1 TARRSON FAMILY ENDOWEDCHAIR IN PERIODONTICS

2 UCLA School of Dentistry

3 Presents Dr. E. Barrie Kenney Professor & Chairman Section of Periodontics

4 Periodontal Disease as a Predictor of AtherosclerosisE. 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 Coronary Artery Disease

6 Epidemiological connection between coronary artery disease and periodontal disease

7 6.9 Million people have coronary heart disease in USA

8 Atherosclerosis Leading Cause of Death in USA

9 Coronary Artery Disease (C. A. D) kills 500,000 people a yearCoronary Artery Disease (C.A.D) kills 500,000 people a year. One of every 4.6 deaths due to C.A.D

10 Periodontal Disease in the United States54% of U.S. population 13 years and older has gingival bleeding on probing In adults an average 19.6% of teeth have periodontal attachment loss of 3mm or more Based on data from NHANES III survey

11 Association between dental health and acute myocardial infarctionMatilla KJ et al Brit. Med. J : 774

12 Used index based on caries, periodontal disease, periapical lesions, pericoronitis.Patients admitted for acute myocardial infarction had higher scores than matched controls.

13 Patients above the upper quartile had twice the risk of acute myocardial infarction than did those with a score of zero.

14 This was comparable to risk of cigarette smoking, hypercholesterolemia and hypertension.

15 Dental Disease and Risk of Coronary Heart Disease and MortalityDe Stefano F et al Brit. Med. J. 1993, 306: 688

16 Analyzed data from National Health and Nutrition examination study I20,249 subjects aged 25 to 74 followed up in 1982 – (only 55 years and older at entry) and 1986 – 1987.

17 Excluded subjects with history of heart disease stroke or cancerExcluded 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 Admitted for Coronary Artery Disease or died of Coronary Artery Disease as indicators of disease

19 Dental evaluation at baselineNumber of carious teeth 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.

20 Percentage of subjectsNo No Disease Gingivitis Periodontitis Tooth death from CHD admission for CHD De stefano

21 ODDS Ratios Risk Women Men Factors 25-49 Mortality 25-49No disease Gingivitis Periodontitis No teeth Periodontal index Oral hygiene index adjusted for age, sex education, poverty level, marital status, blood pressure, cholesterol, diabetes, weight, physical activity, alcohol, smoking De Stefano

22 Analysis of these with data on smoking showed the same pattern.

23 No association between active caries and CHD

24 Periodontal Disease and Coronary Heart Disease RiskHujoel P.P., et al J.A.M.A. 2000, 284:1406

25 Used NHANES population 8032 dentate adults aged 25 to 74 years with no history of cardiovascular disease had periodontitis, 2421 had gingivitis, 3752 healthy. Russel index used. Subjects with prior history of cardiovascular disease eliminated.

26 At follow up 1265 subjects had at least 1 coronary heart disease event, either death, hospitalization or coronary revascularization therapy.

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 Periodontitis Gingivitis HealthyDiabetes 5.2% 2.7% 2.0% Alcohol glass per day Pack years smoking Total cholesterol Age Male 50.4% 38.4% 30.5% White 70.2% 77.5% 88.7% African American 28.0% 21.1% 10.4% Education years Hujoel et al.

29 Hazard Ratios Compared to HealthyUnadjusted Adjusted for Confounders periodontitis gingivitis

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 Oral Health and Systemic Disease: Periodontitis and Cardiovascular DiseaseBeck J.D. Offenbacher S. J. Dent. Edu. 1998, 62:859

32 Odds ratio with more or less sites p.d > 3mmCHD Fatal Stroke CHD 3·1 2·8 1·9 1147 Male Veterans from Boston Beck

33 Number of sites with 20% or more bone lossODDS Ratio for CHD Beck et al

34 Periodontal Disease and prevalent Coronary Heart Disease in the ARIC studyBeck J.D et al J. Dent. Res abst. #2269

35 ODDS Ratio for C.H.D. per cent sites with attachment loss 3mm or more Males Females 0 – 6.5 – 15.2 – 31.1 –

36 Atherosclerosis Risk in Communities study 13. 6% of males 5Atherosclerosis Risk in Communities study 13.6% of males 5.5% of females had coronary heart disease

37 Matthaner, S. S. et al. J. Periodontol 73:1169 2002Investigation of the Association Between Angiographically Defined Coronary Artery Disease and Periodontal Disease Matthaner, S. S. et al. J. Periodontol 73:

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 53 CAD +ve 83% male average 65.3 years 47 CAD -ve 40.4% male average 60.8 years All non diabetics, non smokers for at least 5 years CAD +ve 66% former smokers 15.8 pack years CAD -ve 24.4% former smokers 4.5 pack years Matthaner,

39 CAD +ve CAD -ve Sites with CAL>6mm 6.85 3.32 Radiographic bone loss 3.60mm 3.18mm Mean probing depth 2.67mm 2.59mm Tooth loss When corrected for age previous smoking history Odds ratio Mean CAL Odds ratio CAL>6mm Odds ratio Radiographic bone loss Odds ratio Mean probing depth These patients had minimal periodontal disease so CAL may be recession or pocket related Matthaner,

40 Hyman, J. J. et al. J. Periodontol 73:988 2002Ratio of Cigarette Smoking in the Association Between Periodontal Disease and Coronary Heart Disease Hyman, J. J. et al. J. Periodontol 73:

41 5285 Subjects from NHANES 1988-94, 40 years or olderLoss of Attachment Odds ratio for heart attack history mm 2.64 mm 3.84 4mm or more 5.87 Hyman,

42 Oral Health and Peripheral Arterial DiseaseHung, H.C. et al Circulation 2003:107:1152 45,136 male health workers free of cardiovascular disease followed for 12 years. 342 cases of peripheral arterial disease. Patient repords and diagnosis or treatment of claudication of leg arteries. Self report of periodontal disease

43 Odds Ratio Peripheral Cardiovascular Disease AndPeriodontal Disease Tooth Loss Periodontal Disease & Tooth Loss 1.88 No Periodontal Disease and Tooth Loss Controlled for traditional risk factors for cardiovascular disease. Hung, H.C. et al

44 Holmlund. A. et al J. Periodontol 2006 77: 1173Severity 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 : 1173

45 Odds Ratio Periodontal bone loss And Myocardial InfarctionPeriodontal Disease Smoking Gender Age Controlled for traditional risk factors for cardiovascular disease.Aged 40 to 60 years old.

46 TREATMENT OF PERIODONTITIS AND ENDOTHELIAL FUNCTIONTREATMENT 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 AT 1 DAY INTENSIVE GROUP LOWER VESSEL DILATION THAN PROPHY GROUP AT 60 , 180 DAYS INTENSIVE GREATER DILATION THAN PROPHY ENDOTHELIAL FUNCTION IMPROVEMENTS CORRELATED WITH PERIODONTAL TREATMENT SUCCESS

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 10 ARTERIES --VE, 14 +VE FOR 1 PERIO BACTERIA10 ARTERIES --VE, 14 +VE FOR 1 PERIO BACTERIA. 10 +VE FOR 2, 2+VE FOR 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 Coronary Artery Disease In Women

50 J. Women’s Health and Gender related Med. 9:235,2000Lipid management and control of other coronary risk factors in post menopausal women J. Women’s Health and Gender related Med. 9:235,2000

51 Stroke and myocardial infarction Number one killer of women with 500,000 deaths per year

52 African American and Hispanic women at greater risk than Caucasian women

53 This is more than the next 16 causes of death combined

54 Risk of Myocardial infarction lower in women than men

55 First myocardial infarction in women is more severe and more lethal than they are in men

56 Women’s mortality rate at 6 months post myocardial infarction double that of men

57 Analysis of 350,000 patients after fibrinolytic therapy for infarctionAnalysis of 350,000 patients after fibrinolytic therapy for infarction. Mortality for women 9.3%, men 4.5%

58 Without fibrinolytic therapy16% mortality for women 10.9% for men

59 Coronary artery bypass surgery operative mortality 4. 5% women, 2Coronary artery bypass surgery operative mortality 4.5% women, 2.6% men

60 Menopause often causes increase in total cholesterol and LDL

61 Estrogen increase HDL levels

62 Post menopausal hormonal therapy gave 53% reduction in death from CHD in study using 121,700 registered nurses

63 Framingham Study. Risk of coronary artery disease doubles with onset of menopause

64 Cardiovascular Disease During 6.9 Years of Hormone Therapy20 centers with 2,763 post menopausal with C.H.D. average age 67 years. Hormone group got mg conjugated estrogen, 2.5mg medroxyprogesterone acetate daily. Hormones gave no significant decrease in C.H.D. events - infarct or death hospitalization angina revascularization, congestive heart failure, stroke, ischemia or ventricular arrhythmia Another study on same population showed hormone group had increased rated of venous thrombo-embolism and biliary tract surgery. 261 deaths compared to 239 in controls Grady, D. et al JAMA 2002, 288:49

65 ESTROGEN GROUP SCORE 83.1 CONTROL GROUP SCORE 123.1ESTROGEN THERAPY AND CORONARY ARTERY CALCIFICATION. MANSON, J. E. et al NEJM : 2591 1064 WOMEN 50 TO 59 YEARS OLD AFTER HYSTERECTOMY RANDOMLY GOT ESTROGEN PER DAY OR PLACEBO EVALUATED CORONARY ARTERY CALCIFICATION ESTROGEN GROUP SCORE CONTROL GROUP SCORE

66 Periodontal flap surgery to treat periodontitisPeriodontal flap surgery to treat periodontitis. Note loss of crestal bone.

67 Periodontitis. Histopathologyof intrabony defect showing bone resorption (yellow), inflammation (green) and epithelial proliferation (white).

68 Pathogenesis of Atheroma1. Fatty streak development 2. Atheromatous plaque development 3. Thrombus development

69 Fatty streak development

70 Dr. Enos and Holmes reported on autopsis of 2000 dead soldiers in Korean War average age 22.35% had fatty streaks in coronary arteries 42% had had established atheroma

71 Average adult Aorta, mild fatty streaks, early atheroma.

72 Aorta. Arrow at prominent fatty streak

73 Initiation of atheroma by damage to endothelium which becomes more porous to lipids and monocytes

74 Monocytes from blood stream pass through endothelium into blood vessel wall

75 Healthy Coronary Artery cross section

76

77

78 Initiators of Endothelial DysfunctionBacteria Hypertension Homocysteine Smoking Diabetes Initiators of Endothelial Dysfunction

79 Coronary Artery DiseaseOxidized LDL Coronary Artery Disease Cytokines Glycolated end products Initiation of Monocyte attachment with activation of endothelial transcription nuclear factor Kb (TNF-Kb) by oxidized low density lipids, cytokines, and glycolated end products seen in diabetes.

80 Vascular cell wall adhesion molecule (VCAM-1) is induced by TNF-Kb

81 Vascular cell wall adhesion molecule (VCAM-1) is induced by TNF-KbVACM-1 VACM-1 Vascular cell wall adhesion molecule (VCAM-1) is induced by TNF-Kb

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

83 Low Density Lipids (LDL) pass through damaged endothelium into blood vessel wall

84 Coronary Artery DiseaseLDLO LDLO LDLO LDLO LDL O Coronary Artery Disease LDLO LDLO LDLO LDLO LDL O LDLO LDLO LDLO LDL LDLO O Low density lipids (LDL) oxidized in vessel wall

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.

86 LDLO MMP Prostaglandins Cytokines LDLO Cytokines LDLO MMP

87 Monocytes transform to macrophages and take up LDL to form foam cells

88

89 Monocytes trigger chronic inflammatory reaction with lymphocytes and this results in tissue necrosis and fibrosis

90 LDLO MMP Prostaglandins Cytokines LDLO Cytokines LDLO MMP

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

92 High Density Lipids (HDL) inhibit oxidation of LDL

93 High Density Lipids (HDL)HDL are a heterogeneous lipoproteins produced in the liver and small intestine. HDL contains 70% phospholipid and protein, 25% cholesterol, 5% triglycerides. HDL has 2 antioxidant enzymes Paraoxonase Platelet activating factor acetyl hydrolase Apolipoprotein A-1 stabilizes paraoxonase

94 Enzymes associated with HDL apolipoproptein (apoAL) and para-oxenase (PON) protect by destroying the oxidized pro-inflammatory lipids from LDL

95 PON also inhibits LDL induced Monocyte MigrationPON 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.

96 HDL O LDL HDL O LDL HDL LDL O

97 O LDL HDL LDL HDL LDL HDL O

98 ATHEROMATOUS PLAQUE DEVELOPMENT

99 Blood vessel wall becomes distended and continues to accumulate cholesterol, some areas become calcified

100 Coronary artery with atheromatous plaques (arrows)

101 THROMBUS DEVELOPMENT

102 Coronary Artery with stable atheromaCoronary Artery with stable atheroma. Inflamation and necrosis have replaced the smooth muscle but there is a dense layer of collagen next to lumen (arrows)

103 Bacterial Proteases MMP MMP MMP MMP MMP MMP MMP MMP MMP MMP MMP MMP MMP s from macrophages and proteases from circulating bacteria can destroy collagen to form an unstable atheromatous plaque

104 Blood vessel wall can rupture and then get thrombus formed at region of ulceration

105 Endothelium is destroyed with exposure of collagen and plaque to arterial blood.

106 Coronary Artery DiseasePlatelets aggregate on exposed collagen to form a thrombus.

107 Thrombus formation

108 Oral Bacteria Circulating oral bacteria have peptides that cause platelet aggregation

109 Increase thrombosis can lead to sudden occlusion of vessel

110 Coronary Artery occluded by thrombosis

111 Thrombus formation on atheromataous plaqueThrombus formation on atheromataous plaque. Slits of cholesterol crystals seen in vessel wall.

112 Coronary artery with narrowed lumen and thrombosis (arrows)

113 Oral Bacteria

114 Thrombosis can give occlusion of vesselThrombosis can give occlusion of vessel. This is responsible for 50% of cases of myocardial infarction

115 lumen Calcification (blue area) and distended vessel wall with narrowed lumen of Coronary Artery.

116 Ultrafast CAT Scan of Thorax Showing Cross-Section of HeartUltrafast CAT Scan of Thorax Showing Cross-Section of Heart. Calcified Tissues Stained Pink. Note: Calcified Atheromatous Plaques in Coronary Arteries

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123 BACTERIA

124 Bacteria 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.

125 Gram negative bacteria or LPS given systemically can give following changes in major blood vesselsinflammatory cell infiltrate smooth muscle proliferation fatty degeneration intravascular coagulation

126 Gram Negative Bacterial InfectionsChlamydia pneumonie CHD risk factor 2.3 Heliobactor pylori MI risk factor 1.3 Chlamydia also seen in fatty streaks and atheroma plaques at autopsy

127 CORRELATION BETWEEN ATHEROSCLEROSIS AND PERIODONTAL PUTATIVE PATHOGENIC BACTERIA IN CORONARY AND INTRENAL MAMMARY ARTERIES PUCAR A M ILASIN J LEKOVIC V KENNEY E B ET AL . IN PRESS J. PERIODONTOL.

128 15 PATIENTS AT SURGERY TOOK CORONARY AND INTERNAL MAMMARY ARTERY SECTIONS9 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

129 Identification of Pathogens in Atheromatous PlaquesHaraszthy V.I et al J. Dent. Res. 1998:

130 Looked at bacterial DNA in 27 Atheromatous Coronary Vessels obtained during endarterectomy 19 were positive. A. actinomycetemcomitans 6 cases P. Gingivalis 6 cases P. Intermedia 7 cases

131 Frequency and Distribution of Periodontal Pathogens in the Atheromas of Coronary Arteries.Meyers G.S. Balint Orban Competition AAP Annual Meeting September 2000

132 Used PCR to detect bacterial D. NUsed PCR to detect bacterial D.N.A in atheromatous coronary vessels from 42 post mortems % of atheromas had bacterial D.N.A from periodontal pathogens.

133 Frequency A. actinomycetemcomitans 29% B. Forsythus 24%P. Gingivalis 0% P. Intermedia 2% F. Nucleatum 29%

134 CAROTID ARTERY.POSITIVE FOR P. GINGIVALIS

135

136 ELECTRO N MICROGRAPH OF MACROPHAGE

137 GRAM NEGATIVE BACTERIA IN MACROPHAGE

138 Progulske-Fox, A. et.al. J. Dent. Res. 1999, 34:393Other periodontal bacteria such as, Porphyromonas gingivalis have also been shown to infect endothelial cells. Progulske-Fox, A. et.al. J. Dent. Res. 1999, 34:393

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.)

140 Bacterial Involvement in AtheromaPeriodontal 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. Dorn, B.R. et.al. Infect. Immun :5792 Eikenella corrodens Porphyromas gingivalis and Prevotella intermedia invaded human coronary artery endothelial and smooth muscle cells in culture. Lee J.K. et.al. Invasion of human endothelial cells by Fuscobacterium nucleatum J. Dent. Res. 81-A

141 CORRELATION BETWEEN ATHEROSCLEROSIS AND PERIODONTAL PUTATIVE PATHOGENIC BACTERIAL INFECTIONS IN CORONARY AND INTRNAL MAMMARY ARTERIES . PUCAR A , KENNEY EB et al J. PERIODONT :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.

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

143 Establishment of a mouse model of infective induced atheroma formationChung H.J. et al J. Dent. Res : #1356

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

145 Mean area of atheroma after 3 weeksP. Gingivalis Mm2 Control broth Mm2 Chung et al

146 TNF and PGE levels in chamber were correlated with area of atheroma TNF associated with serum cholesterol. Cholesterol associated with area of atheroma.

147 Bacterial induced periodontal disease increases circulating cytokines which can accentuate inflammation in atheromatous vessels.

148 Early gingivitis with margin of gingiva showing edema, redness and bleeding on probing.

149 Cytokines in Periodontal InflammationIL1ß Recruits inflammatory cells. Stimulates PMNS increased synthesis of prostaglandin and metallo proteinases (MMP). Inhibits collagen synthesis. Activates B and T lymphocytes TNF alpha Stimulates apoptosis, bone resorption, MMP and IL-6 production. IL-6 Stimulate osteoclasts and T cell differentiation.

150 Circukating and local Interleukin 1-b levels (Lemus, C., & Haake, S.)Periodontitis Group Health Group Serum IL-1b 2,55pg/ml 0.76 pg/ml Gingival fluid 5.96 pg/ml` 0.42 pg/ml

151 Chronic bacterial infections including periodontal disease also increase circulating C Reactive Substance

152 C Reactive substance is a marker for inflammation and is predictive of future myocardial infarction and stroke. Periodontitis patients have increased levels of C Reactive Substance.

153 543 Healthy men who developed MI or stroke compared to controls C Reactive protein MI or stroke 1.51 mg/l Controls mg/l High versus lowest quartile of C-Reactive protein had risk factor for MI 2.9

154 Bacteria from the oral cavity and dental plaque can stimulate platelet aggregation.

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 :1646

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 Song K.E., Ouyang T., Herzberg M.C. Infect. Immun. 1998, 66: 5388

157 Effects of oral flora on platelets: Possible consequences in cardiovascular diseaseHerzberg, M. Mayer, M. W. J. Periodont :1138

158 In rabbits S. Sanguis caused platelet aggregationIn 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.

159 Hyperlipedemia caused increased cardiac effects ofS. SanguisHyperlipedemia caused increased cardiac effects ofS. Sanguis. Also have seen similar effects in platelets with P. Gingivalis.

160 Inoculation of Strep Sanguis Strain caused cardiac contractility to fall 60% Strep Sanguis Strain L47 does not affect platelets gave no cardiac changes when inoculated into rabbits

161 Rabbits on high fat diet with hypercholesterolemia In vitro platelet aggregation response to strain accelerated over that seen on normal diet

162 Initiators of Endothelial DysfunctionBacteria Hypertension Homocysteine Smoking Diabetes Initiators of Endothelial Dysfunction

163 HYPERTENSION

164 Hypertension increase chance of endothelial injury

165 Initiators of Endothelial DysfunctionBacteria Hypertension Homocysteine Smoking Diabetes Initiators of Endothelial Dysfunction

166 HOMOCYSTEINE

167 High levels of the Amino acid homocysteine increase risk of coronary artery disease by being toxic to endothelium.

168 Folic acid vitamin B6, B12 reduce levels of homocysteine

169 Hyperhomocysteinema odds ratio CHD 1Hyperhomocysteinema 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, 2mg vit B6 vit B12

170 Initiators of Endothelial DysfunctionBacteria Hypertension Homocysteine Smoking Diabetes Initiators of Endothelial Dysfunction

171 SMOKING

172 Toxic factors in cigarette smoke increase risk endothelial injury

173 Smokers 2.5 times more likely to have heart attack

174 Initiators of Endothelial DysfunctionBacteria Hypertension Homocysteine Smoking Diabetes Initiators of Endothelial Dysfunction

175 DIABETES

176 Consentino, F. et. al. Cardiovasc. Pharmacol. 1998 32 suppl 3:s54.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 Consentino, F. et. al. Cardiovasc. Pharmacol suppl 3:s54.

177 Diabetes increase risk of atheroma because of hyperlipemia

178 Diabetes has high triglycerides And low HDL

179 Low density lipids can initiate endothelial dysfunction and monocyte attachment. LDL’s also interact with periodontal inflammation.

180 Antioxidants increase resistance of LDL to oxidationAntioxidants increase resistance of LDL to oxidation. Vitamin E reduces risks of atheroma production

181 Risk of CVD and MI reduced 77% with 800 IU tocopherol 400 IU gave a 47% reduction

182 Vitamin E has little or no effect on established atheroma

183 Association between Periodontitis and Hyperlipidemia: Cause or Effect?Cutler C.W et al Periodontol :1429

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.

185 Relationship with Periodontal Disease and other variablesodds ratio Age > 50 years 3.5 Serum triglyceride > 100mg/dl 8.6 Serum cholesterol > 200mg/dl 7.0 LPS Reactivity > 2 bands 40.8 Elisa titre > 60 Eu Cutler et al

186 Also did in vitro study to see effect of triglycerides on release of IL1 beta from p.m.n.s.

187 Interleukin 1 beta secretion by PMNS from healthy patientsPMN + P.g. L.P.S 24 PMN+ triglycerides 2.3 PMN +LPS + TG 35 Cutler et al.

188 Short term high fat diet impairs antibacterial function of p. m. nShort 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.

189 Pathophysiological relationships between periodontitis and systemic disease: Recent concepts involving serum lipids Iacopino A.M, Cutler C.W. J. Periodont :1375

190 Periodontitis induced changes in immune cell functions causes metabolic dysregulation of lipid metabolism involving cytokines.

191 From periodontitis elevated serum IL-1ß and TNF change lipid metabolism so get hyperlipidemia.

192 The elevated lipids in diabetes and periodontitis also increases monocytic responsiveness and pmn activity so get increased cytokine production and further periodontal disease.

193 Recommended levels of LDL1 or more risk factor < 160mg / ml 2 or more risk factor < 130mg / ml Presence of atherosclerosis or Diabetes < 100 mg /ml

194 Recommended levels of HDL >35 mg/ml

195 High cholesterol >200mg/ml with LDL >130 mg/ml increases risk of heart attack 2.4 times

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.”

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 to 244mg/dl mg/dl or more 96.2

198 Cholesterol Reducing Drugs Inhibit Synthesis of CholesterolCholesterol Reducing Drugs Inhibit Synthesis of Cholesterol. Up-Regulate Nitric Oxide Sinthetase LIPITOR ( ATORVASTATIN) MEVACOR( LOVASTATIN) ZOCOR (SIMVASTATIN) PRAVACHOL( PRAVASTATIN) REDUCTION OF MI AND GENERAL MORTALITY. ALSO IMPROVE VESSEL NARROWING

199 LOVASTATIN MEVACOR

200 Dr A Gotto Cornell University Am. J. Cardiol. , Dec. 2000 pgDr A Gotto Cornell University Am. J. Cardiol., Dec pg ,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 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%

201 Alcohol 1 to 2 glasses a day reduces cholesterol, reduces clotting

202 One to two drinks of alcohol per day gives percent reduction in CHD in men. Maybe due to increase levels of HDL, or to blood clotting reduction

203 Aspirin inhibits platelet aggregation

204 Aspirin 325 mg every other day for 4.5 years 22000 male MDsAspirin 194 MI deaths Controls 189 MI 18 deaths

205 2418 Israeli women 100 to 500 mg Aspirin every other day for 3 years40% less MI mortality 34% less general mortality

206 Early infarct affecting left ventriclethrombus Early infarct affecting left ventricle

207 Cross section of heart with area of necrosis

208 Infarct in ventricular wall with loss of muscle and scarring

209 Area of previous infarct with rupture of ventricular wall

210 Histology of Myocardial Infarction

211 Normal heart muscle

212 Beginning of infarct, loss of striations and nuclei of cardiac muscle

213 Continued loss of cellular vitality of myocardium

214 Myocardial infarct with replacement of necrotic myocardium with inflammatory cells and fibroblasts

215 Established infarct with fibrotic scarring in myocardium

216 Systematic review of the association between respiratory diseases and oral heaith. Azarpazhooh. A. J. PERIODONT :1465.

217 Association between oral health and pneumonia odds ratio 1. 2 to 9. 6Association 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.

218 FURTHER READING CLINICAL PERIODONTOLOGY 10 th EDITION CHAPTER 18