TARRSON FAMILY ENDOWED CHAIR IN PERIODONTICS
UCLA School of Dentistry
Presents Dr. E. Barrie Kenney Professor & Chairman Section of Periodontics
Periodontal Disease as a Predictor of Atherosclerosis E. Barrie Kenney B.D.Sc., D.D.S., M.S., F.R.A.C.D.S. Tarrson Family ...
Coronary Artery Disease
Epidemiological connection between coronary artery disease and periodontal disease
6.9 Million people have coronary heart disease in USA
Atherosclerosis Leading Cause of Death in USA
Coronary Artery Disease (C.A.D) kills 500,000 people a year.  One of every 4.6  deaths due to C.A.D
Periodontal Disease  in the United States <ul><li>54% of U.S. population 13 years and older has gingival bleeding on probi...
Association between dental health and acute myocardial infarction <ul><li>Matilla KJ et al </li></ul><ul><li>Brit. Med. J....
<ul><li>Used index based on caries, periodontal disease, periapical lesions, pericoronitis. </li></ul><ul><li>Patients adm...
Patients above the upper quartile had  twice the risk of  acute myocardial infarction than did those with a score of zero.
This was comparable to risk of cigarette smoking, hypercholesterolemia and hypertension.
Dental Disease and Risk of Coronary Heart Disease and Mortality  <ul><li>De Stefano F et al </li></ul><ul><li>Brit. Med. J...
<ul><li>Analyzed data from National Health and Nutrition examination study I. 1971 – 1974. </li></ul><ul><li>20,249 subjec...
Excluded subjects with history of heart disease stroke or cancer. Not all subjects were evaluated for smoking so had a sub...
Admitted for Coronary Artery Disease or died of Coronary Artery Disease as indicators of disease
Dental evaluation at baseline  <ul><li>Number of carious teeth </li></ul><ul><li>Periodontal status healthy, gingivitis pe...
Percentage of subjects <ul><li>death from CHD  2.6 4.1 8.4 11.9 </li></ul><ul><li>admission for CHD  6.5 7.4 14.4 19.2 </l...
ODDS Ratios <ul><li>Risk Women Men </li></ul><ul><li>Factors  25-49  Mortality  25-49 </li></ul><ul><ul><li>No disease 1.0...
Analysis of  these with data on smoking showed the same pattern.
No association between active caries and CHD
Periodontal Disease  and Coronary Heart Disease Risk <ul><li>Hujoel P.P., et al </li></ul><ul><li>J.A.M.A. 2000, 284:1406 ...
Used NHANES population 8032 dentate adults aged 25 to 74 years with no history of cardiovascular disease.  1859 had period...
At follow up 1265 subjects had at least 1 coronary heart disease event, either death, hospitalization or coronary revascul...
Periodontal Disease and Myocardial Disease have common risk factors, age, smoking, stress, social economics status, body f...
Diabetes 5.2% 2.7% 2.0% Alcohol glass per day 0.81 0.73 0.55 Pack years smoking 15.9 10.4 8.8 Total cholesterol 222.1 215....
Hazard Ratios Compared to Healthy  <ul><li>Unadjusted Adjusted for  Confounders </li></ul><ul><li>periodontitis 2.66 1.14 ...
“ While this study did provide convincing evidence regarding the absence of a moderate to large association between period...
Oral Health and Systemic Disease:  Periodontitis and Cardiovascular Disease <ul><li>Beck J.D. Offenbacher S. </li></ul><ul...
Odds ratio with more or less sites p.d > 3mm <ul><li>CHD Fatal  Stroke  CHD </li></ul><ul><li>3·1 2·8 1·9 </li></ul>1147 M...
Number of sites with 20% or more bone loss  <ul><li>ODDS Ratio for CHD </li></ul><ul><ul><li>1-2 0.8 </li></ul></ul><ul><u...
Periodontal Disease and prevalent Coronary Heart Disease in the ARIC study <ul><li>Beck J.D et al </li></ul><ul><li>J. Den...
ODDS Ratio for C.H.D.  <ul><li>per cent sites with  attachment loss 3mm or more Males Females </li></ul><ul><li>0 – 6.4 1....
Atherosclerosis Risk  in Communities study 13.6% of males 5.5% of females had coronary heart disease
Investigation of the  Association Between Angiographically Defined Coronary Artery Disease and Periodontal Disease Matthan...
100 patients 53 with coronary artery disease (50% stenosis of at least one vessel) 47 no coronary artery disease (less tha...
<ul><li>CAD +ve CAD -ve Sites with CAL>6mm 6.85 3.32 </li></ul><ul><li>Radiographic bone loss 3.60mm 3.18mm </li></ul><ul>...
Ratio of Cigarette Smoking  in the Association Between Periodontal Disease and Coronary Heart Disease Hyman, J. J. et al. ...
5285 Subjects from NHANES 1988-94, 40 years or older <ul><li>Loss of Attachment Odds ratio for heart attack history </li><...
Oral Health and Peripheral Arterial Disease <ul><li>Hung, H.C. et al </li></ul><ul><li>Circulation 2003:107:1152 </li></ul...
Odds Ratio Peripheral Cardiovascular Disease And   <ul><li>Periodontal Disease 1.41 </li></ul><ul><li>Tooth Loss 1.39 </li...
Severity of Periodontal Disease and number of remaining teeth are related to the prevalence of Infarction and Myocardial H...
Odds Ratio Periodontal bone loss And  Myocardial Infarction <ul><li>Periodontal Disease 2.69 </li></ul><ul><li>Smoking 0.6...
TREATMENT OF PERIODONTITIS AND ENDOTHELIAL FUNCTION.  TONETTI M  S et al  NEJMED.356:911, 2007 59 PATIENTS  SEVERE PERIODO...
CORRELATIONS BETWEEN CLINICAL MEASUREMENTS OF PERIODONTAL DISEASE AND PRESENCE OF BACTERIAL ANTIGENS IN HUMAN ATHEROSCLERO...
10 ARTERIES --VE, 14 +VE FOR 1  PERIO BACTERIA. 10 +VE FOR 2,  2+VE FOR   3  20 HAD  C.M.V 10 HAD CHLAMYDIA POSITIVE CORRE...
Coronary Artery Disease In Women
Lipid management and control of other coronary risk factors in post menopausal women  J. Women’s Health and Gender related...
Stroke and  myocardial infarction Number one killer of women with 500,000 deaths per year
African American and Hispanic women at greater risk than Caucasian women
This is more than the next 16 causes of death combined
Risk of Myocardial infarction lower in women than men
First myocardial infarction in women  is more severe and  more lethal than  they are in men
Women’s mortality rate at 6 months post myocardial infarction double that of men
Analysis of 350,000 patients after fibrinolytic therapy for infarction.   Mortality for  women 9.3%, men 4.5%
Without fibrinolytic therapy <ul><li>16% mortality for women </li></ul><ul><li>10.9% for men </li></ul>
Coronary artery bypass surgery operative mortality 4.5% women,  2.6% men
Menopause  often causes  increase in total cholesterol and LDL
Estrogen increase HDL levels
Post menopausal hormonal  therapy  gave 53% reduction in death from CHD in study using 121,700 registered nurses
Framingham Study.  Risk of coronary artery disease doubles with  onset of menopause
Cardiovascular Disease During 6.9 Years of Hormone Therapy <ul><li>20 centers with 2,763 post menopausal with C.H.D. avera...
ESTROGEN  THERAPY  AND  CORONARY ARTERY  CALCIFICATION.  MANSON, J. E. et al  NEJM. 2007  356: 2591 1064 WOMEN  50 TO 59 Y...
Periodontal flap surgery to treat periodontitis. Note loss of crestal bone.
Periodontitis. Histopathologyof intrabony defect showing bone resorption ( yellow ), inflammation ( green ) and epithelial...
Pathogenesis of Atheroma <ul><li>1. Fatty streak development </li></ul><ul><li>2. Atheromatous plaque development </li></u...
Fatty streak development
Dr. Enos and Holmes reported on autopsis of 2000 dead soldiers in Korean War average age 22.  <ul><li>35% had fatty streak...
Average adult Aorta, mild fatty streaks, early atheroma.
Aorta. Arrow at prominent  fatty streak
Initiation of atheroma by damage to endothelium which becomes more porous to lipids and monocytes
Monocytes from blood stream pass through endothelium into blood vessel wall
Healthy Coronary Artery cross section
 
 
Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
Oxidized LDL Cytokines Glycolated end products Coronary Artery Disease Initiation of Monocyte attachment with activation o...
Vascular cell wall adhesion molecule (VCAM-1)  is induced by TNF-K 
Vascular cell wall adhesion molecule (VCAM-1)  is induced by TNF-K  VACM-1 VACM-1
VCAM-1 and chemokine monocytic chemotactic protein I localizes monocytes in vessel wall. VACM-1 VACM-1 MCP1
Low Density Lipids (LDL) pass through damaged endothelium into blood vessel wall
LDL LDL LDL Coronary Artery Disease Low density lipids (LDL) oxidized in vessel wall O O O LDLO LDLO LDLO LDLO LDLO LDLO L...
LDL’s are oxidized and then induce production of bio active molecules such as Interleukin 1, Interleukin 6, matrix metallo...
MMP MMP Cytokines Cytokines LDLO LDLO LDLO Prostaglandins
Monocytes  transform to macrophages  and take up LDL  to form foam cells
 
Monocytes trigger chronic inflammatory reaction with lymphocytes and this results in tissue necrosis and fibrosis
MMP MMP Cytokines Cytokines LDLO LDLO LDLO Prostaglandins
Circulating bacteria and cytokines add to inflammation. This leads to Atheromatous plaque formation MMP MMP Cytokines Cyto...
High Density Lipids (HDL) inhibit  oxidation of LDL
High Density Lipids (HDL) <ul><li>HDL are a heterogeneous lipoproteins produced in the liver and small intestine. HDL cont...
Enzymes associated with HDL apolipoproptein (apoAL) and para-oxenase (PON) protect by destroying the oxidized pro-inflamma...
PON also inhibits LDL induced Monocyte Migration.Periodontitis may cause reduction in Apo  AI and PON and so increase the ...
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 atheromatous plaques (arrows)
THROMBUS DEVELOPMENT
Coronary Artery with stable atheroma. Inflamation and necrosis have replaced the smooth muscle but there is a dense layer ...
MMP MMP MMP MMP s from macrophages and proteases from  circulating bacteria can destroy collagen to  form an unstable athe...
Blood vessel wall can rupture and then get thrombus formed at region of ulceration
Endothelium is destroyed with exposure of  collagen and plaque to arterial blood.
Platelets aggregate on exposed collagen to form a thrombus. Coronary Artery Disease
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
Thrombus formation on atheromataous plaque.  Slits of cholesterol crystals seen in vessel wall.
Coronary artery with narrowed lumen and thrombosis (arrows) Narrowed Lumen
Oral Bacteria
Thrombosis can give occlusion of vessel. This is responsible for 50% of cases of myocardial infarction
Calcification (blue area) and distended vessel wall with narrowed lumen of Coronary Artery. lumen
Ultrafast CAT Scan of Thorax Showing Cross-Section of Heart. Calcified Tissues Stained Pink. Note: Calcified Atheromatous ...
 
 
 
 
 
 
BACTERIA
Bacteria <ul><li>A number of bacteria and bacterial products have been associated with coronary  artery disease. These inc...
Gram negative bacteria or LPS given systemically can give following changes in major blood vessels <ul><li>inflammatory ce...
Gram Negative Bacterial Infections <ul><li>Chlamydia pneumonie  CHD risk factor 2.3 Heliobactor pylori MI risk factor 1.3 ...
CORRELATION BETWEEN ATHEROSCLEROSIS AND PERIODONTAL PUTATIVE PATHOGENIC BACTERIA IN CORONARY AND INTRENAL MAMMARY ARTERIES...
15 PATIENTS  AT SURGERY TOOK CORONARY AND INTERNAL MAMMARY ARTERY SECTIONS <ul><li>9 OF 15 CORONARY +VE FOR PERIODONTAL BA...
Identification of Pathogens in Atheromatous Plaques <ul><li>Haraszthy V.I et al  </li></ul><ul><li>J. Dent. Res. 1998: 71....
Looked at bacterial DNA in 27 Atheromatous Coronary Vessels obtained during endarterectomy 19 were positive. <ul><li>A. ac...
Frequency and Distribution of Periodontal Pathogens in the Atheromas of Coronary Arteries. <ul><li>Meyers G.S. </li></ul><...
Used PCR to detect bacterial D.N.A in atheromatous coronary vessels from 42 post mortems.  95% of atheromas had bacterial ...
Frequency <ul><li>A. actinomycetemcomitans 29% </li></ul><ul><li>B. Forsythus 24% </li></ul><ul><li>P. Gingivalis 0% </li>...
CAROTID ARTERY.POSITIVE FOR P. GINGIVALIS
 
ELECTRO N MICROGRAPH OF MACROPHAGE
GRAM NEGATIVE BACTERIA IN MACROPHAGE
Other periodontal bacteria such as, Porphyromonas gingivalis have also been shown to infect endothelial cells. <ul><li>Pro...
Electron Micrograph of endothelial cells in culture with Fusobacterium nucleatum bacteria seen on surface and in cytoplasm...
Bacterial Involvement in Atheroma <ul><li>Periodontal bacteria, Chlamydia pneumoniae and virus all seen in high frequency ...
CORRELATION BETWEEN ATHEROSCLEROSIS AND PERIODONTAL PUTATIVE PATHOGENIC BACTERIAL INFECTIONS IN CORONARY AND INTRNAL MAMMA...
CORONARY ARTERIES   P. g IN 8  H.a IN 4  P.i IN 5  T.f IN 2  C, p IN 5  CMV  IN 10   INTERNAL  MAMMARY  ARTERIES 0  PERIOD...
Establishment of a mouse model of infective induced atheroma formation  <ul><li>Chung H.J. et al  </li></ul><ul><li>J. Den...
Used atheroslerosis susceptible mouse with subcutaneous chamber in which was placed live P. Gingivalis and measured athero...
Mean area of atheroma after 3 weeks <ul><li>P. Gingivalis 162.1Mm2 </li></ul><ul><li>Control broth   88.6Mm2 </li></ul>Chu...
TNF and PGE levels  in chamber were  correlated with area of atheroma TNF associated with serum cholesterol.  Cholesterol ...
Bacterial induced periodontal disease increases circulating cytokines which can accentuate inflammation in atheromatous ve...
Early gingivitis with margin of gingiva showing edema, redness and bleeding on probing.
<ul><li>IL1ß Recruits inflammatory cells. Stimulates PMNS increased synthesis of prostaglandin and metallo proteinases (MM...
Circukating and local  Interleukin 1-   levels   (Lemus, C., & Haake, S.) <ul><li>Periodontitis Group Health Group </li><...
Chronic bacterial infections including periodontal disease also increase circulating C Reactive Substance
<ul><li>C Reactive substance is a marker for inflammation and is predictive of future myocardial infarction and stroke. </...
543 Healthy men who developed MI or stroke compared to controls C Reactive protein MI or stroke 1.51 mg/l Controls 1.13 mg...
Bacteria from the oral cavity and dental plaque can stimulate platelet aggregation.
Streptococcus sanguis expresses a cell wall bound protein (PAAP) that induces activation and aggregation of platelets. PAA...
Strep Sanguis isolated from infective endocarditis has an adhesin identified by monoconal antibody, which binds to platele...
Effects of oral flora on platelets: Possible consequences in cardiovascular disease <ul><li>Herzberg, M. Mayer, M. W. </li...
In rabbits S. Sanguis caused platelet aggregation. Hearts had ischemic areas.  Infusion of S. Sanguis caused changes in el...
Hyperlipedemia caused increased cardiac effects ofS. Sanguis. Also have seen similar effects in platelets with  P. Gingiva...
Inoculation of Strep Sanguis Strain 133-79 caused cardiac contractility to fall 60% Strep Sanguis Strain L47 does not affe...
Rabbits on high fat diet with hypercholesterolemia In vitro platelet aggregation response to strain 133-79 accelerated ove...
Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
HYPERTENSION
Hypertension increase chance of endothelial injury
Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
HOMOCYSTEINE
High levels of the Amino acid homocysteine increase risk of coronary artery disease by being toxic to endothelium.
Folic acid vitamin B6, B12 reduce levels of homocysteine
Hyperhomocysteinema odds ratio CHD 1.7 In 28,263 post menopausal women 3 year follow up those with top quartile homocystei...
Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
SMOKING
Toxic factors in cigarette smoke increase risk endothelial injury
Smokers 2.5 times more likely to have heart attack
Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
DIABETES
Hyperglycemia causes endothelial dysfunction by a number of mechanisms including inhibition of endothelial derived nitric ...
Diabetes increase risk of atheroma because of hyperlipemia
Diabetes has high triglycerides  And low HDL
Low density lipids can initiate endothelial dysfunction and monocyte attachment. LDL’s also interact with periodontal infl...
Antioxidants increase resistance of LDL to oxidation. Vitamin E reduces risks of atheroma production
Risk of CVD and MI reduced 77% with 800 IU tocopherol 400 IU gave a 47% reduction
Vitamin E has little or no effect on established atheroma
Association between Periodontitis and Hyperlipidemia:  Cause or Effect? <ul><li>Cutler C.W et al </li></ul><ul><li>Periodo...
51 subjects, 26 with chronic adult periodontitis, 25 healthy controls looked at triglycerides, cholesterol, antibodies aga...
Relationship with Periodontal Disease and other variables  <ul><li>odds  ratio </li></ul><ul><li>Age > 50 years 3.5 </li><...
Also did in vitro study to see effect of triglycerides on release of IL1 beta from p.m.n.s.
Interleukin 1 beta secretion  by PMNS from healthy patients  <ul><li>PMN 2.0 </li></ul><ul><li>PMN + P.g. L.P.S 24 </li></...
Short term high fat diet impairs antibacterial function of p.m.n.s hyperlipidemia can modulate release of cytokines and gr...
Pathophysiological relationships between periodontitis and systemic disease: Recent concepts involving serum lipids <ul><l...
Periodontitis induced changes in immune cell functions causes metabolic dysregulation of lipid metabolism involving cytoki...
From periodontitis elevated serum IL-1ß and TNF change lipid metabolism so get hyperlipidemia.
The elevated lipids in diabetes and periodontitis also increases monocytic responsiveness and pmn activity so get increase...
Recommended levels of LDL <ul><li>1 or more risk factor < 160mg / ml </li></ul><ul><li>2 or more risk factor < 130mg / ml ...
Recommended levels of HDL >35 mg/ml
High cholesterol  >200mg/ml with LDL  >130 mg/ml increases risk of heart attack 2.4 times
Harvard Study, Dr. W.C. Taylor Used data from MR FIT trail for persons without risk factors such as smoking or hypertensio...
Dr J. Stamler Northwestern University Study of 361,662 young and middle aged men. Top 20% of cholesterol levels three time...
Cholesterol Reducing Drugs Inhibit Synthesis of Cholesterol. Up-Regulate Nitric Oxide Sinthetase <ul><li>LIPITOR ( ATORVAS...
LOVASTATIN MEVACOR
Dr A Gotto Cornell University Am. J. Cardiol., Dec. 2000 pg. 1176 6,605 healthy adults aged 47 to 73, 5,608 men, 997women,...
Alcohol 1 to 2 glasses a day reduces cholesterol, reduces clotting
One to two drinks of alcohol per day gives 30-50 percent reduction in CHD in men. Maybe due to increase levels of HDL, or ...
Aspirin inhibits platelet aggregation
Aspirin 325 mg every other day for 4.5 years 22000 male MDs <ul><li>Aspirin  194 MI    5 deaths  </li></ul><ul><li>Control...
2418 Israeli women 100 to 500 mg Aspirin every other day for 3 years  <ul><li>40% less MI mortality  </li></ul><ul><li>34%...
Early infarct affecting left ventricle thrombus
Cross section of heart with area of necrosis
Infarct in ventricular wall with loss of muscle and scarring
Area of previous infarct with rupture of ventricular wall
Histology of  Myocardial Infarction
Normal heart muscle
Beginning of infarct, loss of striations and nuclei of cardiac muscle
Continued loss of cellular vitality of myocardium
Myocardial infarct with replacement of necrotic myocardium with inflammatory cells and fibroblasts
Established infarct with fibrotic scarring in myocardium
Systematic review of the association between respiratory diseases and oral heaith. Azarpazhooh. A. J. PERIODONT.2006.77:14...
Association between oral health and pneumonia odds ratio 1.2 to 9.6. Good evidence of value of periodontal initial therapy...
FURTHER READING CLINICAL PERIODONTOLOGY 10 th EDITION CHAPTER 18
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Coronary Artery Disease

  1. 1. TARRSON FAMILY ENDOWED CHAIR IN PERIODONTICS
  2. 2. UCLA School of Dentistry
  3. 3. Presents Dr. E. Barrie Kenney Professor & Chairman Section of Periodontics
  4. 4. Periodontal Disease as a Predictor of Atherosclerosis E. Barrie Kenney B.D.Sc., D.D.S., M.S., F.R.A.C.D.S. Tarrson Family Endowed Chair in Periodontics. Professor and Chairman Division of Associated Clinical Specialties UCLA School of Dentistry
  5. 5. Coronary Artery Disease
  6. 6. Epidemiological connection between coronary artery disease and periodontal disease
  7. 7. 6.9 Million people have coronary heart disease in USA
  8. 8. Atherosclerosis Leading Cause of Death in USA
  9. 9. Coronary Artery Disease (C.A.D) kills 500,000 people a year. One of every 4.6 deaths due to C.A.D
  10. 10. Periodontal Disease in the United States <ul><li>54% of U.S. population 13 years and older has gingival bleeding on probing </li></ul><ul><li>In adults an average 19.6% of teeth have periodontal attachment loss of 3mm or more </li></ul><ul><li>Based on data from NHANES III survey 1988-19994 </li></ul>
  11. 11. Association between dental health and acute myocardial infarction <ul><li>Matilla KJ et al </li></ul><ul><li>Brit. Med. J. 1989 298: 774 </li></ul>
  12. 12. <ul><li>Used index based on caries, periodontal disease, periapical lesions, pericoronitis. </li></ul><ul><li>Patients admitted for acute myocardial infarction had higher scores than matched controls. </li></ul>
  13. 13. Patients above the upper quartile had twice the risk of acute myocardial infarction than did those with a score of zero.
  14. 14. This was comparable to risk of cigarette smoking, hypercholesterolemia and hypertension.
  15. 15. Dental Disease and Risk of Coronary Heart Disease and Mortality <ul><li>De Stefano F et al </li></ul><ul><li>Brit. Med. J. 1993, 306: 688 </li></ul>
  16. 16. <ul><li>Analyzed data from National Health and Nutrition examination study I. 1971 – 1974. </li></ul><ul><li>20,249 subjects aged 25 to 74 followed up in 1982 – 1985 (only 55 years and older at entry) and 1986 – 1987. </li></ul>
  17. 17. Excluded subjects with history of heart disease stroke or cancer. Not all subjects were evaluated for smoking so had a subset with known history of smoking (1163 subjects)
  18. 18. Admitted for Coronary Artery Disease or died of Coronary Artery Disease as indicators of disease
  19. 19. Dental evaluation at baseline <ul><li>Number of carious teeth </li></ul><ul><li>Periodontal status healthy, gingivitis periodontitis no teeth oral hygiene index 6 teeth 0-3 for debris 0-3 for calculus combined to give OHI. Also periodontal index 0 to 8 for each tooth and average for each patient. </li></ul>
  20. 20. Percentage of subjects <ul><li>death from CHD 2.6 4.1 8.4 11.9 </li></ul><ul><li>admission for CHD 6.5 7.4 14.4 19.2 </li></ul>No No Disease Gingivitis Periodontitis Tooth De stefano
  21. 21. ODDS Ratios <ul><li>Risk Women Men </li></ul><ul><li>Factors 25-49 Mortality 25-49 </li></ul><ul><ul><li>No disease 1.00 1.00 1.00 1.00 </li></ul></ul><ul><ul><li>Gingivitis 1.05 0.98 1.23 1.42 </li></ul></ul><ul><ul><li>Periodontitis 1.25 1.72 1.46 2.12 </li></ul></ul><ul><ul><li>No teeth 1.23 1.71 1.46 2.60 </li></ul></ul><ul><ul><li>Periodontal index 1.04 1.09 1.09 1.11 </li></ul></ul><ul><ul><li>Oral hygiene index 1.12 1.11 1.15 1.23 </li></ul></ul>adjusted for age, sex education, poverty level, marital status, blood pressure, cholesterol, diabetes, weight, physical activity, alcohol, smoking De Stefano
  22. 22. Analysis of these with data on smoking showed the same pattern.
  23. 23. No association between active caries and CHD
  24. 24. Periodontal Disease and Coronary Heart Disease Risk <ul><li>Hujoel P.P., et al </li></ul><ul><li>J.A.M.A. 2000, 284:1406 </li></ul>
  25. 25. Used NHANES population 8032 dentate adults aged 25 to 74 years with no history of cardiovascular disease. 1859 had periodontitis, 2421 had gingivitis, 3752 healthy. Russel index used. Subjects with prior history of cardiovascular disease eliminated.
  26. 26. At follow up 1265 subjects had at least 1 coronary heart disease event, either death, hospitalization or coronary revascularization therapy.
  27. 27. Periodontal Disease and Myocardial Disease have common risk factors, age, smoking, stress, social economics status, body fat, and so potential for confounding is substantial.
  28. 28. Diabetes 5.2% 2.7% 2.0% Alcohol glass per day 0.81 0.73 0.55 Pack years smoking 15.9 10.4 8.8 Total cholesterol 222.1 215.4 212.74 Age 52.4 43.0 42.0 Male 50.4% 38.4% 30.5% White 70.2% 77.5% 88.7% African American 28.0% 21.1% 10.4% Education years 9.6 11.1 12.4 Periodontitis Gingivitis Healthy Hujoel et al.
  29. 29. Hazard Ratios Compared to Healthy <ul><li>Unadjusted Adjusted for Confounders </li></ul><ul><li>periodontitis 2.66 1.14 </li></ul><ul><li>gingivitis 1.20 1.05 </li></ul>
  30. 30. “ While this study did provide convincing evidence regarding the absence of a moderate to large association between periodontitis and CHD, a small causal association could not be ruled out.”
  31. 31. Oral Health and Systemic Disease: Periodontitis and Cardiovascular Disease <ul><li>Beck J.D. Offenbacher S. </li></ul><ul><li>J. Dent. Edu. 1998, 62:859 </li></ul>
  32. 32. Odds ratio with more or less sites p.d > 3mm <ul><li>CHD Fatal Stroke CHD </li></ul><ul><li>3·1 2·8 1·9 </li></ul>1147 Male Veterans from Boston Beck
  33. 33. Number of sites with 20% or more bone loss <ul><li>ODDS Ratio for CHD </li></ul><ul><ul><li>1-2 0.8 </li></ul></ul><ul><ul><li>3-5 1.4 </li></ul></ul><ul><ul><li>6-10 1.9 </li></ul></ul><ul><ul><li>11-20 2.1 </li></ul></ul><ul><ul><li>Beck et al </li></ul></ul>
  34. 34. Periodontal Disease and prevalent Coronary Heart Disease in the ARIC study <ul><li>Beck J.D et al </li></ul><ul><li>J. Dent. Res. 2000. 79. abst. #2269 </li></ul>
  35. 35. ODDS Ratio for C.H.D. <ul><li>per cent sites with attachment loss 3mm or more Males Females </li></ul><ul><li>0 – 6.4 1.0 1.0 </li></ul><ul><li>6.5 – 15.1 1.7 0.7 </li></ul><ul><li>15.2 – 31.0 1.5 0.8 </li></ul><ul><li>31.1 – 100 1.7 0.9 </li></ul>
  36. 36. Atherosclerosis Risk in Communities study 13.6% of males 5.5% of females had coronary heart disease
  37. 37. Investigation of the Association Between Angiographically Defined Coronary Artery Disease and Periodontal Disease Matthaner, S. S. et al. J. Periodontol 73:1169 2002
  38. 38. 100 patients 53 with coronary artery disease (50% stenosis of at least one vessel) 47 no coronary artery disease (less than 50% stenosis in all arteries <ul><li>53 CAD +ve 83% male average 65.3 years </li></ul><ul><li>47 CAD -ve 40.4% male average 60.8 years </li></ul><ul><li>All non diabetics, non smokers for at least 5 years </li></ul><ul><li>CAD +ve 66% former smokers 15.8 pack years </li></ul><ul><li>CAD -ve 24.4% former smokers 4.5 pack years </li></ul>Matthaner ,
  39. 39. <ul><li>CAD +ve CAD -ve Sites with CAL>6mm 6.85 3.32 </li></ul><ul><li>Radiographic bone loss 3.60mm 3.18mm </li></ul><ul><li>Mean probing depth 2.67mm 2.59mm </li></ul><ul><li>Tooth loss 8.9 9.1 </li></ul><ul><li>When corrected for age previous smoking history </li></ul><ul><li>Odds ratio 1.06 Mean CAL </li></ul><ul><li>Odds ratio 1.03 CAL>6mm </li></ul><ul><li>Odds ratio 1.31 Radiographic bone loss </li></ul><ul><li>Odds ratio 2.54 Mean probing depth </li></ul><ul><li>These patients had minimal periodontal disease so CAL may be recession or pocket related </li></ul>Matthaner ,
  40. 40. Ratio of Cigarette Smoking in the Association Between Periodontal Disease and Coronary Heart Disease Hyman, J. J. et al. J. Periodontol 73:988 2002
  41. 41. 5285 Subjects from NHANES 1988-94, 40 years or older <ul><li>Loss of Attachment Odds ratio for heart attack history </li></ul><ul><li>2.00 - 2.99mm 2.64 </li></ul><ul><li>3.00-3.99mm 3.84 </li></ul><ul><li>4mm or more 5.87 </li></ul>Hyman ,
  42. 42. Oral Health and Peripheral Arterial Disease <ul><li>Hung, H.C. et al </li></ul><ul><li>Circulation 2003:107:1152 </li></ul><ul><li>45,136 male health workers free of cardiovascular disease followed for 12 years. </li></ul><ul><li>342 cases of peripheral arterial disease. </li></ul><ul><li>Patient repords and diagnosis or treatment of claudication of leg arteries. </li></ul><ul><li>Self report of periodontal disease </li></ul>
  43. 43. Odds Ratio Peripheral Cardiovascular Disease And <ul><li>Periodontal Disease 1.41 </li></ul><ul><li>Tooth Loss 1.39 </li></ul><ul><li>Periodontal Disease & Tooth Loss 1.88 </li></ul><ul><li>No Periodontal Disease and Tooth Loss 0.92 Controlled for traditional risk factors for cardiovascular disease. </li></ul>Hung, H.C. et al
  44. 44. Severity of Periodontal Disease and number of remaining teeth are related to the prevalence of Infarction and Myocardial Hypertension in a study based on 4254 subjects. Holmlund. A. et al J. Periodontol 2006 77: 1173
  45. 45. Odds Ratio Periodontal bone loss And Myocardial Infarction <ul><li>Periodontal Disease 2.69 </li></ul><ul><li>Smoking 0.69 </li></ul><ul><li>Gender 0.62 </li></ul><ul><li>Age 1.09 Controlled for traditional risk factors for cardiovascular disease.Aged 40 to 60 years old. </li></ul>
  46. 46. TREATMENT OF PERIODONTITIS AND ENDOTHELIAL FUNCTION. TONETTI M S et al NEJMED.356:911, 2007 59 PATIENTS SEVERE PERIODONTITIS GOT PROPHY TYPE CARE 61 GOT ROOT PLANING +ARESTIN AND EXTRACTION HOPELESS TEETH MEASURED BRACHIAL ARTERY FLOW BEFORE AT 1, 7, 30, 60, 180 DAYS AFTER <ul><ul><li>AT 1 DAY INTENSIVE GROUP LOWER VESSEL DILATION THAN PROPHY GROUP </li></ul></ul>AT 60 , 180 DAYS INTENSIVE GREATER DILATION THAN PROPHY ENDOTHELIAL FUNCTION IMPROVEMENTS CORRELATED WITH PERIODONTAL TREATMENT SUCCESS
  47. 47. CORRELATIONS BETWEEN CLINICAL MEASUREMENTS OF PERIODONTAL DISEASE AND PRESENCE OF BACTERIAL ANTIGENS IN HUMAN ATHEROSCLEROSIS. PUCAR A KENNEY EB etal 2007 36 patients got vascular surgery for atheroma 10 ext carotid 3 aorta 5 femoral or iliac 18 coronary P.C. R on vessels and dental plaque forP.gingivalis P,intermedia, Aa .T.forsythensis,C. pneumoniae. C.M.V
  48. 48. 10 ARTERIES --VE, 14 +VE FOR 1 PERIO BACTERIA. 10 +VE FOR 2, 2+VE FOR 3 20 HAD C.M.V 10 HAD CHLAMYDIA POSITIVE CORRELATION BETWEEN POCKETS 6MM. OR GREATER AND PRESENCE OF P. gingivalis AND P.intermedia. C.M.V AND CHLAMYDIA NEGATIVE CORRELATION WITH PERIODONTAL INDEX
  49. 49. Coronary Artery Disease In Women
  50. 50. Lipid management and control of other coronary risk factors in post menopausal women J. Women’s Health and Gender related Med. 9:235,2000
  51. 51. Stroke and myocardial infarction Number one killer of women with 500,000 deaths per year
  52. 52. African American and Hispanic women at greater risk than Caucasian women
  53. 53. This is more than the next 16 causes of death combined
  54. 54. Risk of Myocardial infarction lower in women than men
  55. 55. First myocardial infarction in women is more severe and more lethal than they are in men
  56. 56. Women’s mortality rate at 6 months post myocardial infarction double that of men
  57. 57. Analysis of 350,000 patients after fibrinolytic therapy for infarction. Mortality for women 9.3%, men 4.5%
  58. 58. Without fibrinolytic therapy <ul><li>16% mortality for women </li></ul><ul><li>10.9% for men </li></ul>
  59. 59. Coronary artery bypass surgery operative mortality 4.5% women, 2.6% men
  60. 60. Menopause often causes increase in total cholesterol and LDL
  61. 61. Estrogen increase HDL levels
  62. 62. Post menopausal hormonal therapy gave 53% reduction in death from CHD in study using 121,700 registered nurses
  63. 63. Framingham Study. Risk of coronary artery disease doubles with onset of menopause
  64. 64. Cardiovascular Disease During 6.9 Years of Hormone Therapy <ul><li>20 centers with 2,763 post menopausal with C.H.D. average age 67 years. </li></ul><ul><li>Hormone group got 0.6625mg conjugated estrogen, 2.5mg medroxyprogesterone acetate daily. </li></ul><ul><li>Hormones gave no significant decrease in C.H.D. events - infarct or death hospitalization angina revascularization, congestive heart failure, stroke, ischemia or ventricular arrhythmia </li></ul><ul><li>Another study on same population showed hormone group had increased rated of venous thrombo-embolism and biliary tract surgery. </li></ul><ul><li>261 deaths compared to 239 in controls </li></ul>Grady, D. et al JAMA 2002, 288:49
  65. 65. ESTROGEN THERAPY AND CORONARY ARTERY CALCIFICATION. MANSON, J. E. et al NEJM. 2007 356: 2591 1064 WOMEN 50 TO 59 YEARS OLD AFTER HYSTERECTOMY RANDOMLY GOT 0.625 ESTROGEN PER DAY OR PLACEBO EVALUATED CORONARY ARTERY CALCIFICATION ESTROGEN GROUP SCORE 83.1 CONTROL GROUP SCORE 123.1
  66. 66. Periodontal flap surgery to treat periodontitis. Note loss of crestal bone.
  67. 67. Periodontitis. Histopathologyof intrabony defect showing bone resorption ( yellow ), inflammation ( green ) and epithelial proliferation ( white ).
  68. 68. Pathogenesis of Atheroma <ul><li>1. Fatty streak development </li></ul><ul><li>2. Atheromatous plaque development </li></ul><ul><li>3. Thrombus development </li></ul>
  69. 69. Fatty streak development
  70. 70. Dr. Enos and Holmes reported on autopsis of 2000 dead soldiers in Korean War average age 22. <ul><li>35% had fatty streaks in coronary arteries </li></ul><ul><li>42% had had established atheroma </li></ul>
  71. 71. Average adult Aorta, mild fatty streaks, early atheroma.
  72. 72. Aorta. Arrow at prominent fatty streak
  73. 73. Initiation of atheroma by damage to endothelium which becomes more porous to lipids and monocytes
  74. 74. Monocytes from blood stream pass through endothelium into blood vessel wall
  75. 75. Healthy Coronary Artery cross section
  76. 78. Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
  77. 79. Oxidized LDL Cytokines Glycolated end products Coronary Artery Disease Initiation of Monocyte attachment with activation of endothelial transcription nuclear factor K  (TNF-K  ) by oxidized low density lipids, cytokines, and glycolated end products seen in diabetes.
  78. 80. Vascular cell wall adhesion molecule (VCAM-1) is induced by TNF-K 
  79. 81. Vascular cell wall adhesion molecule (VCAM-1) is induced by TNF-K  VACM-1 VACM-1
  80. 82. VCAM-1 and chemokine monocytic chemotactic protein I localizes monocytes in vessel wall. VACM-1 VACM-1 MCP1
  81. 83. Low Density Lipids (LDL) pass through damaged endothelium into blood vessel wall
  82. 84. LDL LDL LDL Coronary Artery Disease Low density lipids (LDL) oxidized in vessel wall O O O LDLO LDLO LDLO LDLO LDLO LDLO LDLO LDLO LDLO LDLO LDLO LDLO
  83. 85. LDL’s are oxidized and then induce production of bio active molecules such as Interleukin 1, Interleukin 6, matrix metalloproteases, Prostaglandins. Platelet Derived Growth Factor, Tumor Necrosis Factor Alpha.
  84. 86. MMP MMP Cytokines Cytokines LDLO LDLO LDLO Prostaglandins
  85. 87. Monocytes transform to macrophages and take up LDL to form foam cells
  86. 89. Monocytes trigger chronic inflammatory reaction with lymphocytes and this results in tissue necrosis and fibrosis
  87. 90. MMP MMP Cytokines Cytokines LDLO LDLO LDLO Prostaglandins
  88. 91. Circulating bacteria and cytokines add to inflammation. This leads to Atheromatous plaque formation MMP MMP Cytokines Cytokines LDLO LDLO LDLO Bacteria Cytokines Prostaglandins
  89. 92. High Density Lipids (HDL) inhibit oxidation of LDL
  90. 93. High Density Lipids (HDL) <ul><li>HDL are a heterogeneous lipoproteins produced in the liver and small intestine. HDL contains 70% phospholipid and protein, 25% cholesterol, 5% triglycerides. </li></ul><ul><li>HDL has 2 antioxidant enzymes </li></ul><ul><ul><li>Paraoxonase </li></ul></ul><ul><ul><li>Platelet activating factor acetyl hydrolase Apolipoprotein A-1 stabilizes paraoxonase </li></ul></ul>
  91. 94. Enzymes associated with HDL apolipoproptein (apoAL) and para-oxenase (PON) protect by destroying the oxidized pro-inflammatory lipids from LDL
  92. 95. 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.
  93. 96. HDL HDL HDL LDL LDL LDL O O O
  94. 97. HDL HDL HDL LDL LDL LDL O O
  95. 98. ATHEROMATOUS PLAQUE DEVELOPMENT
  96. 99. Blood vessel wall becomes distended and continues to accumulate cholesterol, some areas become calcified
  97. 100. Coronary artery with atheromatous plaques (arrows)
  98. 101. THROMBUS DEVELOPMENT
  99. 102. Coronary Artery with stable atheroma. Inflamation and necrosis have replaced the smooth muscle but there is a dense layer of collagen next to lumen (arrows)
  100. 103. 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
  101. 104. Blood vessel wall can rupture and then get thrombus formed at region of ulceration
  102. 105. Endothelium is destroyed with exposure of collagen and plaque to arterial blood.
  103. 106. Platelets aggregate on exposed collagen to form a thrombus. Coronary Artery Disease
  104. 107. Thrombus formation
  105. 108. Oral Bacteria Circulating oral bacteria have peptides that cause platelet aggregation
  106. 109. Increase thrombosis can lead to sudden occlusion of vessel
  107. 110. Coronary Artery occluded by thrombosis
  108. 111. Thrombus formation on atheromataous plaque. Slits of cholesterol crystals seen in vessel wall.
  109. 112. Coronary artery with narrowed lumen and thrombosis (arrows) Narrowed Lumen
  110. 113. Oral Bacteria
  111. 114. Thrombosis can give occlusion of vessel. This is responsible for 50% of cases of myocardial infarction
  112. 115. Calcification (blue area) and distended vessel wall with narrowed lumen of Coronary Artery. lumen
  113. 116. Ultrafast CAT Scan of Thorax Showing Cross-Section of Heart. Calcified Tissues Stained Pink. Note: Calcified Atheromatous Plaques in Coronary Arteries
  114. 123. BACTERIA
  115. 124. Bacteria <ul><li>A number of bacteria and bacterial products have been associated with coronary artery disease. These include Chlamydia pneumoniae, Heliobacter pylori and gram negative bacteria found in dental plaque. </li></ul>
  116. 125. Gram negative bacteria or LPS given systemically can give following changes in major blood vessels <ul><li>inflammatory cell infiltrate </li></ul><ul><li>smooth muscle proliferation </li></ul><ul><li>fatty degeneration </li></ul><ul><li>intravascular coagulation </li></ul>
  117. 126. Gram Negative Bacterial Infections <ul><li>Chlamydia pneumonie CHD risk factor 2.3 Heliobactor pylori MI risk factor 1.3 Chlamydia also seen in fatty streaks and atheroma plaques at autopsy </li></ul>
  118. 127. CORRELATION BETWEEN ATHEROSCLEROSIS AND PERIODONTAL PUTATIVE PATHOGENIC BACTERIA IN CORONARY AND INTRENAL MAMMARY ARTERIES <ul><li>PUCAR A M ILASIN J LEKOVIC V KENNEY E B ET AL . IN PRESS J. PERIODONTOL. </li></ul>
  119. 128. 15 PATIENTS AT SURGERY TOOK CORONARY AND INTERNAL MAMMARY ARTERY SECTIONS <ul><li>9 OF 15 CORONARY +VE FOR PERIODONTAL BACTERIA DNA. ALL OF INTERNAL MAMMARIES NEGATIVE.BUT 6 HAD CMV, 7 HAD CHLAMYDIA C/F 10 AND 5 FOR CORONARY </li></ul>
  120. 129. Identification of Pathogens in Atheromatous Plaques <ul><li>Haraszthy V.I et al </li></ul><ul><li>J. Dent. Res. 1998: 71. 666. </li></ul>
  121. 130. Looked at bacterial DNA in 27 Atheromatous Coronary Vessels obtained during endarterectomy 19 were positive. <ul><li>A. actinomycetemcomitans 6 cases </li></ul><ul><li>P. Gingivalis 6 cases </li></ul><ul><li>P. Intermedia 7 cases </li></ul>
  122. 131. Frequency and Distribution of Periodontal Pathogens in the Atheromas of Coronary Arteries. <ul><li>Meyers G.S. </li></ul><ul><li>Balint Orban Competition </li></ul><ul><li>AAP Annual Meeting September 2000 </li></ul>
  123. 132. Used PCR to detect bacterial D.N.A in atheromatous coronary vessels from 42 post mortems. 95% of atheromas had bacterial D.N.A from periodontal pathogens.
  124. 133. Frequency <ul><li>A. actinomycetemcomitans 29% </li></ul><ul><li>B. Forsythus 24% </li></ul><ul><li>P. Gingivalis 0% </li></ul><ul><li>P. Intermedia 2% </li></ul><ul><li>F. Nucleatum 29% </li></ul>
  125. 134. CAROTID ARTERY.POSITIVE FOR P. GINGIVALIS
  126. 136. ELECTRO N MICROGRAPH OF MACROPHAGE
  127. 137. GRAM NEGATIVE BACTERIA IN MACROPHAGE
  128. 138. Other periodontal bacteria such as, Porphyromonas gingivalis have also been shown to infect endothelial cells. <ul><li>Progulske-Fox, A. et.al. J. Dent. Res. 1999, 34:393 </li></ul>
  129. 139. Electron Micrograph of endothelial cells in culture with Fusobacterium nucleatum bacteria seen on surface and in cytoplasm of epithelial cells. This shows the ability of periodontaal bacteria to infect endothelium, (Haake, S. et.al.)
  130. 140. Bacterial Involvement in Atheroma <ul><li>Periodontal bacteria, Chlamydia pneumoniae and virus all seen in high frequency in atheromatous plaques. Gram negative periodontal bacteria have the ability to adhere to endothelial cells. </li></ul><ul><li>Dorn, B.R. et.al. Infect. Immun. 1999 67:5792 </li></ul><ul><li>Eikenella corrodens Porphyromas gingivalis and Prevotella intermedia invaded human coronary artery endothelial and smooth muscle cells in culture. </li></ul><ul><li>Lee J.K. et.al. Invasion of human endothelial cells by Fuscobacterium nucleatum J. Dent. Res. 81-A114 2002 </li></ul>
  131. 141. CORRELATION BETWEEN ATHEROSCLEROSIS AND PERIODONTAL PUTATIVE PATHOGENIC BACTERIAL INFECTIONS IN CORONARY AND INTRNAL MAMMARY ARTERIES . PUCAR A , KENNEY EB et al J. PERIODONT. 2007 78:677 CORONARY GRAFT SURGERY IN 15 PATIENTS WITH INT. MAMMARY REPLACEMENT P.C.R. TEST OF BLOOD VESSELS FOR P.gingivalis, H actinomycetemcomitans P. intermedia T forsythensis AND C.pneumoniae Human cyto megalic virus.
  132. 142. CORONARY ARTERIES P. g IN 8 H.a IN 4 P.i IN 5 T.f IN 2 C, p IN 5 CMV IN 10 INTERNAL MAMMARY ARTERIES 0 PERIODONTAL BACTERIA C.p IN 6 CMV IN 7
  133. 143. Establishment of a mouse model of infective induced atheroma formation <ul><li>Chung H.J. et al </li></ul><ul><li>J. Dent. Res. 2000 79: #1356 </li></ul>
  134. 144. Used atheroslerosis susceptible mouse with subcutaneous chamber in which was placed live P. Gingivalis and measured atheroma in aorta. Mice had been primed with previous infection of P. Gingivalis
  135. 145. Mean area of atheroma after 3 weeks <ul><li>P. Gingivalis 162.1Mm2 </li></ul><ul><li>Control broth 88.6Mm2 </li></ul>Chung et al
  136. 146. TNF and PGE levels in chamber were correlated with area of atheroma TNF associated with serum cholesterol. Cholesterol associated with area of atheroma.
  137. 147. Bacterial induced periodontal disease increases circulating cytokines which can accentuate inflammation in atheromatous vessels.
  138. 148. Early gingivitis with margin of gingiva showing edema, redness and bleeding on probing.
  139. 149. <ul><li>IL1ß Recruits inflammatory cells. Stimulates PMNS increased synthesis of prostaglandin and metallo proteinases (MMP). Inhibits collagen synthesis. Activates B and T lymphocytes </li></ul><ul><li>TNF alpha Stimulates apoptosis, bone resorption, MMP and IL-6 production. </li></ul><ul><li>IL-6 Stimulate osteoclasts and T cell differentiation. </li></ul>Cytokines in Periodontal Inflammation
  140. 150. Circukating and local Interleukin 1-  levels (Lemus, C., & Haake, S.) <ul><li>Periodontitis Group Health Group </li></ul><ul><li>Serum IL-1  2,55pg/ml 0.76 pg/ml </li></ul><ul><li>Gingival fluid 5.96 pg/ml` 0.42 pg/ml </li></ul>
  141. 151. Chronic bacterial infections including periodontal disease also increase circulating C Reactive Substance
  142. 152. <ul><li>C Reactive substance is a marker for inflammation and is predictive of future myocardial infarction and stroke. </li></ul><ul><li>Periodontitis patients have increased levels of C Reactive Substance. </li></ul>
  143. 153. 543 Healthy men who developed MI or stroke compared to controls C Reactive protein MI or stroke 1.51 mg/l Controls 1.13 mg/l High versus lowest quartile of C-Reactive protein had risk factor for MI 2.9
  144. 154. Bacteria from the oral cavity and dental plaque can stimulate platelet aggregation.
  145. 155. Streptococcus sanguis expresses a cell wall bound protein (PAAP) that induces activation and aggregation of platelets. PAAP contains a collagen-like platelet interactive domain in a 23 kDa protein fragment. This explains similar platelet effects of collagen and PAAP as well as their immunologic cross reactivity. Erickson, P.R. et. Al. J. Biol. Chem 1993 268:1646
  146. 156. Strep Sanguis isolated from infective endocarditis has an adhesin identified by monoconal antibody, which binds to platelets and hydroxy apatite. This adhesin is common in a variety of Viridans group of streptococci, similar findings with P. Gingivalis reported at American Society for Microbiology 1994 <ul><li>Song K.E., Ouyang T., Herzberg M.C. </li></ul><ul><li>Infect. Immun. 1998, 66: 5388 </li></ul>
  147. 157. Effects of oral flora on platelets: Possible consequences in cardiovascular disease <ul><li>Herzberg, M. Mayer, M. W. </li></ul><ul><li>J . Periodont. 1996 67:1138 </li></ul>
  148. 158. In rabbits S. Sanguis caused platelet aggregation. Hearts had ischemic areas. Infusion of S. Sanguis caused changes in electrocardiogram, blood pressure, heart rate and cardiac contractility all dose dependant and all related to early signs of myocardial infarction.
  149. 159. Hyperlipedemia caused increased cardiac effects ofS. Sanguis. Also have seen similar effects in platelets with P. Gingivalis.
  150. 160. Inoculation of Strep Sanguis Strain 133-79 caused cardiac contractility to fall 60% Strep Sanguis Strain L47 does not affect platelets gave no cardiac changes when inoculated into rabbits
  151. 161. Rabbits on high fat diet with hypercholesterolemia In vitro platelet aggregation response to strain 133-79 accelerated over that seen on normal diet
  152. 162. Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
  153. 163. HYPERTENSION
  154. 164. Hypertension increase chance of endothelial injury
  155. 165. Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
  156. 166. HOMOCYSTEINE
  157. 167. High levels of the Amino acid homocysteine increase risk of coronary artery disease by being toxic to endothelium.
  158. 168. Folic acid vitamin B6, B12 reduce levels of homocysteine
  159. 169. Hyperhomocysteinema odds ratio CHD 1.7 In 28,263 post menopausal women 3 year follow up those with top quartile homocysteine twice the risk of Myocardial infarction or stroke. Suggested supplement intake of 0.4mg folic acid, 2  g vit B6 vit B12
  160. 170. Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
  161. 171. SMOKING
  162. 172. Toxic factors in cigarette smoke increase risk endothelial injury
  163. 173. Smokers 2.5 times more likely to have heart attack
  164. 174. Hypertension Homocysteine Bacteria Smoking Diabetes Initiators of Endothelial Dysfunction
  165. 175. DIABETES
  166. 176. Hyperglycemia causes endothelial dysfunction by a number of mechanisms including inhibition of endothelial derived nitric oxide which reduces the ability of vessel to respond with vasodilation <ul><li>Consentino, F. et. al. Cardiovasc. Pharmacol. 1998 32 suppl 3:s54. </li></ul>
  167. 177. Diabetes increase risk of atheroma because of hyperlipemia
  168. 178. Diabetes has high triglycerides And low HDL
  169. 179. Low density lipids can initiate endothelial dysfunction and monocyte attachment. LDL’s also interact with periodontal inflammation.
  170. 180. Antioxidants increase resistance of LDL to oxidation. Vitamin E reduces risks of atheroma production
  171. 181. Risk of CVD and MI reduced 77% with 800 IU tocopherol 400 IU gave a 47% reduction
  172. 182. Vitamin E has little or no effect on established atheroma
  173. 183. Association between Periodontitis and Hyperlipidemia: Cause or Effect? <ul><li>Cutler C.W et al </li></ul><ul><li>Periodontol 1999 12:1429 </li></ul>
  174. 184. 51 subjects, 26 with chronic adult periodontitis, 25 healthy controls looked at triglycerides, cholesterol, antibodies against P. Gingivalis and L.P.S. and periodontal status.
  175. 185. Relationship with Periodontal Disease and other variables <ul><li>odds ratio </li></ul><ul><li>Age > 50 years 3.5 </li></ul><ul><li>Serum triglyceride > 100mg/dl 8.6 </li></ul><ul><li>Serum cholesterol > 200mg/dl 7.0 </li></ul><ul><li>LPS Reactivity > 2 bands 40.8 </li></ul><ul><li>Elisa titre > 60 Eu 35.0 </li></ul>Cutler et al
  176. 186. Also did in vitro study to see effect of triglycerides on release of IL1 beta from p.m.n.s.
  177. 187. Interleukin 1 beta secretion by PMNS from healthy patients <ul><li>PMN 2.0 </li></ul><ul><li>PMN + P.g. L.P.S 24 </li></ul><ul><li>PMN+ triglycerides 2.3 </li></ul><ul><li>PMN +LPS + TG 35 </li></ul>Cutler et al.
  178. 188. Short term high fat diet impairs antibacterial function of p.m.n.s hyperlipidemia can modulate release of cytokines and growth factor from rat macrophages and monocytes. Cytokines IL1 beta and TNF alpha promote hyperlipidemia.
  179. 189. Pathophysiological relationships between periodontitis and systemic disease: Recent concepts involving serum lipids <ul><li>Iacopino A.M, Cutler C.W. </li></ul><ul><li>J. Periodont. 2000. 71:1375 </li></ul>
  180. 190. Periodontitis induced changes in immune cell functions causes metabolic dysregulation of lipid metabolism involving cytokines.
  181. 191. From periodontitis elevated serum IL-1ß and TNF change lipid metabolism so get hyperlipidemia.
  182. 192. The elevated lipids in diabetes and periodontitis also increases monocytic responsiveness and pmn activity so get increased cytokine production and further periodontal disease.
  183. 193. Recommended levels of LDL <ul><li>1 or more risk factor < 160mg / ml </li></ul><ul><li>2 or more risk factor < 130mg / ml </li></ul><ul><li>Presence of atherosclerosis or </li></ul><ul><li>Diabetes < 100 mg /ml </li></ul>
  184. 194. Recommended levels of HDL >35 mg/ml
  185. 195. High cholesterol >200mg/ml with LDL >130 mg/ml increases risk of heart attack 2.4 times
  186. 196. Harvard Study, Dr. W.C. Taylor Used data from MR FIT trail for persons without risk factors such as smoking or hypertension. “We calculate a gain in life expectancy of 3 days to 3 months from a lifelong program of cholesterol reduction.”
  187. 197. Dr J. Stamler Northwestern University Study of 361,662 young and middle aged men. Top 20% of cholesterol levels three times more likely to die of coronary artery disease than lowest 20% but general mortality not so dramatic. Cholesterol level % living at 7 years 202mg/dl or less 97.8 203 to 244mg/dl 97.3 245mg/dl or more 96.2
  188. 198. Cholesterol Reducing Drugs Inhibit Synthesis of Cholesterol. Up-Regulate Nitric Oxide Sinthetase <ul><li>LIPITOR ( ATORVASTATIN) </li></ul><ul><li>MEVACOR( LOVASTATIN) </li></ul><ul><li>ZOCOR (SIMVASTATIN) </li></ul><ul><li>PRAVACHOL( PRAVASTATIN) </li></ul><ul><li>REDUCTION OF MI AND GENERAL MORTALITY. </li></ul><ul><li>ALSO IMPROVE VESSEL NARROWING </li></ul>
  189. 199. LOVASTATIN MEVACOR
  190. 200. Dr A Gotto Cornell University Am. J. Cardiol., Dec. 2000 pg. 1176 6,605 healthy adults aged 47 to 73, 5,608 men, 997women, Lovastatin or Placebo plus low saturated fat low cholesterol diet followed for 5-2 years. LDL 130-190 mg/dl HDL less than 45 mg/dl triglycerides less than 400mg/dl 12% smokers, 22% hypertensive, 2% diabetic Average Total Cholesterol 221mg/dl LDL 150mg/dl HDL 37mg/dl Total Cholesterol fell 18.4% LDL fell 25% HDL fell 15% Reduction in sudden death, heart attack, unstable angina 36% Reduction in need for angioplasty 33% Reduction in hospitalization for angina 34%
  191. 201. Alcohol 1 to 2 glasses a day reduces cholesterol, reduces clotting
  192. 202. One to two drinks of alcohol per day gives 30-50 percent reduction in CHD in men. Maybe due to increase levels of HDL, or to blood clotting reduction
  193. 203. Aspirin inhibits platelet aggregation
  194. 204. Aspirin 325 mg every other day for 4.5 years 22000 male MDs <ul><li>Aspirin 194 MI 5 deaths </li></ul><ul><li>Controls 189 MI 18 deaths </li></ul>
  195. 205. 2418 Israeli women 100 to 500 mg Aspirin every other day for 3 years <ul><li>40% less MI mortality </li></ul><ul><li>34% less general mortality </li></ul>
  196. 206. Early infarct affecting left ventricle thrombus
  197. 207. Cross section of heart with area of necrosis
  198. 208. Infarct in ventricular wall with loss of muscle and scarring
  199. 209. Area of previous infarct with rupture of ventricular wall
  200. 210. Histology of Myocardial Infarction
  201. 211. Normal heart muscle
  202. 212. Beginning of infarct, loss of striations and nuclei of cardiac muscle
  203. 213. Continued loss of cellular vitality of myocardium
  204. 214. Myocardial infarct with replacement of necrotic myocardium with inflammatory cells and fibroblasts
  205. 215. Established infarct with fibrotic scarring in myocardium
  206. 216. Systematic review of the association between respiratory diseases and oral heaith. Azarpazhooh. A. J. PERIODONT.2006.77:1465.
  207. 217. Association between oral health and pneumonia odds ratio 1.2 to 9.6. Good evidence of value of periodontal initial therapy in treatment of respiratory diseases in high risk elderly .
  208. 218. FURTHER READING CLINICAL PERIODONTOLOGY 10 th EDITION CHAPTER 18

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