Transcript Periodontal Infection and Cardiovascular Disease

Periodontal Disease/Infection
and
Cardiovascular Disease
Maurizio Trevisan, MD MS
The size of the potential problem
 Periodontitis

Leading cause of tooth loss
• 49,000,000 Americans have some form of “gum
disease”
 Cardiovascular

Disease
Leading cause of death and disability
• 13,000,000 Americans have CHD
• 5,500,000 Strokes
Is there a link ?
Is there a link?
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
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
4
2
6
4
Median Pantomography Index
2
0
6
3
17(28)
6(10)
No. (%) with artificial teeth
4(10)
Mattila KJ et al. BMJ 298: 779-782; 1989
PD and CVD a Systematic review
Linda L. Humphrey, Rongwei Fu, David I. Buckley, Michele Freeman, Mark Helfand
J Gen Intern Med. 2008 December; 23(12): 2079–2086
Relative Risk for Cerebrovascular Disease
According to Periodontal Disease Status :
NHANES I Follow-up
PD Status
No Disease
Gingivitis
Periodontitis
Edentulous
Incident Events
Fatal Events
RR†
95% CI
RR†
95% CI
1.00
1.02
1.66
1.23
Referent
0.70 – 1.48
1.15 – 2.39
0.91 – 1.66
1.00
1.09
2.14
1.34
Referent
0.60 – 1.97
1.16 – 3.93
0.76 – 2.37
† Hazard ratio from Cox’s proportional hazard model with adjustment for
baseline information on sex, race, age, education, poverty index, diabetes
status, hypertension, smoking status, average alcohol use, body mass
index, and serum cholesterol using SUDAAN software.
Wu T. Trevisan M. Genco RJ. Dorn JP. Falkner KL. Sempos CT
Archives of Internal Medicine. 160(18):2749-55, 2000.
Is there a link?
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
Incidence of CHD (total) by Level of Oral Bone Loss
The Dental Longitudinal Study
%
50
40
30
20
10
0
None
< 20%
20-40%
Age adjusted level of bone loss
Beck et al J Periodontol 1996 67:1123-1137
> 40%
Is there a link?
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
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
Periodontal Disease and CVD
The role of gender
Odds Ratios of the association between PD and incident MI in men and
women. MYLIFE STUDY
Gender
Unadjusted
OR (95% CI)
Adjusted #
OR (95% CI)
CAL (mm)
1.52 (1.32 – 1.80)
1.36 (1.17 – 1.59)
CAL (mm)
2.83 (2.11 – 3.80)
2.00 (1.42 – 2.80)
Periodontal
measures
Men
(n=828;
cases =443)
Women
(n=633;
cases=131)
# : 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):699-705, 2007.
Periodontal Disease and CVD
The role of smoking
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
CAL (mm)
1.52 (1.29 – 1.80)
CAL (mm)
1.35 (1.02 – 1.77)
(n=850;
cases =395)
Non smokers
(n=580;
cases=160)
# : Age, Gender, years of education, HBP, cholesterol, diabetes, alcohol drinking status, cigarette packyears
# # : 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):699-705, 2007.
Periodontal Disease and Death + Recurrent CVD events
in MI patients (n=884)
Never Smoker
Former Smoker
Current Smoker
(n=252; events=40)
(n=489; events=89)
N=143; events=32)
Hazard Ratio (CI)
Hazard Ratio (CI)
Hazard Ratio (CI)
CAL (mm)
1.41
(1.12-1.76)
1.00
(0.84-1.18)
1.02
(0.81-1.28)
CAL 3+
2.51
(1.21-5.24)
0.88
(0.56-1.37)
1.06
(0.52-2.16)
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.
PD measurements
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
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
Different Indexes of PD and MI
Mean AL (mm)
Adjusted OR
(95%CI)
1.46 (1.26-1.69)
p value
<0.001
Mean PD (mm)
2.19 (1.66-2.89)
<0.001
Mean ACH (mm) 1.30 (1.14-1.49)
<0.001
Missing Teeth (n) 1.04 (1.02-1.07)
<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.
Linda L. Humphrey, Rongwei Fu, David I. Buckley, Michele Freeman, Mark Helfand
J Gen Intern Med. 2008 December; 23(12): 2079–2086
Is there a link?
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
Proposed Role of Infection in CHD
Infection
Pathogens
Bacteremia
Inflammatory
Mediators
Bacteria or
products
(e.g. LPS)
IL-1, IL-6,
TNF
Pathogens
Immune
Responses
Liver
1. Platelet aggregation
2. Invasion of endothelium
3. Digestion of matrix
CRP, SAA,
Fibrinogen,
AT
Heart
1. Antibodies to
bacteria and to cross
reactive antigens e.g.
HSP
2. T-cells sensitized
Periodontal Infection and CVD
 Specific
mechanisms linked to specific
agent
 General mechanisms ?
Periodontal Infections and Coronary Heart Disease:
The role of periodontal bacteria
The Corodont Study
Axel Spahr, et al. Archives of Internal Medicine, 166:554-559; 2006
Prevalence of different organisms in cases and controls
The MY LIFE Study
MI cases
(N= 386)
Controls
(N=840)
Pvalue
(15.9%)
(38.0%)
(40.3%)
(16.2%)
(28.1%)
(57.0%)
(33.0%)
(10.8%)
0.10
< 0.001
< 0.001
< 0.001
0.005
0.81
0.55
0.05
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
212
194
97
139
223
134
57
(19.7%)
(54.9%)
(50.3%)
(25.1%)
(36.0%)
(57.8%)
(34.7%)
(14.8%)
133
319
338
136
236
479
277
91
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.
Association between CA/CO and number of varieties of microorganisms
(n= 1125: cases=343; controls =782)
OR (95%CI) **
p-value
1.13 (1.00-1.27)
0.05
Association
Micro (increase by one:0 to 5)
Any micro in 4 ctg (ref = 0) (n= 431 and removing Bf)
Any one
(n=304)
1.62 (1.10-2.40)
0.02
Any two
(n=198)
1.48 (0.95-2.32)
0.09
1.58 (1.01-2.46)
0.04
Any three or +
(n=192)
Among micro: Pg, Fn, Cr (Group A: lowest prevalence) (n= 431 and
removing Bf)
Any one
(n=264)
Any two or all three (n=125)
1.39 (0.92-2.10)
0.11
2.03 (1.22-3.36)
0.006
Among micro: Pi, Es (Group B: high prevalence) (n= 431 and removing Bf)
Any one
(n=429)
1.45 (1.01 - 2.08)
0.04
All two
(n=196)
1.68 (1.08 - 2.61)
0.02
Adjusted for age, gender, years of education, BMI, cholesterol, HBP, diabetes, smoking status (never,
former, current), lifetime total pack years, # brushing
Periodontal Infection and CVD
 Inflammation

Pathway
C Reactive Protein
Inflammatory Pathways in Atherogenesis
Proinflammatory Risk
Factors
Primary Proinflammatory Cytokines
(eg, IL-1, TNF-α)
IL-6 “Messenger”
Cytokine
ICAM-1
Selectins, HSPs, etc
CRP
SAA
Endothelium
Liver
and Other Cells
Circulation
Libby P, Ridker PM. Circulation. 1999;100:1148–1150.
Risk of High CRP according to PD
NHANES III
Gingival Bleeding Index
2
1.9
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1
Calculus Index
0
0.01-0.24
0.25-1.00
2
1.9
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1
0-0.24
0.25-0.74
0.75-2.00
Odds Ratios
Odds Ratios
Wu T, Trevisan M, Genco RJ, Falkner KL, Dorn JP, Sempos C. American Journal of
Epidemiology. 151(3): pp 273-282, 2000
Periodontal Disease and CVD Biomarkers:
The Health Professionals Study
No PD(n=377)
Yes PD(n=91)
p
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
99.7 (7.8)
101.0 (7.7)
0.36
109.0 (42.6)
121.4 (42.3)
0.09
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
Factor VII (%)
vWF antigen (%)
t-PA (mg/dL)
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
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.
Is there a link?
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
Wu T. Trevisan M. Genco RJ. Dorn JP. Falkner KL. Sempos CT
Archives of Internal Medicine. 160(18):2749-55, 2000.
Is there a link?
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
Risk of MI and Clinical Attachment Loss:
A Dose-response relationship
Men
(n=828; cases = 443)
Adjusted OR
(95% CI)
Women
(n= 633; cases =131)
p-value
Adjusted OR
(95% CI)
p-value
CAL 2nd Quartile
1.55
(0.96 – 2.49)
0.07
3rd Quartile
2.75
(1.71 – 4.42)
<0.001
1.46
(0.74 – 2.87)
0.27
4th Quartile
2.73
(1.71 – 4.35)
<0.001
3.27
(1.64 – 6.51)
0.001
Trend: <0.001
1.35 (0.69-2.67)
0.39
Trend: 0.001
# : Age, years of education, HBP, cholesterol, diabetes, alcohol drinking status, total
cigarette pack-years
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 .
Is there a link?
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
Periodontal Infection and CVD
 Periodontal
Intervention
 Antimicrobial Periodontal Treatment
 Tooth extraction (full mouth)
Prevent Cardiovascular Events ????
Improve CVD surrogate endpoints ????
Periodontal Treatment and Vascular Health
Tonetti MS, D’Aiuto F
Nibali L et al.
NEJM 2007;356:911-920
Periodontal Treatment and Inflammation Markers
Tonetti MS, D’Aiuto F Nibali L et al. NEJM 2007;356:911-920
PAVE Study
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
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.
Published in Journal of Periodontology 2009;80:190-201.
DOI: 10.1902/jop.2009.080007
© 2009 American Academy of Periodontology. All rights reserved.
Figure 1. PAVE study summary.
Six-Month Follow-Up of Periodontal Assessments, GCF-IL-1β
Levels, and Serum Measures of hs-CRP by Treatment Group
Variable*
Community Control Protocol Treatment
(n = 102)
(n = 126)
P Value†
Extent PD ≥4 mm
Mean PD
N PD ≥5 mm
Extent AL ≥3 mm
Mean AL
Extent BOP
Extent subgingival
calculus
16.8 (1.56)
2.57 (0.07)
10.4 (1.36)
40.7 (2.71)
2.72 (0.11)
42.5 (2.56)
58.6 (3.95)
13.3 (1.18)
2.41 (0.06)
7.35 (1.10)
42.5 (2.22)
2.52 (0.08)
38.3 (2.17)
42.8 (3.14)
0.001
0.0009
0.0003
0.02
0.052
0.16
0.002
GCF-IL-1β
Serum hs-CRP
High CRP (>3 mg/l)
(n [%])
222.3 (22.9)
3.53 (0.45)
31 (34.8)
237.5 (35.0)
3.12 (0.38)
33 (31.4)
0.97
0.97
0.62*
Published in Journal of Periodontology 2009;80:190-201.
DOI: 10.1902/jop.2009.080007
© 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
Variable*
Extent PD ≥4 mm
Mean PD
N PD ≥5 mm
Extent AL ≥3 mm
Mean AL
Extent BOP
Extent subgingival
calculus
GCF-IL-1β
Serum hs-CRP
High CRP (>3
mg/l) (n [%])
Community
Protocol
Control (n = 12) Treatment (n = 25)
19.5 (6.12)
14.3 (3.51)
2.77 (0.22)
2.49 (0.16)
9.08 (4.72)
9.48 (3.30)
46.8 (8.10)
33.9 (4.94)
2.95 (0.46)
2.25 (0.19)
45.8 (9.06)
37.09 (5.00)
63.8 (12.10)
29.2 (6.06)
202.6 (102.20)
2.79 (0.71)
5 (33.3)
Published in Journal of Periodontology 2009;80:190-201.
DOI: 10.1902/jop.2009.080007
© 2009 American Academy of Periodontology. All rights reserved.
163.8 (42.30)
3.41 (0.78)
8 (34.8)
P Value†
0.76
0.55
0.89
0.11
0.20
0.88
0.009
0.74
0.74
0.93*
Dental Use During First 6 Months of the Study
Number reporting
non-study dental
visits (%)
Number reporting
non-study
prophylaxis (%)
Number reporting
non-study
subgingival scaling
and root planing (%)
Protocol
Treatment
54 (36.5)
Community
Control
93 (64.1)
<0.0001
6 (4.1)
54 (37.2)
<0.0001
3 (2.0)
26 (19.9)
<0.0001
Published in Journal of Periodontology 2009;80:190-201.
DOI: 10.1902/jop.2009.080007
© 2009 American Academy of Periodontology. All rights reserved.
P Value
Published in Journal of Periodontology 2009;80:190-201.
DOI: 10.1902/jop.2009.080007
© 2009 American Academy of Periodontology. All rights reserved.
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
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) 456-459
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.
The final complex questions we want to answer by combining
biological, epidemiological and computational approaches are:
o
o
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?
Are there haplotype patterns that can predict the
development of myocardial infarction in subjects with
periodontal disease?
Is it possible to develop a model of haplotype prediction
that takes into consideration environmental factors and
quantitative phenotypes in addition to genetic
characteristics?
Metabolic pathways involved in the relation between
periodontal disease and myocardial infarction
Genes
Genes
Env.
IL 1 6
Env.
Genes
Env.
MMP3
Tissue remodelling
Periodontal disease
IL 1 beta
Myocardial infarcion
NFKb
TF
Genes
Thrombosis
Env.
Genes
Env.
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)
Interleukin 2 (IL2)
Nuclear factor of kappa light
polypeptide gene enhancer in B-cells
inhibitor, Alpha (NFKBIa)
Interleukin 4 (IL4)
Matrix Metalloproteinase 3 (MMP3)
Interleukin 6 (IL6)
Matrix metalloproteinase 9 (MMP9)
Interelukin 8 (IL8)
Interleukin 12 (IL12)
C-rective protein (cRP)
IL-receptor antagonist IL-RA)
Fibrinogen beta chain
Urokinase plasminogen activator
(uPA)
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
9294914
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 .
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 .
Smoking history

3 categories:
* 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
* Current smokers : smoked cig ≥ 100 and still smoking at
the time of interview

2 categories [non-smokers; smokers (former and current)]

Duration and intensity of exposure:
* Total pack-years of cigarette smoking
* Number of years since Pts had quit smoking