Transcript
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
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