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- 3. Introduction Coronaryheart 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
- 5. Conditions influencedby periodontal infection: Coronary heart disease (CHD) & CHD-related events such as angina & infarction, atherosclerosis, stroke Diabetes mellitus Preterm labor Chronic obstructive pulmonary disease
- 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.
- 8. Healing Inflammatorylesion 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.
- 9. Healthy Coronary Arterycross section
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- 13. Oxidized LDL Cytokines Glycolated end products Intercellularadhesion molecule-1 (ICAM-1) Endothelial leukocyte adhesion molecule-1 (ELAM-1) Vascular cell wall adhesion molecule (VCAM-1)
- 16. VCAM-1 and chemokinemonocytic chemotactic protein I localizes monocytes in vessel wall. VCAM-1 VCAM-1 MCP1
- 17. 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
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- 19. MMP MMP Cytokines Cytokines Prostaglandins LDLO LDLO LDLO IL- 1, 6,MMP,PGE2, TNF-α Platelet Derived Growth Factor, fibroblast growth factor
- 20. MMP MMP Cytokines Cytokines Prostaglandins LDLO LDLO LDLO Monocytes trigger chronicinflammatory reaction with lymphocytes and this results in tissue necrosis and fibrosis
- 21. Bacteria Cytokines Circulating bacteria andcytokines add to inflammation. This leads to Atheromatous plaque formation MMP MMP Cytokines Cytokines Prostaglandins LDLO LDLO LDLO
- 22. High densitylipoproteins Vit E INHIBIT OXIDATION OF LDL
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- 25. ATHEROMATOUS PLAQUEDEVELOPMENT: Blood vessel wall becomes distended and continues to accumulate cholesterol, some areas become calcified
- 26. Coronary Artery withstable 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 frommacrophages 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 wallcan rupture & thrombus formation at region of ulceration
- 29. Platelets aggregate onexposed collagen
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- 31. Oral Bacteria Circulating oralbacteria have peptides that cause platelet aggregation
- 32. Increase thrombosis canlead to sudden occlusion of vessel
- 33. Coronary Artery occludedby thrombosis
- 34. Coronary artery withnarrowed lumen and thrombosis
- 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 viscosityof blood ischemic heart disease and cerebrovascular accident (stroke)
- 38. Systemic infectionsare 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 Periodontiumacts 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 arenow emerging that support the hypothesis linking transient bacteremias, common in periodontal diseases, causing endothelial dysfunction Amar et al 2003
- 44. Chlamydia pneumonia Helicobacter pylori Periodontal bacteria Cytomegalovirus
- 45. Identification ofperiodontal 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 incidenceof 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)
- 48. P.gingivalis Cardiovasculardisease: Atherosclerosis Arteriosclerotic aneurysms Peripheral arterial disease Coronary heart disease Heart valves of endocarditis Buerger’s disease
- 49. P. gingivalis Soluble Inflammatory mediators Adhesion molecules oxLDL Scavenger receptors Indirect actionDirectaction monocytes Macrophage Foam cell Smooth muscle cell Transformation Transformation
- 50. Under normalphysiologic 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
- 51. Diabetes mellitus Hypertension Hyperlipidemia Smoking
- 53. Research hasclearly 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
- 55. Evidence forthe 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
- 56. 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)
- 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 ithas 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: Acomposite 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 NecrosisFactor-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 etal 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 FactorVIII: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 amyloidA proteins (SAA): Sharp increase in SAA in patients with acute MI. Shainkin –Kestenbaum et al
- 66. Evidence forthe 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
- 69. Microbial constituentsof 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 Depositionin 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 SensitizedT 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
- 74. Stroke isoften 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 epidemiologicand 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
- 78. Beck andcolleagues have provided a model proposing that there is a genetically determined hyperinflammatory monocyte macrophage phenotype in periodontal disease- increases susceptibility for atherosclerosis
- 79. Identification ofa 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 diseasesshared 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, itappears 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.
- 82. IL-6 assessment CRP assessment WBC count Endothelial cell assessment IMT assessment
- 83. Patients athigh 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 ofpatients 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 preventionof 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.
- 87. PICT Pg3 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
- #20 LDL’s are oxidized and then induce production of bio active molecules such as
- #23 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.
- #29 genco
- #37 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
- #62 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.
- #63 Since TNFα can be stimulated by infections it is hypothesized that there exists a connection between periodontal and cardiovascular diseases.12
- #68 However these findings were limited by the low number of subjects in the study
- #70 In pt with atherosclerosis