6. 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.
7.
8. 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.
25. ATHEROMATOUS PLAQUE DEVELOPMENT:
Blood vessel wall becomes distended and continues to
accumulate cholesterol, some areas become calcified
26. 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
27. 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
28. Blood vessel wall can rupture & thrombus
formation at region of ulceration
35. 3 WAYS:
Shared Risk Factors
Subgingival Biofilms: A reservoir of G-ve bacteria
Periodontium: A reservoir of Inflammatory mediators
36. 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
37. Increased viscosity of blood ischemic heart disease and
cerebrovascular accident (stroke)
38. Systemic infections are known to
induce a hypercoagulable state
and increase blood viscosity
39. 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
40. 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
41. Mechanisms are now emerging that support the
hypothesis linking transient bacteremias, common in
periodontal diseases, causing endothelial dysfunction
Amar et al 2003
45. Identification of periodontal pathogens in human carotid
atheromas
30% T. forsythia
26% P. gingivalis
18% A. a
14% P. intermedia
Haraszthy et al 200o
46. Rabbit model
S. sanguis & P.gingivalis platelet activation &
aggregation through the expression of
collagen-like platelet aggregation-associated proteins
(PAAP)
Herzberg & Meyer 1996
47. 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)
50. 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
53. 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
54.
55. 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
57. 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.
58. 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
59. 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.
60. 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.
61. 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
62. 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.
63. 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.
64. 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
65. Serum amyloid A proteins (SAA):
Sharp increase in SAA in patients with acute MI.
Shainkin –Kestenbaum et al
66. 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
67. 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
68.
69. 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.
70. 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
71. 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
72.
73.
74. 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)
75. 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
76.
77.
78. 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
79. 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.
80. "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.
81. 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.
83. 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
84. 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.
85. 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.
86.
87. PICT Pg 3 in yr 2001
Combine wit pg 116 in 1998
88. 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
89. 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
Editor's Notes
LDL’s are oxidized and then induce production of bio active molecules such as
HDL are a heterogeneous lipoproteins produced in the liver and small intestine, Enzymes associated with HDL apolipoproptein (apoAL) and para-oxenase (PON) protect by destroying the oxidized pro-inflammatory lipids from LDL
PON also inhibits LDL induced Monocyte Migration.Periodontitis may cause reduction in Apo AI and PON and so increase the level of oxidized lipids and monocytes in blood vessels walls.
genco
Thrombosis can give occlusion of vessel. This is responsible for 50% of cases of myocardial infarction This is responsible for 50% of cases of myocardial infarction
Although the IL-1 genetic markers for periodontitis and atherosclerosis are different they point to a potential role of IL-1 and inflammatory processes in both diseases.
Since TNFα can be stimulated by infections it is hypothesized that there exists a connection between periodontal and cardiovascular diseases.12
However these findings were limited by the low number of subjects in the study
