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					Coronary Artery Disease


                   TARRSON FAMILY ENDOWED
                          CHAIR IN PERIODONTICS
Coronary Artery Disease
    UCLA School of Dentistry
Coronary Artery Disease
Presents


                          Dr. E. Barrie Kenney
                          Professor & Chairman
                          Section of Periodontics
Coronary Artery Disease
       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
Coronary Artery Disease



     Artery
     Disease
     Coronary
Coronary Artery Disease
                            Epidemiological
                          connection between
                            coronary artery
                              disease and
                          periodontal disease
Coronary Artery Disease

                           6.9 Million people
                          have coronary heart
                            disease in USA
Coronary Artery Disease

                           Atherosclerosis
                          Leading Cause of
                            Death in USA
Coronary Artery Disease
                          Coronary Artery Disease
                           (C.A.D) kills 500,000
                              people a year.
                             One of every 4.6
                           deaths due to C.A.D
Coronary Artery Disease       Periodontal Disease
                              in the United States
                          • 54% 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
                            1988-19994
Coronary Artery Disease
                           Association between
                          dental health and acute
                           myocardial infarction

                                    Matilla KJ et al
                             Brit. Med. J. 1989 298: 774
Coronary Artery Disease   Used index based on caries,
                          periodontal disease, periapical
                          lesions, pericoronitis.

                          Patients admitted for acute
                          myocardial infarction had higher
                          scores than matched controls.
Coronary Artery Disease
                             Patients above the
                             upper quartile had
                               twice the risk of
                              acute myocardial
                          infarction than did those
                            with a score of zero.
Coronary Artery Disease

                           This was comparable to
                          risk of cigarette smoking,
                          hypercholesterolemia and
                                 hypertension.
Coronary Artery Disease
                           Dental Disease and
                          Risk of Coronary Heart
                          Disease and Mortality

                                  De Stefano F et al
                            Brit. Med. J. 1993, 306: 688
Coronary Artery Disease   Analyzed data from National
                          Health and Nutrition examination
                          study I. 1971 – 1974.

                          20,249 subjects aged 25 to 74
                          followed up in 1982 – 1985
                          (only 55 years and older at
                          entry) and 1986 – 1987.
Coronary Artery Disease
                          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)
Coronary Artery Disease

                           Admitted for Coronary
                          Artery Disease or died of
                          Coronary Artery Disease
                          as indicators of disease
Coronary Artery Disease        Dental evaluation at
                                    baseline
                          • Number 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.
Coronary Artery Disease
                             Percentage of subjects
                                          No                                         No
                                          Disease   Gingivitis   Periodontitis      Tooth

                          death from CHD    2.6        4.1           8.4            11.9
                          admission for CHD 6.5        7.4          14.4            19.2




                                                                                 De stefano
Coronary Artery Disease
                                             ODDS Ratios
                                              Risk      Women                        Men
                                             Factors    25-49        Mortality      25-49
                           No disease         1.00       1.00         1.00           1.00
                           Gingivitis         1.05       0.98         1.23           1.42
                           Periodontitis      1.25       1.72         1.46           2.12
                           No teeth           1.23       1.71         1.46           2.60
                           Periodontal index 1.04        1.09         1.09           1.11
                           Oral hygiene index 1.12       1.11         1.15           1.23
                          adjusted for age, sex education, poverty level, marital status,
                          blood pressure, cholesterol, diabetes, weight, physical activity,
                          alcohol, smoking

                                                                                 De Stefano
Coronary Artery Disease

                               Analysis of
                           these with data on
                          smoking showed the
                             same pattern.
Coronary Artery Disease

                          No association
                          between active
                          caries and CHD
Coronary Artery Disease
                          Periodontal Disease
                          and Coronary Heart
                             Disease Risk
                                Hujoel P.P., et al
                            J.A.M.A. 2000, 284:1406
Coronary Artery Disease
                          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.
Coronary Artery Disease
                          At follow up 1265 subjects
                          had at least 1 coronary
                          heart disease event, either
                          death, hospitalization or
                          coronary revascularization
                          therapy.
Coronary Artery Disease
                          Periodontal Disease and
                          Myocardial Disease have
                          common risk factors, age,
                          smoking, stress, social
                          economics status, body fat,
                          and so potential for
                          confounding is substantial.
Coronary Artery Disease
                                             Periodontitis   Gingivitis    Healthy
                          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



                                                                          Hujoel et al.
Coronary Artery Disease               Hazard Ratios
                                    Compared to Healthy
                                           Unadjusted   Adjusted for
                                                        Confounders
                          periodontitis       2.66         1.14
                          gingivitis          1.20         1.05
Coronary Artery Disease
                          “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.”
Coronary Artery Disease
                          Oral Health and Systemic
                           Disease: Periodontitis
                            and Cardiovascular
                                  Disease
                               Beck J.D. Offenbacher S.
                              J. Dent. Edu. 1998, 62:859
Coronary Artery Disease
                          Odds ratio with more or less
                               sites p.d > 3mm

                             CHD    Fatal   Stroke
                                    CHD
                             3·1     2·8     1·9

                          1147 Male Veterans from Boston

                                                           Beck
Coronary Artery Disease
                          Number of sites with 20%
                            or more bone loss
                              ODDS Ratio for CHD

                               1-2                 0.8
                               3-5                 1.4
                               6-10                1.9
                               11-20               2.1

                                                    Beck et al
Coronary Artery Disease
                           Periodontal Disease and
                          prevalent Coronary Heart
                          Disease in the ARIC study

                                      Beck J.D et al
                           J. Dent. Res. 2000. 79. abst. #2269
Coronary Artery Disease
                           ODDS Ratio for C.H.D.

                          per cent sites with
                          attachment loss 3mm or more   Males   Females
                              0 – 6.4                    1.0      1.0
                              6.5 – 15.1                 1.7      0.7
                              15.2 – 31.0                1.5      0.8
                              31.1 – 100                 1.7      0.9
Coronary Artery Disease
                            Atherosclerosis Risk
                           in Communities study
                          13.6% of males 5.5% of
                           females had coronary
                               heart disease
Coronary Artery Disease       Investigation of the
                             Association Between
                           Angiographically Defined
                          Coronary Artery Disease and
                              Periodontal Disease

                                Matthaner, S. S. et al.
                                J. Periodontol 73:1169 2002
Coronary Artery Disease       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,
Coronary Artery Disease                          CAD +ve
                                  Sites with CAL>6mm 6.85
                                                                        CAD -ve
                                                                               3.32
                          Radiographic bone loss 3.60mm                 3.18mm
                          Mean probing depth     2.67mm                 2.59mm
                          Tooth loss             8.9                    9.1

                          When corrected for age previous smoking history
                          Odds ratio             1.06 Mean CAL
                          Odds ratio             1.03 CAL>6mm
                          Odds ratio             1.31 Radiographic bone loss
                          Odds ratio             2.54 Mean probing depth

                          These patients had minimal periodontal disease so CAL may be
                          recession or pocket related
                                                                                 Matthaner,
Coronary Artery Disease
                          Ratio of Cigarette Smoking
                          in the Association Between
                            Periodontal Disease and
                            Coronary Heart Disease

                                 Hyman, J. J. et al.
                                J. Periodontol 73:988 2002
Coronary Artery Disease     5285 Subjects from NHANES 1988-94,
                                      40 years or older


                          Loss of Attachment   Odds ratio for heart attack history
                          2.00 - 2.99mm        2.64
                          3.00-3.99mm          3.84
                          4mm or more          5.87




                                                                        Hyman,
Coronary Artery Disease       Oral Health and Peripheral
                                   Arterial Disease
                          • Hung, 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
Coronary Artery Disease                  Odds Ratio
                              Peripheral Cardiovascular Disease
                                                       And
                          •   Periodontal Disease                              1.41
                          •   Tooth Loss                                       1.39
                          •   Periodontal Disease & Tooth Loss                 1.88
                          •   No Periodontal Disease and Tooth Loss            0.92

                              Controlled for traditional risk factors for cardiovascular
                              disease.


                                                                         Hung, H.C. et al
                             Severity of Periodontal
Coronary Artery Disease     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
Coronary Artery Disease       Odds Ratio Periodontal bone loss
                              And    Myocardial Infarction
                          •   Periodontal Disease                                2.69
                          •   Smoking                                            0.69
                          •   Gender                                             0.62
                          •   Age                                                1.09
                              Controlled for traditional risk factors for cardiovascular
                              disease.Aged 40 to 60 years old.
                                 TREATMENT OF PERIODONTITIS AND
Coronary Artery Disease       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
Coronary Artery Disease        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
Coronary Artery Disease
                          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
Coronary Artery Disease

                          Coronary Artery
                             Disease
                            In Women
Coronary Artery Disease
                             Lipid management
                            and control of other
                           coronary risk factors in
                          post menopausal women
                          J. Women’s Health and Gender related Med. 9:235,2000
Coronary Artery Disease
                              Stroke and
                          myocardial infarction

                          Number one killer of
                          women with 500,000
                            deaths per year
Coronary Artery Disease

                          African American and
                           Hispanic women at
                             greater risk than
                           Caucasian women
Coronary Artery Disease

                          This is more than the
                           next 16 causes of
                            death combined
Coronary Artery Disease

                          Risk of Myocardial
                          infarction lower in
                          women than men
Coronary Artery Disease
                            First myocardial
                          infarction in women
                          is more severe and
                            more lethal than
                            they are in men
Coronary Artery Disease

                           Women’s mortality
                          rate at 6 months post
                          myocardial infarction
                           double that of men
Coronary Artery Disease
                            Analysis of 350,000
                          patients after fibrinolytic
                           therapy for infarction.

                              Mortality for
                          women 9.3%, men 4.5%
Coronary Artery Disease
                          Without fibrinolytic therapy
                          • 16% mortality for women
                          • 10.9% for men
Coronary Artery Disease
                           Coronary artery
                           bypass surgery
                          operative mortality
                            4.5% women,
                              2.6% men
Coronary Artery Disease

                              Menopause
                              often causes
                            increase in total
                          cholesterol and LDL
Coronary Artery Disease


                          Estrogen increase
                             HDL levels
Coronary Artery Disease
                            Post menopausal
                            hormonal therapy
                          gave 53% reduction in
                            death from CHD in
                           study using 121,700
                             registered nurses
Coronary Artery Disease

                            Framingham Study.
                          Risk of coronary artery
                           disease doubles with
                           onset of menopause
Coronary Artery Disease   Cardiovascular Disease During
                          6.9 Years of Hormone Therapy
                          • 20 centers with 2,763 post menopausal with C.H.D.
                            average age 67 years.
                          • Hormone group got 0.6625mg 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
Coronary Artery Disease      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
Coronary Artery Disease




                          Periodontal flap surgery to treat periodontitis. Note loss
                          of crestal bone.
Coronary Artery Disease




                          Periodontitis.
                          Histopathologyof
                          intrabony defect
                          showing bone
                          resorption (yellow),
                          inflammation (green)
                          and epithelial
                          proliferation (white).
Coronary Artery Disease
                                Pathogenesis of
                                   Atheroma
                          1. Fatty streak development
                          2. Atheromatous plaque
                             development
                          3. Thrombus development
Coronary Artery Disease


                          Fatty streak
                          development
Coronary Artery Disease
                          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
Coronary Artery Disease




                          Average adult Aorta, mild fatty
                            streaks, early atheroma.
Coronary Artery Disease




                          Aorta. Arrow at prominent
                                 fatty streak
Coronary Artery Disease

                          Initiation of atheroma by
                          damage to endothelium
                            which becomes more
                             porous to lipids and
                                   monocytes
Coronary Artery Disease

                          Monocytes from blood
                          stream pass through
                            endothelium into
                            blood vessel wall
Coronary Artery Disease




                          Healthy Coronary Artery cross section
Coronary Artery Disease
Coronary Artery Disease
Coronary Artery Disease
                             Bacteria


                            Hypertension



                           Homocysteine


                            Smoking


                           Diabetes




                          Initiators of Endothelial Dysfunction
Coronary Artery Disease
Coronary Artery Disease

                                 Oxidized LDL



                                  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.
Coronary Artery Disease




                          Vascular cell wall adhesion molecule (VCAM-1)
                                       is induced by TNF-Kb
Coronary Artery Disease

                                     VACM-1



                                     VACM-1




                          Vascular cell wall adhesion molecule (VCAM-1)
                                       is induced by TNF-Kb
Coronary Artery Disease

                                     VACM-1

                                                     MCP1
                                     VACM-1




                          VCAM-1 and chemokine monocytic chemotactic
                           protein I localizes monocytes in vessel wall.
Coronary Artery Disease

                            Low Density Lipids
                           (LDL) pass through
                          damaged endothelium
                          into blood vessel wall
Coronary Artery Disease
Coronary Artery Disease
                                                      LDL O
                                                      LDLO




                                                     LDL O
                                                     LDLO



                                                  LDL O
                                                  LDLO


                          Low density lipids (LDL) oxidized in vessel wall
Coronary Artery Disease
                          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.
Coronary Artery Disease
                                LDLO

                                     MMP

                          Prostaglandins
                                           Cytokines
                               LDLO


                             Cytokines
                             LDLO
                                           MMP
Coronary Artery Disease
                               Monocytes
                              transform to
                            macrophages
                           and take up LDL
                          to form foam cells
Coronary Artery Disease
Coronary Artery Disease
                           Monocytes trigger
                          chronic inflammatory
                              reaction with
                            lymphocytes and
                          this results in tissue
                          necrosis and fibrosis
Coronary Artery Disease
                                LDLO

                                     MMP

                          Prostaglandins
                                           Cytokines
                               LDLO


                             Cytokines
                             LDLO
                                           MMP
Coronary Artery Disease
                                                         LDLO

                                     Bacteria                 MMP

                                                   Prostaglandins
                                                                    Cytokines
                                                        LDLO
                                   Cytokines
                                                      Cytokines
                                                      LDLO
                                                                    MMP

                          Circulating bacteria and cytokines add to inflammation.
                               This leads to Atheromatous plaque formation
Coronary Artery Disease

                          High Density Lipids
                             (HDL) inhibit
                           oxidation of LDL
Coronary Artery Disease
                          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
Coronary Artery Disease
                           Enzymes associated with
                          HDL apolipoproptein (apoAL)
                           and para-oxenase (PON)
                           protect by destroying the
                           oxidized pro-inflammatory
                                 lipids from LDL
Coronary Artery Disease
                               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.
Coronary Artery Disease
                              HDL




          HDL
                      HDL




    LDL
                LDL
                            LDL




    O
                             O



                      O
Coronary Artery Disease
                                         O
                           LDL HDL




                           LDL HDL



                          LDL HDL    O
Coronary Artery Disease

                          ATHEROMATOUS
                              PLAQUE
                           DEVELOPMENT
Coronary Artery Disease
                             Blood vessel wall
                          becomes distended and
                          continues to accumulate
                          cholesterol, some areas
                             become calcified
Coronary Artery Disease




                          Coronary artery with atheromatous plaques (arrows)
Coronary Artery Disease


          THROMBUS
         DEVELOPMENT
Coronary Artery Disease




                           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)
Coronary Artery Disease
                          Bacterial       MMP
                                          MMPMMP
                                            MMP
                                           MMP
                                            MMP
                                              MMP
                          Proteases            MMP
                                                MMP

                                      MMP
                                      MMPMMP
                                        MMP
                                       MMP
                                        MMP
                                          MMP
                                           MMP
                                            MMP
                              MMP
                              MMPMMP
                                MMP
                               MMP
                                MMP
                                  MMP
                                   MMP
                                    MMP




                          MMP s from macrophages and proteases from
                           circulating bacteria can destroy collagen to
                              form an unstable atheromatous plaque
Coronary Artery Disease

                          Blood vessel wall can
                          rupture and then get
                           thrombus formed at
                           region of ulceration
Coronary Artery Disease




                          Endothelium is destroyed with exposure of
                            collagen and plaque to arterial blood.
Coronary Artery Disease
Coronary Artery Disease




                          Platelets aggregate on exposed
                           collagen to form a thrombus.
Coronary Artery Disease




 Thrombus formation
Coronary Artery Disease

                                            Oral Bacteria




                          Circulating oral bacteria have peptides that
                                   cause platelet aggregation
Coronary Artery Disease




                          Increase thrombosis can lead to sudden
                                     occlusion of vessel
Coronary Artery Disease




                          Coronary Artery occluded by thrombosis
Coronary Artery Disease




                          Thrombus formation on atheromataous plaque.
                          Slits of cholesterol crystals seen in vessel wall.
Coronary Artery Disease




                          Coronary artery with narrowed lumen and
                                    thrombosis (arrows)
Coronary Artery Disease

              Oral Bacteria
Coronary Artery Disease
                          Thrombosis can give
                          occlusion of vessel.

                          This is responsible for
                          50% of cases of
                          myocardial infarction
Coronary Artery Disease

                                                 lumen




                          Calcification (blue area) and distended vessel wall with
                                     narrowed lumen of Coronary Artery.
Coronary Artery Disease
                             Ultrafast CAT Scan
                             of Thorax Showing
                           Cross-Section of Heart.
                          Calcified Tissues Stained Pink.

                              Note: Calcified Atheromatous
                              Plaques in Coronary Arteries
Coronary Artery Disease
Coronary Artery Disease
Coronary Artery Disease
Coronary Artery Disease
Coronary Artery Disease
Coronary Artery Disease
Coronary Artery Disease



         BACTERIA
Coronary Artery Disease
                                        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.
Coronary Artery Disease   Gram negative bacteria or LPS
                          given systemically can give
                          following changes in major blood
                          vessels
                          •   inflammatory cell infiltrate
                          •   smooth muscle proliferation
                          •   fatty degeneration
                          •   intravascular coagulation
Coronary Artery Disease   Gram Negative Bacterial
                          Infections
                          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
Coronary Artery Disease
                             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.
Coronary Artery Disease

                           15 PATIENTS AT SURGERY TOOK
                              CORONARY AND INTERNAL
                            MAMMARY ARTERY SECTIONS



                          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
Coronary Artery Disease
                               Identification
                             of Pathogens in
                          Atheromatous Plaques
                                  Haraszthy V.I et al
                             J. Dent. Res. 1998: 71. 666.
Coronary Artery Disease
                          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
Coronary Artery Disease
                          Frequency and Distribution
                           of Periodontal Pathogens
                              in the Atheromas of
                               Coronary Arteries.
                                      Meyers G.S.
                                 Balint Orban Competition
                            AAP Annual Meeting September 2000
Coronary Artery Disease
                          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.
Coronary Artery Disease
                          Frequency
                          A. actinomycetemcomitans   29%
                          B. Forsythus               24%
                          P. Gingivalis              0%
                          P. Intermedia              2%
                          F. Nucleatum               29%
Coronary Artery Disease




        CAROTID ARTERY.POSITIVE
        FOR P. GINGIVALIS
Coronary Artery Disease
Coronary Artery Disease




                          ELECTRO N MICROGRAPH OF MACROPHAGE
Coronary Artery Disease




                          GRAM NEGATIVE BACTERIA IN MACROPHAGE
Coronary Artery Disease
                              Other 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
Coronary Artery Disease




                          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.)
Coronary Artery Disease         Bacterial Involvement
                                    in Atheroma
                          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.
                          Dorn, B.R. et.al. Infect. Immun. 1999 67:5792


                          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-A114 2002
Coronary Artery Disease   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.
Coronary Artery Disease   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
Coronary Artery Disease
                              Establishment
                          of a mouse model of
                            infective induced
                          atheroma formation
                                 Chung H.J. et al
                           J. Dent. Res. 2000 79: #1356
Coronary Artery Disease
                          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
Coronary Artery Disease
                               Mean area of
                          atheroma after 3 weeks
                          P. Gingivalis   162.1Mm2
                          Control broth    88.6Mm2


                                               Chung et al
Coronary Artery Disease
                             TNF and PGE levels
                               in chamber were
                            correlated with area of
                          atheroma TNF associated
                           with serum cholesterol.
                            Cholesterol associated
                            with area of atheroma.
Coronary Artery Disease
                               Bacterial induced
                              periodontal disease
                             increases circulating
                             cytokines which can
                           accentuate inflammation
                          in atheromatous vessels.
Coronary Artery Disease




                          Early gingivitis with margin of gingiva showing edema,
                          redness and bleeding on probing.
Coronary Artery Disease
                                  Cytokines in Periodontal
                                       Inflammation
                          IL1ß        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.
Coronary Artery Disease
                                 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
Coronary Artery Disease
                              Chronic bacterial
                             infections including
                          periodontal disease also
                           increase circulating C
                            Reactive Substance
Coronary Artery Disease
                          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.
Coronary Artery Disease    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
Coronary Artery Disease

                           Bacteria from the oral
                          cavity and dental plaque
                           can stimulate platelet
                                aggregation.
Coronary Artery Disease
                          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
Coronary Artery Disease
                          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
Coronary Artery Disease
                                   Effects of
                            oral flora on platelets:
                          Possible consequences in
                           cardiovascular disease
                              Herzberg, M. Mayer, M. W.
                               J. Periodont. 1996 67:1138
Coronary Artery Disease
                          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.
Coronary Artery Disease
                           Hyperlipedemia caused
                          increased cardiac effects
                           ofS. Sanguis. Also have
                            seen similar effects in
                                 platelets with
                                 P. Gingivalis.
Coronary Artery Disease
                          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
Coronary Artery Disease
                            Rabbits on high fat diet
                           with hypercholesterolemia
                          In vitro platelet aggregation
                           response to strain 133-79
                          accelerated over that seen
                                  on normal diet
Coronary Artery Disease
                             Bacteria


                            Hypertension



                           Homocysteine


                            Smoking


                           Diabetes




                          Initiators of Endothelial Dysfunction
Coronary Artery Disease



         HYPERTENSION
Coronary Artery Disease

                             Hypertension
                          increase chance of
                           endothelial injury
Coronary Artery Disease
                             Bacteria


                            Hypertension



                           Homocysteine


                            Smoking


                           Diabetes




                          Initiators of Endothelial Dysfunction
Coronary Artery Disease



         HOMO CYSTEINE
Coronary Artery Disease
                          High levels of the Amino
                              acid homocysteine
                          increase risk of coronary
                           artery disease by being
                            toxic to endothelium.
Coronary Artery Disease

                          Folic acid vitamin B6,
                          B12 reduce levels of
                              homocysteine
Coronary Artery Disease   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, 2mg vit B6 vit B12
Coronary Artery Disease
                             Bacteria


                            Hypertension



                           Homocysteine


                            Smoking


                           Diabetes




                          Initiators of Endothelial Dysfunction
Coronary Artery Disease



         SMOKING
Coronary Artery Disease

                           Toxic factors in
                          cigarette smoke
                            increase risk
                          endothelial injury
Coronary Artery Disease

                          Smokers 2.5 times
                          more likely to have
                             heart attack
Coronary Artery Disease
                             Bacteria


                            Hypertension



                           Homocysteine


                            Smoking


                           Diabetes




                          Initiators of Endothelial Dysfunction
Coronary Artery Disease



         DIABETES
Coronary Artery Disease
                                   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. 1998 32 suppl 3:s54.
Coronary Artery Disease

                          Diabetes increase risk
                          of atheroma because
                             of hyperlipemia
Coronary Artery Disease

                          Diabetes has high
                             triglycerides
                            And low HDL
Coronary Artery Disease
                               Low density lipids
                            can initiate endothelial
                          dysfunction and monocyte
                            attachment. LDL’s also
                           interact with periodontal
                                 inflammation.
Coronary Artery Disease
                          Antioxidants increase
                          resistance of LDL to
                          oxidation. Vitamin E
                            reduces risks of
                          atheroma production
Coronary Artery Disease

                          Risk of CVD and MI reduced
                          77% with 800 IU tocopherol

                          400 IU gave a 47% reduction
Coronary Artery Disease

                          Vitamin E has little or no
                            effect on established
                                  atheroma
Coronary Artery Disease
                          Association between
                           Periodontitis and
                            Hyperlipidemia:
                           Cause or Effect?
                                 Cutler C.W et al
                            Periodontol 1999 12:1429
Coronary Artery Disease
                          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.
Coronary Artery Disease
                           Relationship with Periodontal
                           Disease and other variables
                          odds                              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               35.0

                                                          Cutler et al
Coronary Artery Disease

                           Also did in vitro study to
                          see effect of triglycerides
                            on release of IL1 beta
                                from p.m.n.s.
Coronary Artery Disease
                            Interleukin 1 beta secretion
                          by PMNS from healthy patients

                           PMN                     2.0
                           PMN + P.g. L.P.S         24
                           PMN+ triglycerides      2.3
                           PMN +LPS + TG            35

                                                   Cutler et al.
Coronary Artery Disease
                          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.
Coronary Artery Disease       Pathophysiological
                            relationships between
                          periodontitis and systemic
                          disease: Recent concepts
                            involving serum lipids

                              Iacopino A.M, Cutler C.W.
                             J. Periodont. 2000. 71:1375
Coronary Artery Disease
                             Periodontitis induced
                            changes in immune cell
                          functions causes metabolic
                             dysregulation of lipid
                             metabolism involving
                                   cytokines.
Coronary Artery Disease

                              From periodontitis
                          elevated serum IL-1ß and
                              TNF change lipid
                              metabolism so get
                               hyperlipidemia.
Coronary Artery Disease
                              The elevated lipids in
                           diabetes and periodontitis
                           also increases monocytic
                           responsiveness and pmn
                            activity so get increased
                            cytokine production and
                          further periodontal disease.
Coronary Artery Disease
                          Recommended levels of LDL
                          • 1 or more risk factor < 160mg / ml
                          • 2 or more risk factor < 130mg / ml
                          • Presence of atherosclerosis or
                            Diabetes < 100 mg /ml
Coronary Artery Disease

                          Recommended
                           levels of HDL
                             >35 mg/ml
Coronary Artery Disease

                               High cholesterol
                             >200mg/ml with LDL
                          >130 mg/ml increases risk
                           of heart attack 2.4 times
Coronary Artery Disease   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.”
Coronary Artery Disease
                          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
Coronary Artery Disease   Cholesterol 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
Coronary Artery Disease


            LOVASTATIN MEVACOR
Coronary Artery Disease   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%
Coronary Artery Disease

                          Alcohol 1 to 2 glasses a
                          day reduces cholesterol,
                              reduces clotting
Coronary Artery Disease
                             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
Coronary Artery Disease


                             Aspirin inhibits
                          platelet aggregation
Coronary Artery Disease
                          Aspirin 325 mg every other
                          day for 4.5 years 22000
                          male MDs
                          Aspirin    194 MI    5 deaths
                          Controls   189 MI   18 deaths
Coronary Artery Disease
                          2418 Israeli women 100
                          to 500 mg Aspirin every
                          other day for 3 years
                          • 40% less MI mortality
                          • 34% less general mortality
Coronary Artery Disease


                          thrombus




                                     Early infarct affecting left
                                     ventricle
Coronary Artery Disease




                          Cross section of heart with area of necrosis
Coronary Artery Disease




                          Infarct in ventricular wall with loss of muscle and
                          scarring
Coronary Artery Disease




                          Area of previous infarct with rupture of ventricular
                          wall
Coronary Artery Disease


                             Histology of
                          Myocardial Infarction
Coronary Artery Disease




   Normal heart muscle
Coronary Artery Disease




                          Beginning of infarct, loss of striations and nuclei of
                          cardiac muscle
Coronary Artery Disease




                          Continued loss of cellular vitality of myocardium
Coronary Artery Disease




                          Myocardial infarct with replacement of necrotic
                          myocardium with inflammatory cells and fibroblasts
Coronary Artery Disease




                          Established infarct with fibrotic scarring in
                          myocardium
Coronary Artery Disease    Systematic review of
                              the association
                            between respiratory
                             diseases and oral
                          heaith. Azarpazhooh. A.
                                     J.
                          PERIODONT.2006.77:1
                                    465.
Coronary Artery Disease    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.
Coronary Artery Disease
                              FURTHER
                          READING CLINICAL
                          PERIODONTOLOGY
                            10 th EDITION
                            CHAPTER 18

				
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