-lipid lesion) • Thrombus formation • Accumulation of • Formation of cholesterol esters fibrous cap and and transformation necrotic core to foam cells Inflammatory Vascular adhesion Monocyte Platelet-derived growth Matrix metalloproteinases signals or molecule-1 promoted chemoattractant factor, transforming 1, 8 and 13 promoted events by oxidized lipids, protein-1 growth factor-b, by interleukin-1, interleukin-1, tumor and macrophage interleukin-1, CD40 ligand and necrosis factor-a, colony-stimulating interleukin-6, interfeuron-c disrupted blood flow, factor tumor necrosis factor-a, activation of nuclear macrophage colony- factor-jB pathways stimulating and reduction in nitric factor, monocyte oxide chemoattractant protein-1 and CD40high-saturated-fat diet, obesity hyperglycemia and ogenic diets is the accumulation of modifiedinsulin resistance, promote endothelial cell expres- lipoprotein particles in the arterial intima. Othersion of adhesion molecules that allow attachment of initiators include oxidized lipids (via nuclear factor-leukocytes to the arterial wall, a seminal event in jB-mediated pathways) and pro-inflammatory cyto-inflammation. One such adhesion molecule is vas- kines such as interleukin-1b and tumor necrosiscular cell adhesion molecule-1, which binds mono- factor-a (85).cytes and T lymphocytes, the types of leukocytes Atherosclerotic lesions generally develop in specificfound in early atherosclerotic plaques. Cybulsky areas in animals and humans secondary to the bloodand Gimbrone demonstrated that endothelial cells flow characteristics. Laminar blood flow producesexpressed vascular cell adhesion molecule-1 in cer- shear stress coinciding with several protective mech-tain vascular areas prone to lesion formation in rab- anisms in vessels such as nitric oxide synthasebits fed an atherogenic diet (18). In the same rabbit expression (33). Enzymatic production of the vasodi-model, vascular cell adhesion molecule-1 expression lator, nitric oxide, can down-regulate vascular cellclearly precedes the appearance of macrophages in adhesion molecule-1 gene expression by inhibitingthe artery intima (the layer underneath the endo- nuclear factor-jB activation and platelet aggregationthelium) (56). Similarly, mice prone to atherosclerosis (22). In contrast, areas of the vasculature prone to(i.e. because they cannot produce low-density lipo- atherogenesis experience disturbed blood flow and aprotein receptor or apolipoprotein E) but engineered reduction in these protective mechanisms. For exam-to express a poorly functioning form of vascular cell ple, cultured endothelial cells subjected to disturbedadhesion molecule-1 show a significant reduction in flow exhibit increased expression of nuclear factor-jBatherosclerosis as compared to normal vascular cell compared with cells exposed to laminar flow (30).adhesion molecule-1-producing controls (19). Thisdifference in lesion formation occurs despite similarcholesterol concentrations, lipoprotein profiles and Development of the fatty streakcirculating leukocyte counts in the mice. One recog-nized molecular initiator of vascular cell adhesion The accumulation of monocytes in the vessel intimamolecule-1 expression for animals placed on ather- is a hallmark event in the development of the early114
    • Cardiovascular disease, inflammation, and periodontal infectionatherosclerotic lesion called the Ôfatty streak.Õ Fol-lowing adherence to arterial endothelium, monocytes Progression to complex plaquepenetrate the vessel lining via diapedesis or migrationbetween endothelial cells (Table 1). This cellular While accumulation of foam cells is the hallmark of theevent requires a chemoattractant gradient largely fatty streak, the accumulation of fibrous tissue in ves-because of monocyte chemoattractant protein-1. sels typifies the advanced atherosclerotic lesion calledMice with inactive low-density lipoprotein receptors the Ôcomplex plaque.Õ Smooth muscle cells synthesizeand also lacking the ability to express monocyte the bulk of the extracellular matrix of complex plaques;chemoattractant protein-1 have approximately 80% hence, their arrival and elaboration of extracellularless lipid deposition and fewer macrophages in the matrix provides the transition to a fibrolipid lesion.walls of their aortas despite consuming the same Growth factors and cytokines (e.g. platelet-derivedhigh-fat diet as compared to monocyte chemoat- growth factor) liberated from endothelial or infiltratingtractant protein-1-producing mice (13). In contrast, monocytes stimulate the migration of smooth musclehomozygous apolipoprotein-E-deficient mice also cell from the vessel tunica media into the intima.lacking the ability to express the receptor for mono- Mediators including platelet-derived growth factor,cyte chemoattractant protein-1 (CCR2), exhibit sig- transforming growth factor-b and interleukin-1 sti-nificantly less atherogenesis than do mice with a mulate the smooth muscle cells to produce interstitialnormal CCR2 gene (11). Within the intima, mono- collagen. The formation of complex plaques can occurcytes mature into macrophages, express scavenger at an early age as demonstrated by classic autopsyreceptors, and engulf modified lipoproteins. Choles- studies (99). Indeed, one of six teenagers in the Unitedterol esters accumulate in the cytoplasm of these States already exhibits pathological intimal thickeningmacrophages, which transform into Ôfoam cellsÕ in their coronary arteries (94).(i.e. lipid-laden macrophages in the vessel intima). Endothelial cells do not appear to be passiveAt the same time, the macrophages multiply and responders to immunological stimuli from leukocytesrelease several growth factors and cytokines, which in the formation of complex plaques. For instance,amplify and sustain pro-inflammatory signals. One human endothelial cells exposed to bacterial endo-growth factor, macrophage colony-stimulating factor toxin express interleukin-1b and interleukin-1a mes-appears to be an important mediator of these trans- senger RNA (59). Other cytokines expressed byformation and proliferation steps. It is also over-ex- vascular wall cells have been identified, including tu-pressed in animal models and human atherosclerotic mor necrosis factor-a, tumor necrosis factor-b, inter-plaques (17, 79). Mice prone to atherosclerosis as a leukin-6 along with macrophage colony-stimulatingresult of reduced expression of the low-density lipo- factor and monocyte chemoattractant protein-1 (60).protein receptor or the apolipoprotein E gene and Another pro-inflammatory cytokine, CD40 ligandalso lacking the ability to express macrophage col- (CD154), can also contribute to this phase of athero-ony-stimulating factor show slower atherogenesis genesis because interruption of CD40/CD154 signa-and reduced macrophage accumulation as compared ling slows the initiation and progression of athero-to mice with normal macrophage colony-stimulating sclerosis (63). Accordingly, low-density lipoprotein-factor expression (75, 90). receptor-deficient mice fed a high-cholesterol diet and T lymphocytes also participate in the pathogenesis treated with antibody to CD154 show significantlyand inflammatory events of atherosclerosis. These smaller atherosclerotic lesions as compared to controlimmune cells enter the inflamed artery wall and join groups (treated with either rat immunoglobulin ormacrophages via a number of interferon-c-inducible saline only) (82). This provocative finding reported bychemokines (e.g., c-IP-10, MIG, and I-TAC) that Schonbeck et al. illustrates that inflammation influ-interact with the CXCR3 receptor on T lymphocytes ences the progression of atherosclerosis and that(64). Several other adhesion molecules, chemokines, inhibiting inflammatory events not only prevents thecytokines, and growth factors participate in this pro- formation of new lesions but also slows the progres-cess. For example, the interaction between interleu- sion of existing atherosclerosis.kin-8 and its receptor, CXCR2, can also contribute tolesion formation in mice (10). Nevertheless, vascularcell adhesion molecule-1, monocyte chemoattractant Plaque ruptureprotein-1, and macrophage colony-stimulating factorappear to be the key inflammatory signals in the While atheromatous plaques narrow the lumina ofinitiation and development of the fatty streak (58). affected vessels and compromise blood flow, the 115
    • Paquette et al.major clinical sequelae of atherosclerosis (coronary 90 mmHg), high low-density lipoprotein cholesterolthrombosis, myocardial infarction, and stroke) de- (>100 mg/dl), low high-density lipoprotein choles-velop following plaque rupture and thrombosis terol (<40 mg/dl), diabetes mellitus, family history(Table 1). In coronary arterial thromboses, the of premature coronary heart disease, age (menunderlying atherosclerotic lesion often does not >45 years, women >55 years), obesity (body massproduce critical arterial narrowing (36). Coronary index >30 kg/m2), physical inactivity and an ather-arteries for the most part can enlarge and compen- ogenic diet. It is also recognized that these factors cansate for developing plaques (i.e. up to 40% stenosis) interact with each other to increase the risk of car-thus preserving blood flow to the myocardium (34). diovascular disease in patients (89). For example, the Physical disruption of the atherosclerotic plaque Framingham Heart Study (n ¼ 32,995) showed thatcauses most acute coronary syndromes via thrombus for various cholesterol levels between 185 andformation and sudden expansion of the lesion (58). In 335 mg/dl, cardiovascular risk was elevated with thethe non-ruptured plaque, the Ôfibrous capÕ protects addition of each of the following risk factors: glucosethe blood from the lipid core of the plaque. An intact intolerance, elevated systolic blood pressure, cigar-fibrous cap owes its biomechanical strength and ette smoking, and left ventricular hypertrophy onstability to interstitial collagen. When the fibrous cap electrocardiography (50). Data from the Framinghamfractures, blood comes into contact with the lipid Heart Study and two other large prospective cohortcore, and a thrombus forms. Plaques that have rup- studies, the Chicago Heart Association Detectiontured and caused fatal thromboses in general have Project in Industry (n ¼ 35,642) and the Multiple Riskthin fibrous caps (61). Factor Intervention Trial (n ¼ 347,978) indicate that Inflammation interferes with the integrity of the the majority of patients with fatal coronary arteryfibrous cap in two ways: first, by blocking the creation disease or non-fatal myocardial infarction presentof new collagen fibers, and second by stimulating the with at least one of four risk factors including cigar-destruction of existing collagen. For example, inter- ette smoking, diabetes mellitus, hyperlipidemia, andferon-c produced by T lymphocytes in the plaque hypertension (35). With fatal coronary artery disease,inhibits both basal collagen production and the exposure to at least one risk factor ranged from 87%stimulatory effects transforming growth factor-b, to 100% for all three cohorts. For non-fatal myocar-platelet-derived growth factor and interleukin-1 (3). dial infarction in the Framingham Heart Study co-T lymphocytes also promote the destruction of hort, previous exposure to at least one risk factor wasexisting collagen in vulnerable plaques via the pro- found in 92% of men and 87% of women agedduction of interleukin-1 and CD40 ligand. These 40–59 years at baseline. Furthermore, another recentmediators in atherosclerotic plaques stimulate analysis involving 14 international randomized clin-macrophages to produce collagen-degrading en- ical trials (n ¼ 122,458) showed that one of these fourzymes or matrix metalloproteinases 1, 8, and 13 (42, conventional risk factors was present in 84.6% of92). In addition, mast cells in plaques may release the men and 80.6% of women with coronary artery dis-matrix metalloproteinase-inducer, tumor necrosis ease (52).factor-a, as well as serine proteinases, tryptase and Recent attention has focused on elevated serumchymase that can activate matrix metalloproteinase C-reactive protein as a strong and independent riskpro-enzymes (53, 80). CD40 ligand from T lympho- factor or predictor of cardiovascular disease eventscytes can also promote thrombogenicity of the lipid (68). C-reactive protein is an acute-phase reactantcore via stimulation of macrophage tissue factor primarily produced by the liver in response toexpression. This potent procoagulant when exposed infection or trauma. Other tissues may be involved into factor VII in the blood, initiates the coagulation its synthesis including smooth muscle cells fromcascade and thrombus formation (62). In summary, normal coronary arteries and diseased coronary ar-inflammation influences all of the events in athero- tery bypass grafts (14, 47). C-reactive protein appearsgenesis including the final one, plaque rupture. to be directly involved in augmenting the innate inflammatory response via induction of prothrom- botic factors (e.g. plasminogen activator inhibitor-1,Risk factors and interventions for pro-inflammatory adhesion molecules, and mono-cardiovascular disease cyte chemoattractant protein-1) and interference with endothelial nitric oxide synthase (26, 72, 97,Traditional major risk factors for cardiovascular dis- 102). In the PhysiciansÕ Health Study, an epidemio-ease include cigarette smoking, hypertension (>140/ logical study of over 22,000 healthy middle-aged men116
    • Cardiovascular disease, inflammation, and periodontal infectionwith no clinical evidence of disease, increasing levels end-stage cardiovascular disease, tertiary preventiveof serum high-sensitivity C-reactive protein at study interventions involve physically expanding stenoticentry were associated with up to a threefold increase vessels via angioplasty (with or without stenting)in the risk of incident myocardial infarction and a versus revascularization via coronary bypass surgery.twofold increase in risk of ischemic stroke (76). Whencompared with other potential serum biomarkers[e.g. homocysteine, lipoprotein(a), interleukin-6, Association between periodontalintracellular adhesion molecule-1, and serum amy- and cardiovascular diseasesloid A] and standard lipid measures, C-reactive pro-tein proved to be the single strongest predictor of Patients with periodontal disease share many of thecardiovascular risk in apparently healthy participants same risk factors as patients with cardiovascularin the Women’s Health Study (n ¼ 28,263) (77, 78). disease including age, gender (predominantly male),Accordingly, the relative risk ratio for the highest lower socioeconomic status, stress, and smoking (7).versus lowest quartile of serum C-reactive protein Additionally, a large proportion of patients withconcentrations was 4.4 (95% CI 1.7–11.3). Moreover, periodontal disease also exhibit cardiovascular dis-the addition of serum C-reactive protein to tradi- ease (95). These observations suggest that periodon-tional cholesterol screening enhanced cardiovascular tal disease and atherosclerosis share similar orrisk prediction and proved to be independent of low- common etiological pathways. In 2003, Scannapiecodensity lipoprotein cholesterol. Indeed, the poorest et al. conducted a systematic review of the evidenceevent-free survival in women was among those with supporting or refuting any relationship (81). In re-high low-density lipoprotein cholesterol and high sponse to the focused question, ÔDoes periodontalC-reactive protein levels, and the best event-free disease influence the initiation/progression ofsurvival was among those with low low-density atherosclerosis and therefore cardiovascular disease,lipoprotein cholesterol and low C-reactive protein stroke, and peripheral vascular disease?Õ the investi-levels. Individuals with low low-density lipoprotein gators identified 31 human studies. Table 2 listscholesterol levels but high C-reactive protein levels select influential studies identified in the review pluswere at higher risk than those with high low-density additional recent observational studies discussedlipoprotein cholesterol levels but low C-reactive below. Although the authors did not perform anyprotein levels. These data suggest that elevated meta-analysis because of the differences in reportedC-reactive protein levels may be particularly useful outcomes, the authors noted relative (not absolute)for identifying asymptomatic individuals who may be consistency and concluded, ÔPeriodontal disease mayat high risk for future cardiovascular events but who be modestly associated with atherosclerosis, myo-have average cholesterol levels. cardial infarction, and cardiovascular events.Õ An Preventive interventions (primary or secondary) for accompanying consensus report approved by thecardiovascular disease focus on recognition and American Academy of Periodontology recommends,reduction of modifiable risk factors in patients. These ÔPatients and health care providers should be in-approaches include blood pressure screening, weight formed that periodontal intervention may preventreduction, exercise, smoking cessation, diet modifi- the onset or progression of atherosclerosis-inducedcation, and patient counseling and education. Initi- diseases.Õating and maintaining these lifestyle changes are not Since this review and consensus report, at leasteasy tasks for patients. Pharmacological intervention three meta-analyses on the cardiovascular–perio-with the statin class of drugs is used to further reduce dontal disease association have been conducted andserum lipids and the likelihood of cardiovascular published. Meurman et al. reported a 20% increase inevents, even in those with average low-density lipo- cardiovascular disease risk among patients withprotein concentrations. Numerous clinical trials have periodontal disease (95% CI 1.08–1.32), and an evenconsistently demonstrated that statins reduce car- higher risk ratio for stroke varying from 2.85 (95% CIdiovascular events by at least 25% (55, 69, 85). In 1.78–4.56) to 1.74 (95% CI 1.08–2.81) (67). Similarly,contrast, the effect of statins and other lipid-lowering Vettore and Khader et al. reported relative risk esti-therapies on the extent of vessel stenosis caused mates of 1.19 (95% CI 1.08–1.32) and 1.15 (95% CIby a plaque is much smaller (13); hence, statins may 1.06–1.25), respectively (51, 98). These meta-analyseshave secondary anti-inflammatory effects. Indeed, of the available observational human data suggest aC-reactive protein concentrations decrease 15–50% modest but statistically significant increase in the riskwith statin therapy (2, 70, 93, 96). For patients with for cardiovascular disease with periodontal disease. 117
    • 118 Table 2. Summary of observational studies (case–control and cohort) investigating an association between periodontal and cardiovascular diseases in human populations Paquette et al. Reference Study design Population Periodontal outcome Cardiovascular outcome Findings and conclusions or exposure Matilla et al. (65) Case–control 100 cases and Dental Severity Index (sum of Evidence of myocardial Dental health significantly 102 controls scores for caries, periodontal infarction from ECG and worse in patients with disease, periapical pathosis, elevated enzyme levels myocardial infarction versus and pericoronitis) (creatinine phosphokin- controls after adjusting for ase isoenzyme MB) smoking, social class, smoking, serum lipids, and diabetes Matilla et al. (66) Case–control 100 cases Dental Severity Index Clinical diagnosis or Significant association between radiographically dental infections and severe confirmed myocardial coronary atheromatosis in men infarction (but not women) Arbes et al. (5) Case–control 5,564 subjects Per cent attachment loss of all Self-reported myocardial Positive association between (NHANES III) teeth (>3 mm) and infarction periodontal disease and categorized according to four coronary heart disease (OR levels 3.8 for severe attachment loss) after adjusting for age, gender, race, etc.) DeStefano et al. (24) Cohort 9,760 subjects Subjects classified with no Hospital admission or Periodontitis is associated with (NHANES I) periodontal disease, with death due to coronary small increased risk for gingivitis, periodontitis heart disease coronary heart disease (‡4 mm probing depth) (RR 1.7) among men or edentulous Beck et al. (6) Cohort 1,147 men Percent radiographic alveolar Incidence of total and Periodontal disease associated (Normative bone loss fatal coronary heart with moderate risk for Aging Study) disease and stroke coronary heart disease (OR 1.5–1.9) and stroke after adjusting for age and cardiovascular disease risk factors (OR 2.9) Joshipura et al. (48) Cohort 44,119 subjects Self-reported number of teeth Fatal and non-fatal A small association between (Health and history of periodontal myocardial infarction or tooth loss and coronary heart Professionals disease sudden death (revascu disease risk for men (RR 1.7) Follow-up Study) larization cases excluded)
    • Table 2. Continued Reference Study design Population Periodontal outcome Cardiovascular outcome Findings and conclusions or exposure Wu et al. (101) Cohort 9,962 subjects Subjects classified with no Incident cases of stroke Compared to periodontal (NHANES I periodontal disease, with health, relative risk for stroke and follow-up) gingivitis, periodontitis with periodontitis was 2.1 and (‡4 teeth with overt significant pocketing) or edentulous Beck et al. (8) Cohort 6,017 subjects Severe periodontitis defined as Carotid artery intima- Periodontitis may influence (ARIC Study) clinical attachment loss media wall thickness atheroma formation (OR 1.3) ‡3 mm at ‡30% of sites ‡1 mm Hujoel et al. (44) Cohort 8,032 dentate Periodontal pocketing and Death or hospitalization Periodontitis was not adults (NHANES I) attachment loss due to coronary heart associated with a significant disease or revasculariza- increased risk for coronary tion obtained from heart disease medical records Howell et al. (43) Cohort 22,037 male subjects Self-reported presence or Incident fatal and non- No significant association (Physician’s Health absence of periodontal fatal myocardial between self-reported Study I) disease at baseline infarction or stroke periodontal disease and cardiovascular disease events Hung et al. (45) Cohort 41,407 men from the Self-reported tooth loss at Incident fatal and non- For men with tooth loss, the HPFS and 58,974 baseline fatal myocardial relative risk for coronary women from the infarction or stroke heart disease was 1.36. For NHS women with tooth loss, the relative risk was 1.64 Pussinen et al. (73) Cohort 6,950 Finnish subjects Serum antibodies to Incident fatal or non-fatal Seropositive subjects had an in the Mobile Clinic P. gingivalis or stroke OR of 2.6 for stroke Health Survey A. actinomycetemcomitans Beck et al. (9) Cohort 15,792 subjects (ARIC Serum antibodies to Carotid artery Presence of antibody to Study) periodontal pathogens intima-media wall C. rectus was associated with thickness ‡1 mm carotid atherosclerosis (OR 2.3) Engebretson et al. (29) Cohort 203 subjects from Radiographic alveolar bone Carotid plaque thickness Severe periodontal bone loss INVEST loss via ultrasonography was independently associated with carotid atherosclerosis (OR 3.64) Cardiovascular disease, inflammation, and periodontal infection119
    • Paquette et al. Recent findings from several worldwide population (RR 1.29) and stroke (RR 1.12) Tooth loss was associated with was independently associated an increased odds for death studies warrant detailed consideration. These studies Severe periodontal bone loss with carotid atherosclerosis from myocardial infarction Findings and conclusions include the Atherosclerosis Risk in Communities Study, the Health Professional Follow-up Study, the Nurses Health Study, and the Oral Infections and Vascular Disease Epidemiology Study conducted in the United States. Other studies have involved pop- (OR 3.64) ulations from Sweden, Finland, and China. Beck et al. have collected periodontal probing data on 6,017 persons, 52–75 years of age, participating in the Atherosclerosis Risk in Communities study (8, 9, 27). These investigators assessed both the presence of Cardiovascular outcome myocardial infarction clinical coronary heart disease (myocardial infarction or revascularization procedure) and subclinical intima-media wall thickness ‡1 mm Incidence of fatal atherosclerosis (carotid artery intima-media wall thickness using B-mode ultrasound) as dependent Carotid artery variables in the population. Individuals with both or stroke high attachment loss (‡10% of sites with attachment loss >3 mm) and high tooth loss exhibited elevated odds of prevalent coronary heart disease as com- pared to individuals with low attachment loss and low tooth loss (odds ratio 1.5, 95% CI 1.1–2.0 and Subgingival bacterial burden odds ratio 1.8, CI 1.4–2.4, respectively) (27). A second logistic regression analysis indicated a significant Periodontal outcome association between severe periodontitis and thick- ened carotid arties after adjusting for covariates like age, gender, diabetes, lipids, hypertension, and or exposure Tooth loss smoking (8). Accordingly, the odds ratio for severe periodontitis (i.e. 30% or more of sites with ‡3 mm clinical attachment loss) and subclinical carotid atherosclerosis was 1.31 (95% CI 1.03–1.66). In a third report, these investigators quantified serum immunoglobulin G antibody levels specific for 17 29,584 rural Chinese 1,056 subjects from periodontal organisms using a whole bacterial ECG, electrocardiogram; OR, odds ratio; RR, relative risk. Modified from Ref. (81). checkerboard immunoblotting technique (9). Ana- Population lyzing the mean carotid intima-media wall thickness subjects INVEST (‡1 mm) as the outcome and serum antibody levels as exposures for this same population, the investi- gators noted that the presence of antibody to Cam- pylobacter rectus increased the risk for subclinical atherosclerosis twofold (odds ratio 2.3, 95% CI 1.83– Study design 2.84). In particular, individuals with both high C. rectus and Peptostreptococcus micros antibody titers Cohort Cohort had almost twice the prevalence of carotid athero- sclerosis as compared to those with only a high C. rectus antibody (8.3% versus 16.3%). Stratification by Desvarieux et al. (25) Table 2. Continued smoking indicated that all microbial models signifi- cant for smokers were also significant for never Abnet et al. (1) smokers except for Porphyromonas gingivalis. Thus, Reference clinical signs of periodontitis are associated with coronary heart disease and subclinical atheroscler- osis in the Atherosclerosis Risk in Communities population, and exposures to specific periodontal120
    • Cardiovascular disease, inflammation, and periodontal infectionpathogens significantly increase the risk for athero- to those with less bone loss (<50%) (29). Indeed, thesclerosis in smoking and non-smoking subjects. group noted a clear dose–response relationship when Hung et al. assessed self-reported periodontal dis- they plotted subject tertiles of periodontal bone lossease outcomes and incident cardiovascular disease in against carotid plaque thickness graphically. Thetwo extant databases, the Health Professional Follow- investigators next collected subgingival plaque fromup Study (n ¼ 41,407 men followed for 12 years) and 1,056 subjects and tested for the presence of 11the Nurses Health Study (n ¼ 58,974 women fol- known periodontal bacteria using DNA techniqueslowed for 6 years) (45). After controlling for import- (25). The investigators found that cumulative perio-ant cardiovascular risk factors, men with a low dontal bacterial burden was significantly related tonumber of reported teeth (£10 at baseline) had a carotid intima-media wall thickness after adjustingsignificantly higher risk of coronary heart disease for cardiovascular disease risk factors. Whereas mean(relative risk 1.36 95% CI 1.11–1.67) as compared to intima-media wall thickness values were similarmen with a high number of teeth (25 or more). For across burden tertiles for putative (orange complex)women with the same reported extent of tooth loss, and health-associated bacteria, values rose with eachthe relative risk for coronary heart disease was 1.64 tertile of etiological bacterial burden (Actinobacillus(95% CI 1.31–2.05) as compared to women with at ancinomycetemcomitans, P. gingivalis, Treponemaleast 25 teeth. The relative risks for fatal coronary denticola and Tannerella forsythia). Similarly, whiteheart disease events increased to 1.79 (95% CI 1.34– blood cell values (but not serum C-reactive protein)2.40) for men and 1.65 (95% CI 1.11–2.46) for women increased across these burden tertiles. These datawith tooth loss respectively. In a second report, the from INVEST provide evidence of a direct relation-investigators evaluated the association between self- ship between periodontal microbiology and sub-reported periodontal disease and serum elevations in clinical atherosclerosis independent of C-reactivecardiovascular disease biomarkers cross-sectionally protein.in a subset of Health Professional Follow-up Study Consistent associations between periodontal out-participants (n ¼ 468 men) (49). Serum biomarkers comes and atherosclerosis have been recently dem-included C-reactive protein, fibrinogen, factor VII, onstrated among populations in Europe and Asia. Fortissue plasminogen activator, low-density lipoprotein 131 adult Swedes, mean carotid intima-media wallcholesterol, von Willebrand factor, and soluble tumor thickness values were significantly higher in subjectsnecrosis factor receptors 1 and 2. In multivariate with clinical and/or radiographic evidence of perio-regression models controlling for age, cigarette dontal disease as compared to periodontally healthysmoking, alcohol intake, physical activity, and aspirin controls (91). Multiple logistic regression analysisintake, self-reported periodontal disease was associ- identified periodontal disease as a principal inde-ated with significantly higher levels of C-reactive pendent predictor of carotid atherosclerosis with anprotein (30% higher among periodontal cases com- odds ratio of 4.64 (95% CI 1.64–13.10). Pussinen et al.pared with non-cases), tissue plasminogen activator monitored antibody responses for A. actinomyce-(11% higher), and low-density lipoprotein cholesterol temcomitans and P. gingivalis among 6,950 Finnish(11% higher). These analyses reveal significant subjects for whom cardiovascular disease outcomesassociations between self-reported number of teeth over 13 years were available (Mobile Clinic Healthat baseline and risk of coronary heart disease Survey) (73). Compared with the subjects who wereand between self-reported periodontal disease and seronegative for these pathogens, seropositive sub-serum biomarkers of endothelial dysfunction and jects had an odds ratio of 2.6 (95% CI 1.0–7.0) for adyslipidemia. secondary stroke. In a second report on 1,023 men One population study, the Oral Infections and (Kuopio Ischemic Heart Disease Study), PussinenVascular Disease Epidemiology Study (or INVEST), et al. observed that cases with myocardial infarctionhas been planned a priori and conducted exclusively or coronary heart disease death were more oftento evaluate the association between cardiovascular seropositive for A. actinomycetemcomitans than thosedisease and periodontal outcomes in a cohort pop- controls who remained healthy (15.5% versus 10.2%)ulation. Engebretson et al. reported that for a group (74). In the highest tertile of A. actinomycetemcomi-of 203 stroke-free subjects (ages 54–94 years) at tans antibodies, the relative risk for myocardialbaseline, mean carotid plaque thickness (measured infarction or coronary heart disease death was 2.0with B-mode ultrasound) was significantly greater (95% CI 1.2–3.3) compared with the lowest tertile.among dentate subjects with severe periodontal bone For P. gingivalis antibody responses, the relative riskloss (‡50% measured radiographically) as compared was 2.1 (95% CI 1.3–3.4). Abnet et al. recently 121
    • Paquette et al.published findings from a cohort study of 29,584 strate elevations in C-reactive protein and fibrinogenhealthy, rural Chinese adults monitored for up to among periodontally diseased subjects (88, 101).15 years (1). Tooth loss was evaluated as an exposure Experiments with animal models demonstrateoutcome for periodontal disease, and mortality from that specific infections with periodontal pathogensheart disease or stroke were modeled as dependent accelerate atherogenesis. For example, inbred het-variables. Individuals with greater than the age- erozygous and homozygous apolipoprotein-E-defici-specific median number of teeth lost exhibited a sig- ent mice exhibit increased aortic atherosclerosisnificantly increased risk of death from myocardial when challenged orally or intravenously with invasiveinfarction (relative risk 1.28, 95% CI 1.17–1.40) and strains of P. gingivalis (15, 32, 54, 57). While P. gin-stroke (relative risk 1.12, 95% CI 1.02–1.23). These givalis challenges increased aortic atherosclerosis inelevated risks were present in both men and women apolipoprotein-E-deficient mice in a hypercholes-irrespective of smoking status. Collectively, these terolemic background only, normocholesterolemicfindings indicate consistent associations for perio- pigs were recently shown to develop both coronarydontal disease and pathogenic exposures with cardio- and aortic lesions with P. gingivalis challenges (12).vascular disease for European and Asian populations. This finding suggests that P. gingivalis bacteremias may exert an atherogenic stimulus independent of the high cholesterol levels in pigs. It is worth notingBiological plausibility and that a wide range of P. gingivalis doses was used inexperimental evidence these animal studies. While the clinically relevant dose for human subjects is unknown at present, itSince periodontal infections result in low-grade probably varies greatly (21, 38, 46). Importantly,bacteremias and endotoxemias in affected patients P. gingivalis challenge enhances atherosclerosis, de-(83, 86), systemic effects on vascular physiology via spite different routes of administration and dosingthese exposures appear biologically plausible. Four regimens, in both species. The P. gingivalis 16 ribo-specific pathways have been proposed to explain the somal DNA was detected by polymerase chain reac-plausibility of a link between cardiovascular disease tion in atheromas from some but not all of theseand periodontal infection. These pathways (acting mutant mice and pigs. These experiments suggestindependently or collectively) include: that both the host response and the virulence of the• direct bacterial effects on platelets, specific P. gingivalis strains appear to be important• autoimmune responses, variables in these infection–atherogenesis models.• invasion and/or uptake of bacteria in endothelial Evidence in humans demonstrating the beneficial cells and macrophages, effects of periodontal therapy on cardiovascular dis-• endocrine-like effects of pro-inflammatory media- ease outcomes is limited and indirect at present. tors. D’Auito et al. recently demonstrated that periodon-In support of the first pathway, two oral bacteria, titis patients treated with scaling and root planingP. gingivalis and Streptococcus sanguis, express viru- exhibited significant serum reductions in the car-lence factors, the collagen-like platelet aggregation diovascular disease biomarkers, C-reactive proteinassociated proteins, that induce platelet aggregation and interleukin-6 (20). In particular, patients whoin vitro and in vivo (39, 40). Second, autoimmune clinically responded to periodontal therapy in termsmechanisms may play a role because antibodies that of pocket depth reductions were four times morecross-react with periodontal bacteria and human likely to exhibit serum decreases in C-reactive proteinheat-shock proteins have been identified (41, 87). relative to patients with a poor clinical periodontalDeshpande et al. have thirdly demonstrated that the response. Elter et al. also report decreases in theseP. gingivalis can invade aortic and heart endothelial serum biomarkers plus improved endothelial func-cells via fimbriae (23). Several investigative groups tion (i.e. flow-mediated dilation of the brachialhave independently identified specific oral pathogens artery) for 22 periodontitis patients treated within atheromatous tissues (16, 37). In addition, macro- Ôcomplete mouth disinfectionÕ (i.e. scaling and rootphages incubated in vitro with P. gingivalis and planing, periodontal flap surgery and extraction oflow-density lipoprotein take up the bacteria intra- hopeless teeth within a 2-week period) (28). Similarly,celluarly and transform into foam cells (31). In the Seinost et al. tested endothelial function in 30 pa-last potential pathway, systemic pro-inflammatory tients with severe periodontitis and compared thismediators are upregulated for endocrine-like effects with 31 periodontally healthy control subjects (84).in vascular tissues, and studies consistently demon- Before the interventions, flow-mediated dilation was122
    • Cardiovascular disease, inflammation, and periodontal infectionsignificantly lower in patients with periodontitis than 5. Arbes SJ. Slade GD. and Beck JD. Association betweenin control subjects. Periodontitis patients with favo- extent of periodontal attachment loss and self-reported history of heart attack: an analysis of NHANES III Data.rable clinical responses to non-surgical periodontal J Dent Res 1999: 78: 1777–1782.therapy (i.e. scaling and root planing, topical and 6. Beck JD, Garcia R, Heiss G, Vokonas P, Offenbacher S.peroral antimicrobials plus mechanical retreatment) Periodontal disease and cardiovascular disease. J Period-exhibited concomitant improvements in flow-medi- ontol 1996: 67: 1123–1137.ated dilatation of the brachial artery and serum 7. Beck JD, Offenbacher S, Williams RC, Gibbs P, Garcia K. Periodontitis: a risk factor for coronary heart disease?C-reactive protein concentrations. While the effects Ann Periodontol 1998: 3: 127–141.of periodontal therapy on cardiovascular disease 8. Beck J, Elter J, Heiss G, Couper D, Mauriello S, Offenba-events in patients have yet to be determined, the cher S. Relationship of periodontal disease to carotid ar-available pilot data suggest that periodontal therapies tery intima-media wall thickness: the Atherosclerosis Riskcan improve surrogate cardiovascular disease out- in Communities (ARIC) Study. Arterioscler Thromb Vasccomes like serum biomarkers and endothelial dys- Biol 2001: 21: 1816–1822. 9. Beck JD, Eke P, Lin D, Madianos P, Couper D, Moss K,function. Elter J, Heiss G, Offenbacher S. Associations between IgG antibody to oral organisms and carotid intima-medial thickness in community-dwelling adults. AtherosclerosisConclusions 2005: 183: 342–348. 10. Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA. A leukocyte homologue of the IL-8 receptor CXCR-2Inflammation plays a central role in atherogenesis mediates the accumulation of macrophages in athero-from endothelial cell expression of adhesion mole- sclerotic lesions of LDL receptor-deficient mice. J Clincules to the development of the fatty streak, estab- Invest 1998: 101: 353–363.lished plaque, and finally plaque rupture. Human 11. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesionobservational studies and experimental animal mod- formation in CCR2)/) mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998: 394: 894–897.els continue to implicate periodontal infection as a 12. Brodala NME, Bellinger DA, Damrongsri D, Offenbachersystemic exposure that may perpetuate these inflam- S, Beck J, Madianos P, Sotres D, Chang YL, Koch G,matory events in vessels. Although treatments aimed Nichols TC. Porphyromonas gingivalis bacteremia indu-at decreasing periodontal infection and inflammation ces coronary and aortic atherosclerosis in normocholes-can reduce serum inflammatory biomarkers predic- terolemic and hypercholesterolemic pigs. Arterioscler Thromb Vasc Biol 2005: 25: 1446–1451.tive of cardiovascular disease and improve vascular 13. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC,responses, the clinical relevance of these surrogate Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P,changes to reduced risks for myocardial infarction or Frohlich J, Albers JJ. Simvastatin and niacin, antioxidantstroke are not known at this time. Nevertheless, vitamins, or the combination for the prevention of cor-clinicians and patients should be knowledgeable onary disease. N Engl J Med 2001: 345: 1583–1592.about this consistent association and the potential 14. Calabro P, Willerson JT, Yeh ET. Inflammatory cytokines stimulated C-reactive protein production by human cor-preventive benefits of periodontal interventions. onary artery smooth muscle cells. Circulation 2003: 108: 1930–1932. 15. Chi H, Messas E, Levine RA, Graves DT, Amar S. Inter-References leukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet 1. Abnet CC, Qiao YL, Dawsey SM, Dong ZW, Taylor PR, in a murine apolipoprotein E heterozygote model: phar- Mark SD. Tooth loss is associated with increased risk of macotherapeutic implications. Circulation 2004: 110: total death and death from upper gastrointestinal cancer, 1678–1685. heart disease, and stroke in a Chinese population-based 16. Chiu B. Multiple infections in carotid atherosclerotic cohort. Int J Epidemiol 2005: 34: 467–474. plaques. Am Heart J 1999: 138: 534–536. 2. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of 17. Clinton SK, Underwood R, Hayes L, Sherman ML, Kufe statin therapy on C-reactive protein levels: the pravastatin DW, Libby P. Macrophage colony-stimulating factor gene inflammation/CRP evaluation (PRINCE): a randomized expression in vascular cells and in experimental and hu- trial and cohort study. J Am Med Assoc 2001: 286: 64–70. man atherosclerosis. Am J Pathol 1992: 140: 301–316. 3. Amento EP, Ehsani N, Palmer H, Libby P. Cytokines and 18. Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a growth factors positively and negatively regulate intersti- mononuclear leukocyte adhesion molecule during ather- tial collagen gene expression in human vascular smooth ogenesis. Science 1991: 251: 788–791. muscle cells. Arterioscler Thromb 1991: 11: 1223–1230. 19. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, 4. American Heart Association. Heart, disease and stroke Davis V, Gutierrez-Ramos JC, Connelly PW, Milstone S. A statistics – 2004 update. Dallas, TX: American Heart major role for VCAM-1, but not ICAM-1, in early athero- Association, 2003. sclerosis. J Clin Invest 2001: 107: 1255–1262. 123
    • Paquette et al. 20. D’Aiuto F, Ready D, Tonetti MS. Periodontal disease 35. Greenland P, Knoll MD, Stamler J, Neaton JD, Dyer AR, and C-reactive protein-associated cardiovascular risk. Garside DB, Wilson PW. Major risk factors as antecedents J Periodontal Res 2004: 39: 236–241. of fatal and nonfatal coronary heart disease events. J Am 21. Daly CG, Mitchell DH, Highfield JE, Grossberg DE, Stew- Med Assoc 2003: 290: 891–897. art D. Bacteremia due to periodontal probing: a clinical 36. Hackett D, Davies G, Maseri A. Pre-existing coronary and microbiological investigation. J Periodontol 2001: 72: stenoses in patients with first myocardial infarction are 210–214. not necessarily severe. Eur Heart J 1988: 9: 1317–1323. 22. De Caterina R, Libby P, Peng HB, Thannickal VJ, Raja- 37. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ. vashisth TB, Gimbrone MA Jr, Shin WS, Liao JK. Nitric Identification of periodontal pathogens in atheromatous oxide decreases cytokine-induced endothelial activation. plaques. J Periodontol 2000: 71: 1554–1560. Nitric oxide selectively reduces endothelial expression of 38. Haynes WG, Stanford C. Periodontal disease and athero- adhesion molecules and proinflammatory cytokines. sclerosis: from dental to arterial plaque. Arterioscler J Clin Invest 1995: 96: 60–68. Thromb Vasc Biol 2003: 23: 1309–1311. 23. Deshpande RG, Khan MB, Genco CA. Invasion of aortic 39. Herzberg ME, Meyer MW. Dental plaque, platelets and and heart endothelial cells by Porphyromonas gingivalis. cardiovascular diseases. Ann Periodontol 1998: 3: 152–160. Infect Immun 1998: 66: 5337–5343. 40. Herzberg MC, Myer MW. Effects of oral flora on platelets: 24. DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell possible consequences in cardiovascular disease. J Perio- CM. Dental disease and risk of coronary heart disease and dontol 1996: 67: 1138–1142. mortality. Br Med J 1993: 306: 688–691. 41. Hinode D, Nakamura R, Grenier D, Mayrand D. Cross- 25. Desvarieux M, Demmer RT, Rundek T, Boden-Albala B, reactivity of specific antibodies directed to heat shock Jacobs DR Jr, Sacco RL, Papapanou PN. Periodontal proteins from periodontopathogenic bacteria and of hu- microbiota and carotid intima-media thickness: the Oral man origin. Oral Microbiol Immunol 1998: 13: 55–58. Infections and Vascular Disease Epidemiology Study 42. Horton DB, Libby P, Schonbeck U. Ligation of CD40 on (INVEST). Circulation 2005: 111: 576–582. vascular smooth muscle cells mediates loss of interstitial 26. Devaraj S, Xu DY, Jialal I. C-reactive protein increases collagen via matrix metalloproteinase activity. Ann N Y plasminogen activator inhibitor-1 expression and activity Acad Sci 2001: 947: 329–336. in human aortic endothelial cells implications for the 43. Howell TH, Ridker PM, Ajani UA, Hennekens CH, Chris- metabolic syndrome and atherothrombosis. Circulation ten WG. Periodontal disease and risk of subsequent car- 2003: 107: 398–404. diovascular disease in U.S. male physicians. J Am Coll 27. Elter JR, Champagne CM, Offenbacher S, Beck JD. Rela- Cardiol 2001: 37: 445–450. tionship of periodontal disease and tooth loss to prevalence 44. Hujoel PP, Drangsholt M, Spiekerman C, Depouen TA. of coronary heart disease. J Periodontol 2004: 75: 782–790. Periodontal disease and coronary heart disease risk. JAMA 28. Elter JR, Hinderliter AL, Offenbacher S, Beck JD, Caughey 2000: 284: 1406–1410. M, Brodala N, Madianos PN. The effects of periodontal 45. Hung HC, Joshipura KJ, Colditz G, Manson JE, Rimm EB, therapy on vascular endothelial function: a pilot trial. Speizer FE, Willet WC. The association between tooth loss Am Heart J 2006: 151: 47.e1–47.e6. and coronary heart disease in men and women. J Public 29. Engebretson SP, Lamster IB, Elkind MS, Rundek T, Serman Health Dent 2004: 64: 209–215. NJ, Demmer RT, Sacco RL, Papapanou PN, Desvarieux M. 46. Ide M, Jagdev D, Coward PY, Crook M, Barclay GR, Wilson Radiographic measures of chronic periodontitis and RF. The short-term effects of treatment of chronic perio- carotid artery plaque. Stroke 2005: 36: 561–566. dontitis on circulating levels of endotoxin, C-reactive 30. Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding protein, tumor necrosis factor-alpha, and interleukin-6. HA, Gimbrone MA Jr, Luster AD, Luscinskas FW, Rose- J Periodontol 2004: 75: 420–428. nzweig A. MCP-1 and IL-8 trigger firm adhesion of 47. Jabs WJ, Theissing E, Nitschke M, Bechtel JF, Duchrow M, monocytes to vascular endothelium under flow condi- Mohamed S, Jahrbeck B, Sievers HH, Steinhoff J, Bartels tions. Nature 1999: 398: 718–723. C. Local generation of C-reactive protein in diseased 31. Giacona MB, Pappanou PN, Lamster IB, Rong LL, D’Agati coronary artery venous bypass grafts and normal vascular VD, Schmidt AM, Lalla E. Porphyromonas gingivalis tissue. Circulation 2003: 108: 1428–1431. induces uptake by human macrophages and promotes 48. Joshipura KJ, Rimm EB, Douglas CW, Trichopoulos D, foam cell formation in vitro. FEMS Microbiol Lett 2004: Ascherio A, Willett WC. Poor oral health and coronary 241: 95–101. heart disease. J Dent Res 1996: 75: 1631–1636. 32. Gibson FC III, Hong C, Chou HH, Yumoto H, Chen J, Lien E, 49. Joshipura KJ, Wand HC, Merchant AT, Rimm EB. Perio- Wong J, Genco CA. Innate immune recognition of invasive dontal disease and biomarkers related to cardiovascular bacteria accelerates atherosclerosis in apolipoprotein disease. J Dent Res 2004: 83: 151–155. E-deficient mice. Circulation 2004: 109: 2801–2806. 50. Kannel WB. High-density lipoproteins epidemiologic 33. Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, profile and risks of coronary artery disease. Am J Cardiol Garcia-Cardena G. Endothelial dysfunction, hemody- 1983: 52(Suppl.): 9B–12B. namic forces, and atherogenesis. Ann N Y Acad Sci 2000: 51. Khader YS, Albashaireh ZS, Alomari MA. Periodontal dis- 902: 230–239. eases and the risk of coronary heart and cerebrovascular 34. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, diseases: a meta-analysis. J Periodontol 2004: 75: 1046– Kolettis GJ. Compensatory enlargement of human 1053. atherosclerotic coronary arteries. N Engl J Med 1987: 316: 52. Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM, 1371–1375. Brener SJ, Ellis SE, Lincoff AM, Topol EJ. Prevalence of124
    • Cardiovascular disease, inflammation, and periodontal infection conventional risk factors in patients with coronary heart randomised placebo-controlled trial. Lancet 2002: 360: disease. J Am Med Assoc 2003: 290: 898–904. 7–22.53. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of 70. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, activated mast cells at the site of coronary atheromatous Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, erosion or rupture in myocardial infarction. Circulation Grines CL, DeMaria AN: REVERSAL Investigators. Effect of 1995: 92: 1084–1088. intensive compared with moderate lipid-lowering therapy54. Lalla E, Lamster IB, Hofmann MA, Bucciarelli L, Jerud AP, on progression of coronary atherosclerosis: a randomized Tucker S, Lu Y, Papapanou PN, Schmidt AM. Oral infec- controlled trial. J Am Med Assoc 2004: 291: 1071–1080. tion with a periodontal pathogen accelerates early 71. O’Connor S, Taylor C, Campbell LA, Epstein S, Libby P. atherosclerosis in apolipoprotein E-null mice. Arterioscler Potential infectious etiologies of atherosclerosis: a multi- Thromb Vasc Biol 2003: 23: 1405–1411. factorial perspective. Emerg Infect Dis 2001: 7: 780–787.55. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of 72. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory coronary disease: a meta-analysis of randomized con- effect of C-reactive protein on human endothelial cells. trolled trials. J Am Med Assoc 1999: 282: 2340–2346. Circulation 2000: 102: 2165–2168.56. Li H, Cybulsky MI, Gimbrone MA Jr, Libby P. An athero- 73. Pussinen PJ, Alfthan G, Rissanen H, Reunanen A, Asikai- genic diet rapidly induces VCAM-1, a cytokine-regulatable nen S, Knekt P. Antibodies to periodontal pathogens and mononuclear leukocyte adhesion molecule, in rabbit aor- stroke risk. Stroke 2004: 35: 2020–2023. tic endothelium. Arterioscler Thromb 1993: 13: 197–204. 74. Pussinen PJ, Nyyssonen K, Alfthan G, Salonen R, Lauk-57. Li L, Messas E, Batista EL Jr, Levine RA, Amar S. Porphy- kanen JA, Salonen JT. Serum antibody levels to Actino- romonas gingivalis infection accelerates the progression bacillus actinomycetemcomitans predict the risk for of atherosclerosis in a heterozygous apolipoprotein coronary heart disease. Arterioscler Thromb Vasc Biol E-deficient murine model. Circulation 2002: 105: 861–867. 2005: 25: 833–838.58. Libby P. Inflammation and cardiovascular disease 75. Rajavashisth T, Qiao JH, Tripathi S, Tripathi J, Mishra N, mechanisms. Am J Clin Nutr 2006: 83(Suppl.):456S–460S. Hua M, Wang XP, Loussararian A, Clinton S, Libby P, Lusis59. Libby P, Ordovas JM, Auger KR, Robbins AH, Birinyi LK, A. Heterozygous osteopetrotic (op) mutation reduces Dinarello CA. Endotoxin and tumor necrosis factor induce atherosclerosis in LDL receptor-deficient mice. J Clin interleukin-1 gene expression in adult human vascular Invest 1998: 101: 2702–2710. endothelial cells. Am J Pathol 1986: 124: 179–185. 76. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Henne-60. Libby P, Ridker PM, Maseri A. Inflammation and athero- kens CH. Inflammation, aspirin, and the risk of cardio- sclerosis. Circulation 2002: 105: 1135–1143. vascular disease in apparently healthy men. N Engl J Med61. Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of 1997: 336: 973–979. fibrous cap thickness on peak circumferential stress in 77. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive model atherosclerotic vessels. Circ Res 1992: 71: 850–858. protein and other markers of inflammation in the pre-62. Mach F, Schonbeck U, Bonnefoy JY, Pober JS, Libby P. diction of cardiovascular disease in women. N Engl J Med Activation of monocyte/macrophage functions related to 2000: 342: 836–843. acute atheroma complication by ligation of CD40: 78. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Com- induction of collagenase, stromelysin, and tissue factor. parison of C-reactive protein and low-density lipoprotein Circulation 1997: 96: 396–399. cholesterol levels in the prediction of first cardiovascular63. Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P. events. N Engl J Med 2002: 347: 1557–1565. Reduction of atherosclerosis in mice by inhibition of 79. Rosenfeld ME, Yla-Herttuala S, Lipton BA, Ord VA, CD40 signalling. Nature 1998: 394: 200–203. Witztum JL, Steinberg D. Macrophage colony-stimula-64. Mach F, Sauty A, Iarossi AS, Sukhova GK, Neote K, Libby ting factor mRNA and protein in atherosclerotic lesions P, Luster AD. Differential expression of three T lympho- of rabbits and humans. Am J Pathol 1992: 140: 291– cyte-activating CXC chemokines by human atheroma- 300. associated cells. J Clin Invest 1999: 104: 1041–1050. 80. Saren P, Welgus HG, Kovanen PT. TNF-alpha and IL-1beta65. Matilla K, Nieminen M, Valtonen V, Rasi V, Kesaniemi Y, selectively induce expression of 92-kDa gelatinase by Syrjala S, Jungul P, Isoluoma M, Hietaniemi K, Jokinen M, human macrophages. J Immunol 1996: 157: 4159–4165. Huttunen J. Association between dental health and acute 81. Scannapieco FA, Bush RB, Paju S. Associations between myocardial infarction. Br Med J 1989: 298: 779–782. periodontal disease and risk for atherosclerosis, cardio-66. Matilla KJ, Valle MS, Nieminen MS, Valtonen VV, Hie- vascular disease, and stroke. A systematic review. Ann taniemi KL. Dental infections and coronary atheroscler- Periodontol 2003: 8: 38–53. osis. Atherosclerosis 1993: 103: 205–211. 82. Schonbeck U, Sukhova GK, Shimizu K, Mach F, Libby P.67. Meurman JH, Sanz M, Janket SJ. Oral health, athero- Inhibition of CD40 signaling limits evolution of estab- sclerosis and cardiovascular disease. Crit Rev Oral Biol lished atherosclerosis in mice. Proc Natl Acad Sci U S A Med 2004: 15: 403–413. 2000: 97: 7458–7463.68. Mora S, Ridker PM. Justification for the use of Statins in 83. Sconyers JR, Crawford JJ, Moriarty JD. Relationship of Primary Prevention: an Intervention Trial Evaluating bacteremia to toothbrushing in patients with periodonti- Rosuvastatin (JUPITER) – can C-reactive protein be used tis. J Am Dent Assoc 1973: 87: 616–622. to target statin therapy in primary prevention? Am J 84. Seinost G, Wimmer G, Skerget M, Thaller E, Brodmann M, Cardiol 2006: 97(Suppl.): 33A–41A. Gasser R, Bratschko RO, Pilger E. Periodontal treatment69. MRC/BHF Heart Protection Study of cholesterol lowering improves endothelial dysfunction in patients with severe with simvastatin in 20,536 high-risk individuals: a periodontitis. Am Heart J 2005: 149: 1050–1054. 125
    • Paquette et al. 85. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, randomized trial comparing the effects of atorvastatin and Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McIn- pravastatin on carotid intima medial thickness. Circula- nes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J; tion 2002: 106: 2055–2060. ASCOT Investigators. Prevention of coronary and stroke 94. Tuzcu EM, Kapadia SR, Tutar E, Ziada KM, Hobbs RE, events with atorvastatin in hypertensive patients who McCarthy PM, Young JB, Nissen SE. High prevalence of have average or lower-than-average cholesterol concen- coronary atherosclerosis in asymptomatic teenagers and trations, in the Anglo-Scandinavian Cardiac Outcomes young adults: evidence from intravascular ultrasound. Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre Circulation 2001: 103: 2705–2710. randomised controlled trial. Lancet 2003: 361: 1149–1158. 95. Umino M, Nagao M. Systemic diseases in elderly dental 86. Silver JG, Martin AW, McBride BC. Experiment transient patients. Int Dent J 1993: 43: 213–218. bacteremias in human subjects with varying degrees of 96. van de Ree MA, Huisman MV, Princen HM, Meinders plaque accumulation and gingival inflammation. J Clin AE, Kluft C. Strong decrease of high sensitivity Periodontol 1980: 4: 92–99. C-reactive protein with high-dose atorvastatin in 87. Sims TJ, Lernmark A, Mancl LA, Schifferle RE, Page RC, patients with type 2 diabetes mellitus. Atherosclerosis Persson GR. Serum IgG to heat shock proteins and Por- 2003: 166: 129–135. phyromonas gingivalis antigens in diabetic patients with 97. Verma S, Wang CH, Li SH, Dumont AS, Fedak PW, Badi- periodontitis. J Clin Periodontol 2002: 29: 551–562. walam MV, Dhillon B, Weisel RD Li RK, Mickle DA, 88. Slade GD, Offenbacher S, Beck JD, Heiss G, Pankow JS. Stewart DJ. A self-fulfilling prophecy C-reactive protein Acute-phase inflammatory response to periodontal dis- attenuates nitric oxide production and inhibits angio- ease in the US population. J Dent Res 2000: 79: 49–57. genesis. Circulation 2002: 106: 913–919. 89. Smith SC. Current and future directions of cardiovascular 98. Vettore MV. Periodontal disease and cardiovascular dis- risk prediction. Am J Cardiol 2006: 97(Suppl.): 28A–32A. ease. Evid Based Dent 2004: 5: 69. 90. Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata 99. Virmani R, Robinowitz M, Geer JC, Breslin PP, Beyer JC, M. Decreased atherosclerosis in mice deficient in both McAllister HA. Coronary artery atherosclerosis revisited in macrophage colony-stimulating factor (op) and apolipo- Korean war combat casualties. Arch Pathol Lab Med 1987: protein E. Proc Natl Acad Sci U S A 1995: 92: 8264–8268. 111: 972–976. ¨ ¨ 91. Soder PO, Soder B, Nowak J, Jogestrand T. Early carotid 100. World Health Organization. The World Health Report atherosclerosis in subjects with periodontal diseases. 1997. Geneva: World Health Organization, 1997. Stroke 2005: 36: 1195–1200. 101. Wu T, Trevisan M, Genco RJ, Falkner KL, Dorn JP, Sempos 92. Sukhova GK, Schonbeck U, Rabkin E, Schoen FJ, Poole AR, CT. An examination of the relation between periodontal Billinghurst RC, Libby P. Evidence for increased colla- health status and cardiovascular risk factors. Serum total genolysis by interstitial collagenases-1 and -3 in vulner- and HDL cholesterol, C-reactive protein, and plasma able human atheromatous plaques. Circulation 1999: 99: fibrinogen. Am J Epidemiol 2000: 85: 180–189. 2503–2509. 102. Zwaka TP, Hombach V, Torzewski J. C-reactive protein- 93. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, mediated low density lipoprotein uptake by macrophages Vernalis MN. ARBITER: Arterial Biology for the Investi- implications for atherosclerosis. Circulation 2001: 103: gation of the Treatment Effects of Reducing Cholesterol: a 1194–1197.126