1.
GOOD MORNING

2.
 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

3.
 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

4.
 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.

5.
 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”.
Atherosclerosis 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.

6.
Healthy Coronary Artery cross section

7.
Hypertension
Homocysteine
Bacteria
Smoking
Diabetes
Initiators of Endothelial
Dysfunction

8.
Oxidized LDL
Cytokines
Glycolated
end products
Intercellular adhesion molecule-1 (ICAM-1)
Endothelial leukocyte adhesion molecule-1 (ELAM-1)
Vascular cell wall adhesion molecule (VCAM-1)

9.
VCAM-1 and chemokine monocytic
chemotactic protein I localizes monocytes in
vessel wall.
VCAM-1
VCAM-1
MCP1

10.
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

11.
Foam cells

12.
MMP
MMP
Cytokines
Cytokines
Prostaglandins
LDLO
LDLO
LDLO
IL- 1, 6,MMP, PGE2, TNF-α
Platelet Derived Growth Factor, fibroblast growth factor

13.
MMP
MMP
Cytokines
Cytokines
Prostaglandins
LDLO
LDLO
LDLO
Monocytes trigger chronic inflammatory reaction with
lymphocytes and this results in tissue necrosis and fibrosis

14.
Bacteria
Cytokines
Circulating bacteria and cytokines add to
inflammation. This leads to Atheromatous
plaque formation
MMP
MMP
Cytokines
Cytokines
Prostaglandins
LDLO
LDLO
LDLO

15.
 High density lipoproteins
 Vit E
INHIBIT OXIDATION OF
LDL

16.
HDL
HDL
HDL
LDL
LDL
LDL
O
O
O

17.
HDL
HDL
HDL
LDL
LDL
LDL
O
O

18.
 ATHEROMATOUS PLAQUE DEVELOPMENT:
 Blood vessel wall becomes distended and continues to
accumulate cholesterol, some areas become calcified

19.
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

20.
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

21.
Blood vessel wall can rupture & thrombus
formation at region of ulceration

22.
Platelets aggregate on exposed collagen

23.
Thrombus formation

24.
Oral Bacteria
Circulating oral bacteria have peptides
that cause platelet aggregation

25.
Increase thrombosis can lead to sudden
occlusion of vessel

26.
Coronary Artery occluded by thrombosis

27.
Coronary artery with narrowed lumen and
thrombosis

28.
 3 WAYS:
 Shared Risk Factors
 Subgingival Biofilms: A reservoir of G-ve bacteria
 Periodontium: A reservoir of Inflammatory mediators

29.
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

30.
 Increased viscosity of blood ischemic heart disease and
cerebrovascular accident (stroke)

31.
 Systemic infections are known to
induce a hypercoagulable state
and increase blood viscosity

32.
 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

33.
 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

34.
 Mechanisms are now emerging that support the
hypothesis linking transient bacteremias, common in
periodontal diseases, causing endothelial dysfunction
Amar et al 2003

35.
 Chlamydia pneumonia
 Helicobacter pylori
 Periodontal bacteria
 Cytomegalovirus

36.
 Identification of periodontal pathogens in human carotid
atheromas
 30%  T. forsythia
 26%  P. gingivalis
 18%  A. a
 14%  P. intermedia
Haraszthy et al 200o

37.
 Rabbit model
 S. sanguis & P.gingivalis  platelet activation &
aggregation through the expression of
collagen-like platelet aggregation-associated proteins
(PAAP)
Herzberg & Meyer 1996

38.
 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)

39.
 P.gingivalis
 Cardiovascular disease:
 Atherosclerosis
 Arteriosclerotic aneurysms
 Peripheral arterial disease
 Coronary heart disease
 Heart valves of endocarditis
 Buerger’s disease

40.
P. gingivalis
Soluble
Inflammatory
mediators
Adhesion
molecules
oxLDL
Scavenger
receptors
Indirect actionDirect action
monocytes
Macrophage
Foam cell
Smooth
muscle cell
Transformation
Transformation

41.
 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

42.
 Diabetes mellitus
 Hypertension
 Hyperlipidemia
 Smoking

43.
 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

44.
 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

45.
 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)

46.
 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.

47.
 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

48.
 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.

49.
 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.

50.
 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

51.
 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.

52.
 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.

53.
 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

54.
 Serum amyloid A proteins (SAA):
 Sharp increase in SAA in patients with acute MI.
Shainkin –Kestenbaum et al

55.
 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

56.
 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

57.
 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.

58.
Periodontal disease
Promotes lipid
Deposition in
atheroma
Binds to epitopes on
Lipid membranes of
damaged cells
CRP
Liver
SAA fibrogen
Thrombus
formation
Atheroma formation
Coronary heart disease
CRP-C1 activation leads
To neutrophil chemotaxis.
Activated phagocytes cause
Tissue damage
Oxidation of lipids
Other factors
Heart
endothelium
Smooth
Muscle cells
Upregulation
Of ICAM-1
Production
of sICAM-1
Collagen
Elastin
PMN, macrophages
Foam cells
Bacteria, cytokines

59.
Periodontal disease
Heart
To bacteria
Sensitized T cells
To cross-reacting
Antigens (HSP-60)
Atheroma formation
Coronary heart disease
Activated T-cells
CMI
response
Cytokines
Antibodies to
Cross-reacting antigens
(HSP-60)
Antibodies
To bacteria
Heart HSP-60
(exposed in
response to stress)
Heart
(bacterial antigens)
In situ immune
complexes
In situ immune
Complex formation
Bacteria, cytokines
Antibodies
Phagocytes
Other factors

60.
 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)

61.
 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

62.
 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

63.
 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.

64.
 "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.

65.
 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.

66.
 IL-6 assessment
 CRP assessment
 WBC count
 Endothelial cell assessment
 IMT assessment

67.
 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

68.
 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.

69.
 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.

70.
 PICT Pg 3 in yr 2001
 Combine wit pg 116 in 1998

71.
 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

72.
 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