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Periodontal Disease/Infection and Cardiovascular Disease Maurizio Trevisan, MD MS.

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1 Periodontal Disease/Infection and Cardiovascular Disease Maurizio Trevisan, MD MS

2 The size of the potential problem  Periodontitis Leading cause of tooth loss Leading cause of tooth loss 49,000,000 Americans have some form of “gum disease”49,000,000 Americans have some form of “gum disease”  Cardiovascular Disease Leading cause of death and disability Leading cause of death and disability 13,000,000 Americans have CHD13,000,000 Americans have CHD 5,500,000 Strokes5,500,000 Strokes

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5 Is there a link ?

6 The Bradford Hill Criteria 1: Strength of Association 2: Temporality 3: Consistency 4: Theoretical Plausibility 5: Coherence 6: Specificity in the causes 7: Dose Response Relationship 8: Experimental Evidence 9: Analogy Is there a link?

7 Dental Health in two series of patients with MI and their matched controls as indicated by total dental index, pantomography index, and no teeth. Series 1 Series 2 Patients(n=40)Controls(n=40)Patients(n=65)Controls(n=65) Median Total Dental Index 4264 Median Pantomography Index 2063 No. (%) with artificial teeth 4(10)17(28)6(10) Mattila KJ et al. BMJ 298: ; 1989

8 PD and CVD a Systematic review Linda L. Humphrey, Rongwei Fu, David I. Buckley, Michele Freeman, Mark Helfand J Gen Intern Med December; 23(12): 2079–2086

9 Relative Risk for Cerebrovascular Disease According to Periodontal Disease Status : NHANES I Follow-up Wu T. Trevisan M. Genco RJ. Dorn JP. Falkner KL. Sempos CT Archives of Internal Medicine. 160(18): , 2000.

10 The Bradford Hill Criteria 1: Strength of Association 2: Temporality 3: Consistency 4: Theoretical Plausibility 5: Coherence 6: Specificity in the causes 7: Dose Response Relationship 8: Experimental Evidence 9: Analogy Is there a link?

11 Incidence of CHD (total) by Level of Oral Bone Loss The Dental Longitudinal Study Age adjusted level of bone loss % < 20% 20-40% > 40% None Beck et al J Periodontol :

12 The Bradford Hill Criteria 1: Strength of Association 2: Temporality 3: Consistency 4: Theoretical Plausibility 5: Coherence 6: Specificity in the causes 7: Dose Response Relationship 8: Experimental Evidence 9: Analogy Is there a link?

13 Danesh J. Coronary heart disease, Helicobacter pylori, dental disease, Chlamydia pneumoniae, and cytomegalovirus: meta-analyses of prospective studies. American Heart Journal. 138(5 Pt 2):S434-7, 1999

14 Periodontal Disease and CVD The role of gender

15 Odds Ratios of the association between PD and incident MI in men and women. MYLIFE STUDY Gender Periodontal measures Unadjusted OR (95% CI) Adjusted # OR (95% CI) Men (n=828; cases =443) CAL (mm) 1.52 (1.32 – 1.80) 1.36 (1.17 – 1.59) Women (n=633; cases=131) CAL (mm)2.83 (2.11 – 3.80)2.00 (1.42 – 2.80) # : Age, years of education, HBP, cholesterol, diabetes, alcohol drinking status, total cigarette pack-years Andriankaja OM. Genco RJ. Dorn J. Dmochowski J. Hovey K. Falkner KL. Trevisan M. European Journal of Epidemiology. 22(10): , 2007.

16 Periodontal Disease and CVD The role of smoking

17 Odds Ratios of the association between PD and incident MI in smokers and non smokers. MYLIFE STUDY Gender Periodontal measures Adjusted # OR (95% CI) Smokers (n=850; cases =395) CAL (mm) 1.52 (1.29 – 1.80) Non smokers (n=580; cases=160) CAL (mm)1.35 (1.02 – 1.77) # : Age, Gender, years of education, HBP, cholesterol, diabetes, alcohol drinking status, cigarette pack- years # # : Age, Gender, years of education, HBP, cholesterol, diabetes, alcohol drinking status Andriankaja OM. Genco RJ. Dorn J. Dmochowski J. Hovey K. Falkner KL. Trevisan M. European Journal of Epidemiology. 22(10): , 2007.

18 Never Smoker (n=252; events=40) Former Smoker (n=489; events=89) Current Smoker N=143; events=32) Hazard Ratio (CI) CAL (mm) 1.41( )1.00( )1.02( ) CAL ( )0.88( )1.06( ) Periodontal Disease and Death + Recurrent CVD events in MI patients (n=884) Model includes: Age (years), Gender, Education (years) Dorn JM. Genco RJ. Grossi SG. Falkner KL. Hovey KM. Iacoviello L. Trevisan M. Journal of Periodontology. 81(4):502-11, 2010 Apr.

19 1. Probing Pocket Depth (PPD): actual measure of the pocket; distance from the gingival margin to the base of pocket 2. Clinical Attachment Loss (CAL): exposed root surface; distance from CEJ to the base of pocket, **6 sites for each tooth (except 3rd molars) for PPD and CAL. **CAL: use of inter-proximal sites only PD measurements

20 3. Alveolar Crest Height (ACH) = Distance from CEJ to the most coronal part of the inter-proximal alveolar bone crest 4. Missing teeth: Actual number of missing teeth

21 Different Indexes of PD and MI Adjusted OR (95%CI) p value Mean AL (mm) 1.46 ( ) <0.001 Mean PD (mm) 2.19 ( ) <0.001 Mean ACH (mm) 1.30 ( ) <0.001 Missing Teeth (n) 1.04 ( ) <0.01 Adjusted: Age, gender, hypertension, cholesterol, diabetes, total pack-years cig Andriankaja O. Trevisan M. Falkner K. Dorn J. Hovey K. Sarikonda S. Mendoza T. Genco R. Community Dentistry & Oral Epidemiology. 39(2):177-85, 2011 Apr.

22 Linda L. Humphrey, Rongwei Fu, David I. Buckley, Michele Freeman, Mark Helfand J Gen Intern Med December; 23(12): 2079–2086

23 The Bradford Hill Criteria 1: Strength of Association 2: Temporality 3: Consistency 4: Theoretical Plausibility 5: Coherence 6: Specificity in the causes 7: Dose Response Relationship 8: Experimental Evidence 9: Analogy Is there a link?

24 Proposed Role of Infection in CHD Infection Infection Bacteremia Inflammatory Mediators Immune Responses Liver 1. Platelet aggregation 2. Invasion of endothelium 3. Digestion of matrix CRP, SAA, Fibrinogen,AT 1. Antibodies to bacteria and to cross reactive antigens e.g. HSP 2. T-cells sensitized Pathogens Bacteria or products (e.g. LPS) IL-1, IL-6, TNF  Pathogens Heart

25 Periodontal Infection and CVD  Specific mechanisms linked to specific agent  General mechanisms ?

26 Periodontal Infections and Coronary Heart Disease: The role of periodontal bacteria The Corodont Study Axel Spahr, et al. Archives of Internal Medicine, 166: ; 2006

27 MI cases (N= 386) Controls (N=840) P- value Microorganisms (each type) Pg (Porphyromonas Gingivalis) Bf (Bacteroide Forsythus) PI (Prevotella Intermedia) Cr (Campylobacter Recta) Es (Eubacterium Saburreum) Ss (Streptococcus Sanguis) Cap (Capnocytophaga Sp) Fn (Fusobacterium Nucleatum) 76 (19.7%) 212 (54.9%) 194 (50.3%) 97 (25.1%) 139 (36.0%) 223 (57.8%) 134 (34.7%) 57 (14.8%) 133 (15.9%) 319 (38.0%) 338 (40.3%) 136 (16.2%) 236 (28.1%) 479 (57.0%) 277 (33.0%) 91 (10.8%) 0.10 < Prevalence of different organisms in cases and controls The MY LIFE Study Andriankaja O. Trevisan M. Falkner K. Dorn J. Hovey K. Sarikonda S. Mendoza T. Genco R. Community Dentistry & Oral Epidemiology. 39(2):177-85, 2011 Apr.

28 Association between CA/CO and number of varieties of microorganisms (n= 1125: cases=343; controls =782) Association OR (95%CI) **p-value Micro (increase by one:0 to 5)1.13 ( )0.05 Any micro in 4 ctg (ref = 0) (n= 431 and removing Bf) Any one (n=304)1.62 ( )0.02 Any two (n=198)1.48 ( )0.09 Any three or + (n=192)1.58 ( )0.04 Among micro: Pg, Fn, Cr (Group A: lowest prevalence) (n= 431 and removing Bf) Any one (n=264)1.39 ( )0.11 Any two or all three (n=125)2.03 ( )0.006 Among micro: Pi, Es (Group B: high prevalence) (n= 431 and removing Bf) Any one (n=429)1.45 ( )0.04 All two (n=196)1.68 ( )0.02 Adjusted for age, gender, years of education, BMI, cholesterol, HBP, diabetes, smoking status (never, former, current), lifetime total pack years, # brushing

29 Periodontal Infection and CVD  Inflammation Pathway C Reactive Protein C Reactive Protein

30 Libby P, Ridker PM. Circulation. 1999;100:1148–1150. Inflammatory Pathways in Atherogenesis Primary Proinflammatory Cytokines (eg, IL-1, TNF-α) IL-6 “Messenger” Cytokine ICAM-1 Selectins, HSPs, etc Liver Proinflammatory Risk Factors Endothelium and Other Cells CRP SAA Circulation

31 Risk of High CRP according to PD NHANES III Wu T, Trevisan M, Genco RJ, Falkner KL, Dorn JP, Sempos C. American Journal of Epidemiology. 151(3): pp , 2000 Gingival Bleeding Index Calculus Index

32 CRP (mg/dL)0.47 (0.31)0.61 (0.10)0.02 Fibrinogen (mg/mL)286.5 (22.1)288.4 (21.9)0.61 Factor VII (%)99.7 (7.8)101.0 (7.7)0.36 vWF antigen (%)109.0 (42.6)121.4 (42.3)0.09 t-PA (mg/dL)15.9 (3.1)17.6 (3.1)0.001 sTNF-R1 (pg/mL)1129 (179.8)1092 (126.7)0.22 sTNF-R2 (pg/mL)1656 (270.9)1610 (188.0)0.31 LDL-C (mg/dL)108.5 (20.1)120.0 (14.6)0.001 No PD(n=377) Yes PD(n=91) p Periodontal Disease and CVD Biomarkers: The Health Professionals Study Joshipura KJ. Wand HC. Merchant AT. Rimm EB. Periodontal disease and biomarkers related to cardiovascular disease. Journal of Dental Research. 83(2):151-5, 2004

33 Periodontal Infection and CVD :the role of Inflammation (CRP) Desvarieux M. Demmer RT. Rundek T. Boden-Albala B. Jacobs DR Jr. Sacco RL. Papapanou PN. Periodontal microbiota and carotid intima-media thickness: the Oral Infections and Vascular Disease Epidemiology Study (INVEST). Circulation. 111:576-82, 2005.

34 The Bradford Hill Criteria 1: Strength of Association 2: Temporality 3: Consistency 4: Theoretical Plausibility 5: Coherence 6: Specificity in the causes 7: Dose Response Relationship 8: Experimental Evidence 9: Analogy Is there a link?

35 Wu T. Trevisan M. Genco RJ. Dorn JP. Falkner KL. Sempos CT Archives of Internal Medicine. 160(18): , 2000.

36 The Bradford Hill Criteria 1: Strength of Association 2: Temporality 3: Consistency 4: Theoretical Plausibility 5: Coherence 6: Specificity in the causes 7: Dose Response Relationship 8: Experimental Evidence 9: Analogy Is there a link?

37 Men (n=828; cases = 443) Women (n= 633; cases =131) Adjusted OR (95% CI) p-valueAdjusted OR (95% CI) p-value CAL 2 nd Quartile 3 rd Quartile 4 th Quartile 1.55 (0.96 – 2.49) 2.75 (1.71 – 4.42) 2.73 (1.71 – 4.35) 0.07 <0.001 Trend: < ( ) 1.46 (0.74 – 2.87) 3.27 (1.64 – 6.51) Trend: # : Age, years of education, HBP, cholesterol, diabetes, alcohol drinking status, total cigarette pack-years Risk of MI and Clinical Attachment Loss: A Dose-response relationship

38 Saremi A. Nelson RG. Tulloch-Reid M. Hanson RL. Sievers ML. Taylor GW. Shlossman M. Bennett PH. Genco R. Knowler WC. Periodontal disease and mortality in type 2 diabetes. Diabetes Care. 28:27-32, Periodontal Disease and Cardiovascular Health In Pima Indians

39 The Bradford Hill Criteria 1: Strength of Association 2: Temporality 3: Consistency 4: Theoretical Plausibility 5: Coherence 6: Specificity in the causes 7: Dose Response Relationship 8: Experimental Evidence Is there a link?

40 Periodontal Infection and CVD  Periodontal Intervention  Antimicrobial Periodontal Treatment  Tooth extraction (full mouth) Prevent Cardiovascular Events ???? Improve CVD surrogate endpoints ????

41 Periodontal Treatment and Vascular Health Tonetti MS, D’Aiuto F Nibali L et al. NEJM 2007;356:

42 Periodontal Treatment and Inflammation Markers Tonetti MS, D’Aiuto F Nibali L et al. NEJM 2007;356:

43 The Periodontitis and Vascular Events (PAVE) pilot study was conducted to investigate the feasibility of a randomized secondary prevention trial to test whether treatment of periodontal disease reduces the risk for cardiovascular disease. PAVE Study

44 Five clinical centers recruited participants with documented coronary heart disease and met study criteria for periodontal disease. Eligible participants were randomized to receive periodontal therapy provided by the study or community dental care. Follow-up telephone calls and clinic visits were planned to alternate at 3-month intervals after randomization, with all participants followed until at least the 6-month clinic visit. Participants were followed for adverse events and periodontal and cardiovascular outcomes. PAVE Study

45 Figure 1. PAVE study summary. Published in Journal of Periodontology 2009;80: DOI: /jop © 2009 American Academy of Periodontology. All rights reserved.

46 Variable * Community Control (n = 102) Protocol Treatment (n = 126) P Value † Extent PD ≥4 mm16.8 (1.56)13.3 (1.18)0.001 Mean PD2.57 (0.07)2.41 (0.06) N PD ≥5 mm10.4 (1.36)7.35 (1.10) Extent AL ≥3 mm40.7 (2.71)42.5 (2.22)0.02 Mean AL2.72 (0.11)2.52 (0.08)0.052 Extent BOP42.5 (2.56)38.3 (2.17)0.16 Extent subgingival calculus 58.6 (3.95)42.8 (3.14)0.002 GCF-IL-1β222.3 (22.9)237.5 (35.0)0.97 Serum hs-CRP3.53 (0.45)3.12 (0.38)0.97 High CRP (>3 mg/l) (n [%]) 31 (34.8)33 (31.4)0.62* Published in Journal of Periodontology 2009;80: DOI: /jop © 2009 American Academy of Periodontology. All rights reserved. Six-Month Follow-Up of Periodontal Assessments, GCF-IL-1β Levels, and Serum Measures of hs-CRP by Treatment Group

47 Variable * Community Control (n = 12) Protocol Treatment (n = 25) P Value † Extent PD ≥4 mm19.5 (6.12)14.3 (3.51)0.76 Mean PD2.77 (0.22)2.49 (0.16)0.55 N PD ≥5 mm9.08 (4.72)9.48 (3.30)0.89 Extent AL ≥3 mm46.8 (8.10)33.9 (4.94)0.11 Mean AL2.95 (0.46)2.25 (0.19)0.20 Extent BOP45.8 (9.06)37.09 (5.00)0.88 Extent subgingival calculus 63.8 (12.10)29.2 (6.06)0.009 GCF-IL-1β202.6 (102.20)163.8 (42.30)0.74 Serum hs-CRP2.79 (0.71)3.41 (0.78)0.74 High CRP (>3 mg/l) (n [%]) 5 (33.3)8 (34.8)0.93* Published in Journal of Periodontology 2009;80: DOI: /jop © 2009 American Academy of Periodontology. All rights reserved. One year Follow-Up of Periodontal Assessments, GCF-IL-1β Levels, and Serum Measures of hs-CRP by Treatment Group

48 Protocol Treatment Community Control P Value Number reporting non-study dental visits (%) 54 (36.5)93 (64.1)< Number reporting non-study prophylaxis (%) 6 (4.1)54 (37.2)< Number reporting non-study subgingival scaling and root planing (%) 3 (2.0)26 (19.9)< Dental Use During First 6 Months of the Study Published in Journal of Periodontology 2009;80: DOI: /jop © 2009 American Academy of Periodontology. All rights reserved.

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50 Periodontal Infection and CVD  CRP (and possibly inflammation) is not the whole story  There is need to better understand the mechanisms linking PD to CVD

51 HbA1c at Baseline, 4 and 8 months by treatment group % P=0.030 Calabrese N, D’Aiuto FD, Calabrese A, Patel K, Calabrese G, Massi-Benedetti M Diabetes and Metabolism 37(2011)

52 Investigate the role of Genes and Environment in the link between Periodontal Disease (PD) and Myocardial infarction (MI).  In 1381 healthy controls we will evaluate the association between genetic and biochemical markers of pathophysiological pathways (inflammation and inflammation-mediated hemostasis/thrombosis) involved in the etiology of both PD and MI.  In the case-control study ( 953 cases of MI and 1381 healthy controls) we will evaluate the potential role of genetic markers and environmental exposures (smoking and alcohol use) of these pathways in modulating the observed association between PD and MI.  We will extend the follow-up of the 953 MI cases to evaluate whether these genetic markers and the environmental exposures can modulate the longitudinal association between periodontal disease and secondary cardiovascular events.

53 The final complex questions we want to answer by combining biological, epidemiological and computational approaches are: o Is the association between periodontal disease and myocardial infarction mediated by the genetic control of metabolic pathways involved in the pathogenesis of both diseases? o Are there haplotype patterns that can predict the development of myocardial infarction in subjects with periodontal disease? o Is it possible to develop a model of haplotype prediction that takes into consideration environmental factors and quantitative phenotypes in addition to genetic characteristics?

54 IL 1 beta IL 1 6 MMP3 TF NFKb Metabolic pathways involved in the relation between periodontal disease and myocardial infarction Tissue remodelling Thrombosis Periodontal disease Myocardial infarcion GenesEnv. GenesEnv. GenesEnv. GenesEnv. GenesEnv.

55 Genes selected Inflammatory genes: Haemostatic system genes: Interleukin 1 beta Il 1-b) Tissue Factor (TF) Tumor necrosis factor (TNF) Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, beta (NFKBIb) NFKBIb Interleukin 2 (IL2) Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, Alpha (NFKBIa) NFKBIa Interleukin 4 (IL4) Matrix Metalloproteinase 3 (MMP3) Interleukin 6 (IL6) Matrix metalloproteinase 9 (MMP9) Interelukin 8 (IL8) Fibrinogen beta chain Interleukin 12 (IL12) Urokinase plasminogen activator (uPA) C-rective protein (cRP) IL-receptor antagonist IL-RA)

56 Periodontal Disease and CVD  The association has important potential Public Health implications  The observed association satisfies many of the Bradford Hill criteria for causality  Missing definite experimental evidence  Need to better evaluate the potential mechanisms linking PD to CVD

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59 Periodontal Disease and Cardiovascular Health In Pima Indians Saremi A. Nelson RG. Tulloch-Reid M. Hanson RL. Sievers ML. Taylor GW. Shlossman M. Bennett PH. Genco R. Knowler WC. Periodontal disease and mortality in type 2 diabetes. Diabetes Care. 28:27-32, 2005.

60 Periodontal Disease and Cardiovascular Health In Pima Indians

61 Smoking history 3 categories: 3 categories: * Non-smokers * Non-smokers - - never smoked in the entire life - smoked < 100 cig. (~5 packs) in the entire life * Former smokers: smoked cig ≥ 100 and quit smoking * Former smokers: smoked cig ≥ 100 and quit smoking * Current smokers : smoked cig ≥ 100 and still smoking at * Current smokers : smoked cig ≥ 100 and still smoking at the time of interview the time of interview 2 categories [non-smokers; smokers (former and current)] 2 categories [non-smokers; smokers (former and current)] Duration and intensity of exposure: Duration and intensity of exposure: * Total pack-years of cigarette smoking * Total pack-years of cigarette smoking * Number of years since Pts had quit smoking * Number of years since Pts had quit smoking


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