6. cvs

GOOD MORNING

RELATIONSHIP BETWEEN PERIODONTAL

DISEASE & CARDIOVASCULAR

DISEASE

Introduction Coronary heart diseases Atherosclerosis Periodontitis & systemic disease susceptibility Potential linkage mechanisms for Periodontal Disease &

MI Cerebrovascular disease (stroke) Management of periodontal disease in patients

at high risk for atherosclerosis Conclusion References

CONTENT

INTRODUCTION

Conditions influenced by periodontal infection: Coronary heart disease (CHD) & CHD-related

events such as angina & infarction, atherosclerosis, stroke

Diabetes mellitus Preterm labor Chronic obstructive pulmonary disease

Cardiovascular diseases (CVD) and in particular atherothrombotic disease causing coronary heart disease , stroke or peripheral arterial disease remains the leading cause of death

This perio-systemic connection is of major current interest to periodontology.

CARDIOVASCULAR DISEASES

CORONARY HEART DISEASE (MI)

Healing Inflammatory lesion Dr. Russell Ross response-to-injury hypothesis of

atherosclerosis, states that “ the initial lesion results from injury to endothelium & leads to a chronic inflammatory process in the artery”.

ATHEROSCLEROSISAtherosclerosis is a focal thickening of the arterial intima, the innermost layer lining the vessel lumen, and the media, the thick layer under the intima consisting of smooth muscle, collagen & elastic fibers.

Healthy Coronary Artery cross section

Hypertension

Homocysteine

Bacteria

Smoking

Diabetes

Initiators of Endothelial Dysfunction

Oxidized LDL

Cytokines

Glycolatedend products

Intercellular adhesion molecule-1 (ICAM-1)Endothelial leukocyte adhesion molecule-1 (ELAM-1)

Vascular cell wall adhesion molecule (VCAM-1)

VCAM-1 and chemokine monocytic chemotactic protein I localizes

monocytes in vessel wall.

VCAM-1

VCAM-1

MCP1

LDL

LDL

LDL

Low density lipids (LDL) oxidized in vessel wall

O

O

OLDLO

LDLO

LDLO

LDLO

LDLO

LDLO

LDLO

LDLO

LDLO

LDLO

LDLO

LDLO

Low Density Lipids (LDL) pass through damaged endothelium into blood vessel wall

Foam cells

MMP

MMP

Cytokines

Cytokines

Prostaglandins

LDLO

LDLO

LDLO

IL- 1, 6,MMP, PGE2, TNF-α Platelet Derived Growth Factor, fibroblast growth factor

MMP

MMP

Cytokines

Cytokines

Prostaglandins

LDLO

LDLO

LDLO

Monocytes trigger chronic inflammatory reaction with lymphocytes and this results in tissue necrosis and fibrosis

Bacteria

Cytokines

Circulating bacteria and cytokines add to inflammation. This leads to Atheromatous

plaque formation

MMP

MMP

Cytokines

Cytokines

Prostaglandins

LDLO

LDLO

LDLO

High density lipoproteins Vit E

INHIBIT OXIDATION OF LDL

HDL

HDL

HDL

LDL

LDL

LDL

O

O

O

HDL

HDL

HDL

LDL

LDL

LDL

O

O

ATHEROMATOUS PLAQUE DEVELOPMENT: Blood vessel wall becomes distended and

continues to accumulate cholesterol, some areas become calcified

Coronary Artery with stable atheroma. Inflammation and necrosis have replaced the smooth muscle but there is a dense layer of

collagen next to lumen

THROMBUS DEVELOPMENT

MMP

MMP

MMP

MMP s from macrophages and proteases from

circulating bacteria can destroy collagen to

form an unstable atheromatous plaque

Bacterial Proteases

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

MMP

Blood vessel wall can rupture & thrombus formation at region of ulceration

Platelets aggregate on exposed collagen

Thrombus formation

Oral Bacteria

Circulating oral bacteria have peptides that cause platelet

aggregation

Increase thrombosis can lead to sudden

occlusion of vessel

Coronary Artery occluded by thrombosis

Coronary artery with narrowed lumen and thrombosis

Narrowed Lumen

3 WAYS: Shared Risk Factors Subgingival Biofilms: A reservoir of G-ve bacteria Periodontium: A reservoir of Inflammatory

mediators

PERIODONTITIS & SYSTEMIC DISEASE SUSCEPTIBILITY

Risk factors

Not modifiable

•Gender•Age •Race•Family history•Hypertension•Diabetes mellitus•Body mass index•Homocysteine•Lipoprotein a•White blood cells•Fibrinogen•Total cholesterol•LDL

Modifiable •Lack of exercise•Stress •Alcohol consumption•Diet •Smoking •Infections•C-reactive proteins

Increased viscosity of blood ischemic heart disease and cerebrovascular accident (stroke)

Systemic infections are known to induce a hypercoagulable state and increase blood viscosity

Systemic infections

Mastication & oral hygiene procedures result in frequent bacteremia with oral organisms

It is much more greater than from dental procedures

Periodontal disease may predispose the patient to virulent g -ve organisms

An estimated 8% of all cases of IE are associated with periodontal or dental disease

Drangsholt MT, Ann Periodontol 1998

Daily activity

Diseased Periodontium acts as a reservoir of endotoxins (LPS)

The concentration of endotoxin present was more than 4 fold greater in those with periodontitis than in healthy subjects

Geerts SO, Nys M, De MP et al. JP 2002

Mechanisms are now emerging that support the hypothesis linking transient bacteremias, common in periodontal diseases, causing endothelial dysfunction

Amar et al 2003

Chlamydia pneumonia Helicobacter pylori Periodontal bacteria Cytomegalovirus

Infections & Atherosclerosis

Identification of periodontal pathogens in human carotid atheromas

30% T. forsythia 26% P. gingivalis 18% A. a 14% P. intermedia

Haraszthy et al 200o

Periodontal pathogens

Rabbit model S. sanguis & P.gingivalis platelet activation &

aggregation through the expression of collagen-like platelet aggregation-associated proteins (PAAP)

Herzberg & Meyer 1996

The incidence of periodontal bacteria in atherosclerotic plaque by DNA analysis from 20 subjects was studied

A. actinomycetemcomitans C. rectus, F. nucleatum P. gingivalis, P. intermedia T .forsythia T. denticola Zaremba et al.(2007)

P.gingivalis Cardiovascular disease: Atherosclerosis Arteriosclerotic aneurysms Peripheral arterial disease Coronary heart disease Heart valves of endocarditis Buerger’s disease

P. gingivalis

Soluble Inflammatory mediators

Adhesionmolecules

oxLDL

Scavengerreceptors

Indirect actionDirect action

monocytes

Macrophage

Foam cell

Smooth muscle

cell

Transformation

Transformation

Under normal physiologic conditions, not possible for anaerobic bacterium to invade normal endothelial cells

An indirect mechanism

However Direct invasion – endothelial function/ structure is

destroyed Hokamura et al 2009

Diabetes mellitus Hypertension Hyperlipidemia Smoking

Research has clearly shown wide variation in host response to bacterial challenge

Patients with abnormally exuberant inflammatory responses often have a hyperinflammatory monocyte/macrophage phenotype(MØ+)

They secrete significantly increased levels of pro-inflammatory mediators(IL-1, TNF-α, PGE2)

Aggressive periodontitis, refractory periodontitis & type 1 DM

Evidence for the Role of Inflammatory Mediators:

Acute –phase response defines a characteristic pattern of alteration in the concentration of plasma proteins that occurs following a different forms of inflammation.

Host encounters with pathogens. Proinflammatory & Anti-inflammatory effects

Potential linkage mechanisms for PD & MI

C-Reactive Proteins IL-1 Tumor Necrosis Factor-α Fibrinogen ICAM-1 & VCAM-1 Coagulation Factor VIII:Von Willibrand factors Serum amyloid A proteins (SAA)

C-Reactive proteins: Elevation of CRP is positively associated with acute

myocardial infarction (MI) and sudden cardiac related death.

These findings were confirmed by Tracy et al in 400 subject study after adjusting for age, smoking and gender.

The association between CRP and MI was also confirmed by Kuller et al in a 17 year study involving 246 subjects.

Thus it has been confirmed that CRP is an independent risk factor for coronary heart disease.

Elevated levels of CRP have been associated with periodontal disease

IL-1: A composite polymorphism in the IL-1 gene

cluster of allele 2 of both IL-1A (+4845) & IL-1B (+3954) is associated with an increased risk for periodontitis.

Thus genetic polymorphisms of IL-1 may contribute to atherogenesis and cardiovascular diseases via stimulation of inflammatory processes.

Tumor Necrosis Factor-α: It is an inducible cytokine with wide range of pro

inflammatory & immunoregulatory mechanisms & increases the synthesis of triglycerides in the liver and inhibits lipoprotein lipase.

Macrophages and smooth muscle cells producing TNFα are also present in atherosclerotic plaques.

Jovinge et al conducted a study on 152 post MI patients and 63 controls and found a significantly higher concentration of TNFα in MI patients.

Fibrinogen : It is mainly synthesized in the liver in response

to IL-6 and its levels increase during infections & inflammatory conditions including periodontal diseases.

High levels of fibrinogen have also been associated with peripheral vascular disease and cardiac events

ICAM-1 & VCAM-1: (ICAM-1) & (VCAM-1) are important in the firm

endothelial cell attachment and transendothelial migration of leukocytes and thus play a central role in leukocyte recruitment and their function in inflammatory reactions.

They may act as modulators of cell to cell interactions activators of certain target cells neutrophil chemo attractants.

Ridker et al conducted a study in 15000 subjects and reported that subjects with high plasma levels of ICAM-1 had an 80% higher risk of developing MI.

Coagulation Factor VIII:Von Willibrand factors:

Hemostasis Bleeding disorders- Hemophilia A Low relative risk of CHD in plasma levels of factor VIII:vWF complex-

acute-phase proteins Serum levels of vWF correlate with levels of

adhesion molecules Link b/w vWF release & leukocyte-endothelial

interaction

Serum amyloid A proteins (SAA): Sharp increase in SAA in patients with acute MI.

Shainkin –Kestenbaum et al

Evidence for the Role of Immunologic Mechanisms:

Immunologically competent cell types & products

T & B cells, neutrophils, monocytes, macrophages, mast cells, immunoglobulin, complement, immune complexes & proinflammatory cytokines

Heat-Shock Proteins IL-12

Heat-Shock Proteins: Produced in response to environment &

metabolic stress Surface expression of 60kD HSP on endothelial

& smooth muscle cells in atheromatous & carotid plaques

Antibodies to HSP are present in high titers

Microbial constituents of periodontal pathogens may induce 4 overlapping acute responses in the host:

1. Direct interaction with host components including blood cells & heart tissue

2. Production of acute-phase proteins

3. Innate immune responses through cytokine mediation

4. Stress defense including HSP expression.

Potential linking mechanisms

Hypothetical roles of inflammatory mediators as a link b/w periodontal infections & MI

Periodontal disease

Promotes lipidDeposition inatheroma

Binds to epitopes on Lipid membranes of damaged cells

CRP

Liver

SAA fibrogen

Thrombus formation

Atheroma formationCoronary heart disease

CRP-C1 activation leadsTo neutrophil chemotaxis.Activated phagocytes causeTissue damage

Oxidation of lipids

Other factors

Heart endothelium

SmoothMuscle cells

UpregulationOf ICAM-1Productionof sICAM-1

CollagenElastin

PMN, macrophagesFoam cells

Bacteria, cytokines

Hypothetical roles of immune mediators as a link b/w periodontal infections & MI

Periodontal disease

Heart

To bacteria

Sensitized T cells

To cross-reactingAntigens (HSP-60)

Atheroma formationCoronary heart disease

Activated T-cells

CMIresponse

Cytokines

Antibodies to Cross-reacting antigens(HSP-60)

AntibodiesTo bacteria

Heart HSP-60(exposed in response to stress)

Heart(bacterial antigens)In situ immunecomplexes

In situ immuneComplex formation

Bacteria, cytokines

Antibodies

Phagocytes Other factors

Studies supporting an association between periodontal

disease and cardiovascular disease

Stroke is often preceded by systemic bacterial or viral infection

Patients with cerebral ischemia are 5 times more likely to have had a systemic infection within 1 week before an ischemic event

Poor dental health is a significant risk factor for cerebrovascular ischaemia

(SyrjanenJ et.al 1998; Grau AJ et.al 1997;Arbes SJ et.al 1999)

CEREBROVASCULAR DISEASE (STROKE)

Both epidemiologic and systematic reviews have suggested an approximate threefold increased risk of stroke in subjects with periodontitis (Janket S et.al 2003; Wu T et.al 2000)

Most cases of stroke are caused by thromboembolic events, whereas others are related to cerebrovascular atherosclerosis

Periodontal infections may contribute directly & indirectly in the pathogenesis of atherosclerosis, thrombus formation and subsequent thromboembolism, the leading cause of stroke

Studies of the Association between Periodontal Disease and Other Oral Conditions and Stroke

Beck and colleagues have provided a model proposing that there is a genetically determined hyperinflammatory monocyte macrophage phenotype in periodontal disease- increases susceptibility for atherosclerosis

COMMON GENETIC PREDISPOSITION FOR PERIODONTAL DISEASE AND

ATHEROSCLEROSIS

Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.

Schaefer AS et al 2009 the known association of two neighboring

linkage disequilibrium regions on human chromosome 9p21.3 with CHD and show the additional strong association of these loci with the risk of aggressive periodontitis.

"these diseases shared the same loci, but they were not necessarily the same variants," Schaefer explained.

In fact, the diseases seem to exhibit "opposite phenotypes."

Periodontitis is caused by inflammation and results in severe tissue destruction, where bone is destroyed and not replaced, with reduced cell proliferation in response to inflammation.

In contrast, one part of the inflammatory response of CHD is the result of monocytes entering the intima media of blood vessels, resulting in active cell proliferation.

Thus, it appears likely that the gene or alleles involved are differentially regulated in different vessels,

"It's the same locus, the same pathway, but the underlying genetics might be different: one variant could increase the risk for CHD and another could increase the risk for periodontitis.

IL-6 assessment CRP assessment WBC count Endothelial cell assessment IMT assessment

Blood markers of inflammation

Patients at high risk for atherosclerotic disease should be subjected to a complete periodontal examination

Patients that have periodontal disease should have a thorough medical history evaluating systemic conditions, medications, and risk factors for atherosclerosis and related conditions such as heart disease and stroke

MANAGEMENT OF PERIODONTAL DISEASE IN

PATIENTS AT HIGH RISK FOR ATHEROSCLEROSIS

Treatment of patients with periodontal disease and pre-existing atherosclerotic disease, should be coordinated among health professionals to ensure that patients are adequately managed taking into account medical as well as dental considerations and complications.

Aggressive prevention of periodontal disease should be undertaken in patients at high risk for atherosclerotic disease.

Patients should be made completely aware of the possible relationship between heart disease, stroke, and periodontal disease, so that they may participate in the modification of risk factors, such as smoking.

CONCLUSION

PICT Pg 3 in yr 2001 Combine wit pg 116 in 1998

Clinical Periodontology. 10th edition. Newman, Takei, Klokkevold & Carranza

Clinical periodontology and Implant dentistry, 5th edition, Jan Lindhe.

Periodontal medicine. Rose, Genco, Cohen and Mealey. Periodontal medicine, surgery & implants. Rose &

Mealey. Persson GR, Persson RE. Cardiovascular disease and

periodontitis: an update on the associations and risk. J Clin Periodontol 2008; 35 (Suppl. 8): 362–379

REFERENCES

Gordon D.O.Lowe. The relationship between infection, inflammation, and cardiovascular disease: An Overview. Ann Periodontol 2001;6:1-8

Beck & Offenbacher. The association between periodontal diseases and cardiovascular diseases:A State-of-the-science Review. Ann Periodontol 2001;6:9-15

Ernesto. The role of inflammatory and immunological mediators in periodontitis and cardiovascular disease. Ann Periodontol 2001;6:30-40