Correlation between carotid area calcifications and periodontitis: a retrospective study of digital panoramic radiographic findings in pretreatment cancer patients

Correlation between carotid area calcifications and periodontitis: a retrospective study of digital panoramic radiographic findings in pretreatment cancer patients Brice W. Beckstrom, DMD, MS,a Scott H. Horsley, BS, DDS, MS,b James P. Scheetz, PhD,c Zafrulla Khan, DDS,d Anibal M. Silveira, DDS,e Stephen J Clark, DMD,f Henry Greenwell, DMD, JD, MSD,g and Allan G. Farman, BDS, PhD, DSc, MBA,h Louisville, KY THE UNIVERSITY OF LOUISVILLE

Objectives. The objective of this study was to examine the prevalence of carotid area calcifications retrospectively detected on digital panoramic radiographs of pretreatment cancer subjects, and to correlate the finding of such calcifications with radiographic evidence of periodontal bone loss in the same subjects. Study design. Digital panoramic radiographs of 201 subjects were evaluated for calcifications projected in the carotid artery bifurcation area as well as for alveolar bone loss as a result of periodontal disease. Inclusion criteria were unobscured carotid artery bifurcation regions bilaterally and sufficient index teeth present with a definable cementoenamel junction and alveolar crest. Radiographs were independently observed for carotid area calcifications and for periodontal status. Image enhancements permitted for detection of calcifications projected in the carotid area included window/level, inverse, and emboss. Periodontal measurements were made on index teeth using proprietary imaging software and a mouse-driven measurement algorithm. A 3-factor analysis of variance was performed with 3 betweensubjects comparisons. Percentage of bone loss was the dependent variable. Independent variables were age, subject sex, and the presence or absence of carotid area calcifications. Results. Differences measured in percentage of bone loss between sexes were not statistically significant. While bone loss did increase with age, comparison of the mean bone loss of each age category revealed no statistical significance. There was a highly significant correlation between carotid artery area calcifications visible on panoramic radiographs and percent alveolar bone loss. Radiographs showing unilateral and bilateral calcifications had a mean percent bone loss of 24.2% ⫾ 12.6% and 25.7% ⫾ 13.0% respectively, compared to those with no calcification at 10.4% ⫾ 9.9%. Conclusions. Nearly 1 in 4 subjects in this study evidenced calcifications projected in the carotid bifurcation region. The finding of such calcifications was significantly related to the calculated percentage of alveolar bone loss. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:359-66)

In the United States, each year close to a million people die as the result of vascular disease (⬃960,000 in 1998).1 There are 12.6 million individuals living with diagnosed coronary artery disease and 4.6 million suffering from the effects of a cerebral vascular acci-

From the School of Dentistry, The University of Louisville. a Graduate student in Orthodontics. b Graduate student in Endodontics. c Professor of Biostatistics. d Professor of Prosthodontics; and Director of Maxillofacial Prosthetics and Oncologic Dentistry, The James Graham Brown Cancer Center. e Associate Professor of Orthodontics. f Associate Professor of Endodontics and Director of the Endodontics Graduate Program. g Professor and Chair of Periodontics. h Professor and Head of Oral Radiology and Imaging Science. Received for publication Dec 16, 2005; returned for revision Aug 7, 2006; accepted for publication Aug 23, 2006. 1079-2104/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2006.08.016

dent.1,2 At the genesis of both disorders lies the formation of atherosclerotic plaques, partially or completely blocking blood flow to tissues lying beyond the obstruction. The atherosclerotic process begins with the disruption of the endothelial lining of an artery. As part of an inflammatory response to the damaged artery, platelet-derived growth factors pass through the hyperpermeable vessel lining causing proliferation of smooth muscle, an integral part of the vessel wall. Lipoproteins in the bloodstream become lodged in the vessel wall where damage has occurred, further adding size to the developing plaque. This thickened and raised lesion protrudes into the vessel lumen altering blood flow.2 Severe periodontitis occurs in 10% to 30% of different populations.3 The associated immune response may exert an endothelial cytotoxic effect known to be a risk for atherosclerosis. Elevated serum concentrations of inflammatory mediators such as serum amyloid A, Creactive protein (CRP), fibrinogen, tumor necrosis factor-alpha, and interleukin-6 (IL-6) have been reported in periodontal patients.4-6 Periodontal treatment has 359

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been reported to decrease the serum concentrations of CRP, IL-6, and tumor necrosis factor.7-9 Systemic inflammation could well be activated in conjunction with the local response of the inflamed periodontium.6,10 Periodontal pathogens have been demonstrated in atherosclerotic plaques removed during carotid endarterectomy.11 Severe periodontal bone loss has proven to be associated with carotid atherosclerosis.12-14 An association between periodontal disease and ischemic stroke has also been reported.15-18 Approximately 730,000 people, or 120 per 100,000, have strokes (cerebral vascular accidents) each year.19 Stroke is the third leading cause of death in the United States surpassed only by cardiovascular disease and cancer. It is also a major public health issue, being the leading cause of acquired severe disability. Treatment of stroke costs $40 billion annually in the United States alone.19 There are 2 major types of stroke, ischemic and hemorrhagic. Hemorrhagic stroke, caused by leaking or ruptured arteries in the cerebrum, represents only 15% of all strokes.20 In a hemorrhagic stroke blood from a ruptured vessel spills into the surrounding brain tissue depriving oxygen and nutrients to neural tissues distal to the rupture. Ischemic stroke usually results from atherosclerotic plaques and thrombolytic emboli. It accounts for 85% of all strokes. The principal blood supply to the head and neck is the bilateral common carotid arteries. The right common carotid artery commences at the bifurcation of the subclavian artery behind the sternoclavicular joint. The left common carotid artery arises from the highest part of the aortic arch and consists of a thoracic and a cervical portion. The common carotid arteries ascend in the neck and, at the level of the superior border of the thyroid cartilage, they bifurcate into internal and external carotid arteries. The external carotids supply the exterior of the head, the face, and the majority of the neck while the internal carotid supplies the majority of structures within the cranial and orbital cavities. Factors predisposing to carotid atherosclerosis include advancing age, male sex, systolic hypertension, hypercholesterolemia, cigarette smoking, diabetes mellitus, obesity, haemostatic factors, sleep apnea, head and neck radiation therapy, and coronary artery disease.21-27 Patients with such conditions have a greater prevalence of calcified carotid atheromas visible on panoramic radiographs than do healthy age-matched persons.21-27 Carotid atheromatous calcifications appear as vertico-linear, nodular, or heterogeneous radiopaque masses projected to the lower corners of standard dental panoramic radiographs. This is at the level of the lower margin of the third and entirety of the fourth cervical vertebra, and about 1.5 to 2.5 cm inferior-posterior to the angle of the mandible.20,28

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Published studies of the prevalence of carotid artery calcifications appearing on panoramic radiographs report a range of 2% to 5% for the general population.1,29 The prevalence of calcified carotid plaques is approximately 5% for individuals 55 years or older.29 At our institution, Chen et al.30 studied pretreatment patients with cancer and found a prevalence of 7% with carotid calcifications using analog panoramic radiographs. In 2002, Almog et al.29 correlated calcifications at the carotid bifurcation with clinically relevant carotid artery stenosis by using duplex ultrasound. Clinically significant carotid stenosis (⬍ 50% luminal narrowing) was present in 50% of the sides with calcification compared with 21% of the sides without calcification. Cohen et al.1 determined that patients having calcified carotids demonstrated on panoramic radiographs had a relatively high rate of major end-points such as stroke, myocardial infarction, and sudden death. It has been reported that patients with more than 60% carotid artery occlusion could have their risk of stroke cut in half if endarterectomy is performed to remove the atheroma from the blocked artery.31 Those individuals with lesser degrees of stenosis can reportedly be treated with a drug regimen that reduces embolus formation.32,33 Most prior studies have used analog film-based imaging precluding post-enhancement of images except with use of “hot light” illumination. The objectives of this study are to examine the prevalence of carotid-area calcifications retrospectively detected on digital panoramic radiographs of pretreatment cancer subjects, and to correlate the finding of such calcifications with radiographic evidence of periodontal bone loss of the same subjects. This study also provided the opportunity to compare determined prevalence of carotid area calcifications in digital panoramic radiographs for a population previously investigated using analog film panoramic radiographs.30 STUDY DESIGN With institutional review board approval, digital panoramic radiographs of 262 subjects diagnosed with head/neck cancer were evaluated for inclusion in the study. The panoramic radiographs had been made between June 2000 and September 2004 using an Instrumentarium OP 100 D (Tuusula, Finland) digital panoramic system, set at 73 kVp and 10 mA for an exposure cycle of 17.6 seconds. Images were stored on a desktop computer and viewed using CliniView software (Instrumentarium). Inclusion criteria were (1) preradiation cancer patient, (2) unobscured carotid artery bifurcation regions bilaterally, (3) presence of index teeth (as described later in this section), and (4) a definable cementoenamel junction (CEJ) and alveolar crest for each index

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Fig. 1. Detail of a panoramic radiograph showing nodular heterogeneous radiopaque calcification in region of right carotid artery bifurcation. In this case the lesion was obvious without subsequent image enhancements and window/level adjustment was not needed.

tooth. Of the 262 radiographs initially evaluated, 18 were excluded because of inadequate visualization of 1 or more carotid regions of interest and 43 were excluded because of lack of the requisite index teeth. Of the remaining 201 subject radiographs that were included in the study, 138 were from men and 63 from women. The mean age of the included subjects was 52.1 years (range 11-87 years). A board-certified oral and maxillofacial radiologist verified that the soft tissue triangles anterior to the third and fourth cervical vertebrae were included in the image. Subjects were excluded because of inadequate coverage of 1 or more carotid regions of interest (ROI). The remaining images were then window and leveled to adjust brightness and contrast to better reveal the contents of the soft tissues in the ROI. Each ROI was zoomed to magnify the carotid bifurcation regions bilaterally. The contrast of each

ROI was gradually increased both in positive and in negative display modes. An emboss algorithm provided in the proprietary software was also applied in each case (Fig. 1). Calcifications projected in the carotid region on the digital panoramic radiographs were noted on a spreadsheet and also recorded by saving enhanced regions of interest as JPEG files. Calcifications of obvious anatomic origin other than the carotid (e.g., epiglottis and rhomboid-shaped calcifications of the trititious cartilage) were excluded; however, subjects were not recalled for additional tests to verify findings. Hence inclusion of some false-positive findings was possible. Evaluation for calcifications in the “carotid region” was performed by a board-certified oral and maxillofacial radiologist. The panoramic images were then independently examined for radiographic evidence of periodontal bone

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loss by the first author who had been calibrated by a board-certified periodontist, and was blinded to the findings with respect to carotid-area calcifications. Percent alveolar bone loss was calculated using the Progressive Rate Index (PRI) devised and reported by Craft et al.34 Periodontal measurements were made on index teeth using CliniView (Instrumentarium) proprietary imaging software. The alveolar crest was considered to be that point at which the periodontal ligament maintained a normal width. The normal height of the alveolar crest was defined as 1 mm apical to the CEJ. The radiographic root length of all teeth was measured from the CEJ to the root tip. To determine the percentage of bone loss for each tooth, the distance from the CEJ to the alveolar crest minus 1 was divided by the root length and multiplied by 100. Total bone loss was calculated in a similar manner by adding the individual values from a given subject then dividing the total by the number of teeth. As the measures were essentially ratios, magnification implicit in panoramic radiography was factored out automatically. The 6 tooth indices included the mesial of the maxillary and mandibular first molars, second premolars, and central incisors. If 1 of these teeth was missing or unreadable, the most clearly observed next tooth surface in the same sextant was used as a replacement. If no other tooth in the sextant was present, or all teeth in the sextant were deemed unreadable, then no measurement was performed for that sextant. If measurements were impossible for 1 or 2 sextants for a given patient, the sum of 4 measurements from their respective sextants was used in the conversion to percent bone loss. A 3-factor analysis of variance (ANOVA) was performed with 3 between-subjects comparisons. Percent bone loss was used as the dependent variable. The 3 independent variables were age, subject sex, and the presence or absence of carotid artery calcifications unilaterally or bilaterally. Subjects were divided into the following age categories: (1) younger than 50 years; (2) 50 to 59 years; (3) 60 to 69 years; and (4) 70 years or older. The arithmetic means, standard deviations, and correlations in each category were also determined. Descriptive measures were graphically summarized using box and whisker plots. RESULTS Of the 201 subjects included in the study, 23 (11.4%) had unilateral calcifications and 24 (11.9%) had bilateral calcifications in the anatomic region of the carotid bifurcation. No calcifications were visible on panoramic radiographs for the other 154 (76%).

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Fig. 2. Distribution of carotid area calcifications according to subject sex.

Subject sex Of the 138 male subjects, 121 (87.7%) had no detectable calcifications, 17 (12.3%) had unilateral calcifications, and 14 (10.1%) had bilateral calcifications in the region consistent with possible calcified carotid atheroma. Of the 63 female subjects, 57 (90.5%) had no detectable calcifications, 6 (9.5%) were found to have unilateral calcifications, and 10 (15.9%) had bilateral calcifications (Fig. 2). Differences measured in percent bone loss comparing the 2 sexes were not statistically significant (P ⫽ .203). Males had a mean bone loss of 14.7% ⫾ 12.4%, while the mean bone loss for females was 11.8% ⫾ 11.9% (Fig. 3). Subject age Of the 81 subjects younger than 50 years, 70 (86.4%) had no detected calcifications in the region consistent with possible calcified carotid atheroma, 5 (6.2%) were positive for unilateral calcification, and 6 (7.4%) were positive for bilateral calcifications (Fig. 4). Of the 63 subjects 50 to 59 years, 54 (85.7%) had no detected calcifications in the region consistent with possible calcified carotid atheroma, 4 (6.4%) had unilateral calcifications, and 5 (7.9%) bilateral calcifications. Of the 32 patients 60 to 69 years, 19 (59.4 %) had no detected calcifications in the region consistent with possible calcified carotid atheroma, 6 (18.8%) had unilateral calcifications, and seven (21.9%) bilateral calcifications. Of the 25 patients 70 years or older, 11 (46%) had no detected calcified atheroma, 8 had unilateral calcifications (32%), and 6 (24%) had bilateral calcifications. Persons younger than 50 years had a mean percent bone loss of 9.9% ⫾ 12.0. Those aged 50 to 59 years had a mean bone loss of 14.5% ⫾ 12.0%. Those aged 60 to 69 years had a mean bone loss of 18.4% ⫾ 11.3%. Those aged 70 years and older had a mean bone loss of 18.7% ⫾ 11.5% (Fig. 5). While bone loss did increase with age, comparison of the mean bone loss of each age

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Fig. 3. Distribution of periodontal bone loss experience according to subject sex.

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Fig. 5. Distribution of periodontal bone loss experience according to subject age grouping.

Table I. Percent periodontal bone loss (age groups compared)

Fig. 4. Distribution of carotid area calcifications according to subject age grouping.

Age, y

n

Mean % bone loss

SD

P

⬍50

81

9.90

⫾12.03

50–59

63

14.54

⫾11.99

60–69

32

18.44

⫾11.27

70⫹

25

18.68

⫾11.50

.361 (vs 50–59) .994 (vs 60–69) 1.000 (vs 70⫹) .361 (vs ⬍50) .187 (vs 60–69) .602 (vs 70⫹) .994 (vs ⬍50) .187 (vs 50–59) .947 (vs 70⫹) 1.000 (vs ⬍50) .602 (vs 50–59) .947 (vs 60–69)

category revealed no statistically significant differences (Table I). Carotid area calcifications There was a highly significant correlation between carotid artery–area calcifications visible on panoramic radiographs and percent alveolar bone loss (Fig. 6, Table II). Radiographs showing unilateral and bilateral calcifications had a mean percent bone loss of 24.2% ⫾ 12.6% (P ⫽ .000) and 25.7% ⫾ 13.0% (P ⫽ .000), respectively, compared to those with no calcification at 10.4% ⫾ 9.9% (P ⫽ .845). There was an interaction between calcification and subject sex that should be taken into account when evaluating the findings. DISCUSSION Periodontitis is a common disease in most populations; hence, its possible contribution to vascular disease is of potential importance.3,6 Bacterial release of lipopolysaccharide results in an inflammatory state that

may trigger cytokines and tissue destructive mediators in circulating inflammatory mediator cells.6 Elevated serum concentrations of inflammatory mediators such as serum amyloid A, CRP, fibrinogen, tumor necrosis factor-alpha, and IL-6 have been reported in periodontal patients.4,5 Furthermore, as stated in the introduction, periodontal treatment has been reported to decrease the serum concentrations of CRP, IL-6, and tumor necrosis factor-alpha.7-9 Therefore, the pathogenesis for systemic inflammation could be activated in conjunction with the local response of the inflamed periodontium.6 Chronic inflammation is directly associated with atherogenesis; CRP predicts future coronary ischemic events in initially healthy individuals and in patients with preexisting coronary heart disease (CHD).35 The combination of chronic infection and elevated CRP concentration is associated with a signif-

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Fig. 6. Correlation between periodontal bone loss and carotid area calcifications.

Table II. Percent periodontal bone loss versus carotid area calcification Carotid area calcification

n

Mean % bone loss

SD

P

154

10.41

⫾ 9.94

Unilateral

23

24.17

⫾12.61

Bilateral

24

25.67

⫾13.03

⬍.001(vsunilat) ⬍.001(vs bilat) ⬍.001(vs none) .845(vs bilat) ⬍.001(vs none) .845(vsunilat)

None

icantly higher CHD risk than either factor by itself.7,36 This also might apply to periodontitis.10 It has been hypothesized that oral microorganisms, including periodontal bacterial pathogens, that enter the blood stream during transient bacteremias could play a role in the development and progression of atherosclerosis leading to cardiovascular disease.11 Human specimens were obtained during carotid endarterectomy and examined for Chlamydia pneumoniae, human cytomegalovirus, and bacterial 16S ribosomal RNA. Periodontal pathogens were present in atherosclerotic plaques.37 D’Aiuto et al.17 studied the correlation between periodontitis and atherogenesis. Subjects with severe generalized periodontitis were enrolled into a prospective single blind longitudinal intervention trial. Serum CRP and IL-6 levels were assessed. Serological and clinical periodontal parameters were evaluated at baseline and 2 and 6 months after completion of nonsurgical periodontal therapy. In the subjects who completed this trial there were improvements in all clinical periodontal parameters accompanied with significant reductions in

serum IL-6 and CRP concentrations. In a multivariate model, serum CRP levels were significantly associated with the outcome of periodontal treatment after correcting for potential covariates. It was concluded that control of periodontitis, achieved with nonsurgical periodontal therapy, significantly decreased serum mediators and markers of acute phase response. The results of D’Aiuto et al.’s study17 indicated that severe generalized periodontitis causes systemic inflammation. This is consistent with a causative role of periodontitis in atherogenesis. Our study found that 47 (24%) of 201 preradiation head and neck cancer patients were positive for calcifications in the carotid bifurcation region that were visible on panoramic radiographs. This differs drastically from results found in 2001 by Chen et al.30 also studying panoramic radiographs for calcifications in the region consistent with possible calcified carotid atheroma. One explanation for the disparity between the two studies (7% versus 24%) is the difference in viewing techniques. The 2001 study was performed on a similar study population but film-based radiographs were viewed on a light box. In the current study digital radiographs were used and the resulting images could be enhanced to better visualize the carotid bifurcation region. It is also plausible that increased visibility of noise could lead to some of the discrepancy as this might produce an increased number of false positives using the digital system. This question awaits further research. Other studies reporting the frequency of carotid calcifications on panoramic radiographs have ranged from 0.43% on an African American population to 37% on a population of white males with a history of recent stroke.20,21 Consensus from previous studies has been that the frequency of calcifications visible on panoramic radiographs of individuals aged 55 and older is approximately 5% and in the general population averages around 2.5%.29 However, if the previous studies were repeated using the imaging techniques employed in our study, the detection rates might well be higher. In 1995, Engebretson et al.14 found a nearly 4-fold increase in the presence of carotid artery plaques in patients with severe periodontal disease. Ravon et al.12 reported that patients with carotid artery calcifications detected by duplex ultrasound were more likely to have more teeth with over 5 mm of alveolar bone loss measured on a panoramic radiographs than those negative for carotid artery atherosclerosis (P ⫽ .001). Our study is in agreement with these 2 previous studies finding significance between the presence of carotid artery calcifications visible on panoramic radiographs and increased percent alveolar bone loss (P ⫽ .000). While carotid artery pathoses potentially can be ob-

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served using dental panoramic radiographs, problems inherently exist with this imaging modality limiting its usefulness in diagnosing atherosclerosis. While many atheromatous plaques are calcified, thus appearing as radiopacities on standard radiographs, many are not. Also it is possible for calcifications to appear in the lining of blood vessels without the presence of atherosclerosis. Additional limitations of panoramic imaging include the inability of practitioners to quantify the amount of stenosis of a vessel with a recognized radiopacity and the difficulty of accurately diagnosing these lesions as true carotid plaques without advanced training. Different panoramic systems result in nonidentical radiographic images. Some panoramic systems are likely to be less able to detect carotid area calcifications than are others. Some machines position the label of demographic information and date of exposure in a position that may obscure the carotid artery. Because of these limitations panoramic radiographs should never be used to clear someone of vascular disease or to make a definitive diagnosis. It should only be used as an adjunctive screening tool during normal dental examination and treatment.38 Given the high prevalence of atherosclerosis in many studies conducted in the United States, perhaps the provision of duplex ultrasound screening of all males aged 40 years and older and women aged 50 years and older would be a valuable public health objective. Until that happens, the dentist may well be the first to detect carotid atheroma that heralds more widespread vascular disease. This study did not use ultrasound confirmation of findings so it probably does include some calcifications other than those caused by carotid atheroma. Further, periodontal assessments were made using panoramic radiographs alone. So while precision was consistent, it is perhaps less than would be achieved with a thorough clinical assessment using probing combined with a series of standardized intraoral radiographs using paralleling geometry. These caveats should be kept in mind when considering the results. CONCLUSIONS Nearly 1 in 4 pretreatment cancer patients studied using digital panoramic radiographs evidenced calcifications on panoramic radiographs projected in the carotid bifurcation region. The finding of such calcifications was significantly related to the severity of alveolar bone loss calculated in this study. The 24% prevalence for carotid-area calcifications in the present study using digital panoramic radiographs is substantially greater than the 7% prevalence previously determined for a similar population at the same institution when analog radiographs produced on a different panoramic system were examined several years ago. It is hypothesized

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that this difference is because of the enhancement capabilities provided with digital images. REFERENCES 1. Cohen SN, Friedlander AH, Jolly DA, Date L. Carotid calcifications on panoramic radiographs: an important marker for vascular risk. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:510-4. 2. Friedlander AH, Altman L. Carotid artery atheromas in postmenopausal women. Their prevalence on panoramic radiographs and their relationship to atherogenic risk factors. J Am Dent Assoc 2001;132:1130-6. 3. Papapanou PN. Epidemiology of periodontal diseases: an update. J Int Acad Periodontol 1999;1:110-6. 4. Amar S, Gokce N, Morgan S, Loukideli M, Van Dyke TE, Vita JA. Periodontal disease is associated with brachial artery endothelial dysfunction and systemic inflammation. Arterioscler Thromb Vasc Biol 2003;23:1245-9. 5. Scannapieco FA, Bush RB, Paju S. Association between periodontal disease and risk for atherosclerosis, cardiovascular disease, and stroke. A systematic review. Ann Periodontal 2003;8: 38-53. 6. Pussinen PJ, Mattila K. Periodontal infections and atherosclerosis: mere associations? Curr Opin Lipidol 2004;15:583-8. 7. Mattila K, Vesanen M, Valtonen V, Nieminen M, Palosuo T, Rasi V, et al. Effects of treating periodontitis on C-reactive protein levels: a pilot study. BMC Infect Dis 2002;2:30. 8. Iwamoto Y, Nishimura F, Soga Y, Takeuchi K, Kurihara M, Takashiba S, et al. Antimicrobial periodontal treatment decreases serum C-reactive protein, tumor necrosis factor-alpha, but not adiponectin levels in patients with chronic periodontitis. J Periodontol 2003;74:1231-6. 9. D’Aiuto F, Parkar M, Andreou G, Brett PM, Ready D, Tonetti MS. Periodontitis and atherogenesis: causal association or simple coincidence? J Clin Periodontol 2004;31:402-11. 10. Ajwani S, Mattila KJ, Narhi TO, Tilvis RS, Ainamo A. Oral health status, C-reactive protein and mortality: a 10 year follow-up study. Gerodontology 2003;20:32-40. 11. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ. Identification of periodontal pathogens in atheromatous plaques. J Periodontol 2000;71:1554-60. 12. Ravon NA, Hollender LG, McDonald V, Persson GR. Signs of carotid calcification from dental panoramic radiographs are in agreement with Doppler sonography results. J Clin Periodontol 2003;30:1084-90. 13. Desvarieux M, Demmer RT, Rundek T, Boden-Albala B, Jacobs DR Jr, Papapanou PN, et al. Relationship between periodontal disease, tooth loss, and carotid artery plaque: the Oral Infections and Vascular Disease Epidemiology Study (INVEST). Stroke 2003;34:2120-5. 14. Engebretson SP, Lamster IB, Elkind MS, Rundek T, Serman NJ, Demmer RT et al. Radiographic measures of chronic periodontitis and carotid artery plaque. Stroke 2005;36:561-6. 15. Beck JD, Elter JR, Heiss G, Couper D, Mauriello SM, Offenbacher S. Relationship of periodontal disease to carotid artery intima-media wall thickness: the atherosclerosis risk in communities. Arterioscler Thromb Vasc Biol 2001;21:1816-22. 16. Joshipura KJ, Hung HC, Rimm EB, Willett WC, Ascherio A. Periodontal disease, tooth loss, and incidence of ischemic stroke. Stroke 2003;34:47-52. 17. D’Aiuto F, Parkar M, Andreou G, Suvan J, Brett PM, Ready D, et al. Periodontitis and systemic inflammation: control of the local infection is associated with a reduction in serum inflammatory markers. J Dent Res 2004; 83:156-60.

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29. Almog DM, Horev T, Illig KA, Green RM, Carter LC. Correlating carotid artery stenosis detected by panoramic radiography with clinically relevant carotid artery stenosis determined by duplex ultrasound. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:768-73. 30. Chen J, Beckstrom B, Greenwell H, Drisko CL, Abaskaron M, Khan Z, et al. Incidence of carotid artery calcification in a head and neck cancer population. Amer Assoc Dent Res, Chicago, IL. J Dent Res 2001;80(SI):70 (Abstract 276) 31. Towne JB. Current status of operative treatment for asymptomatic carotid stenosis. Can J Surg 1994;37:128-34. 32. Clagett GP, Graor RA, Salzman EW. Antithrombotic therapy in peripheral arterial occlusive disease. Chest 1992;102:516S-28S. 33. Cesarone MR, Laurora G, DeSanctis MT, Incandela L, Fugazza L, Girardello R, et al. Effects of triflusal on arteriosclerosis progression assessed with high-resolution arterial ultrasound. Angiology 1999;50:455-63. 34. Craft G, Wang A, Vance G, Yancey J, Greenwell H. The periodontitis progression rate index: methodologic considerations. Periodontal Insights 2000;6:37-44. 35. Muhlestein JB, Anderson JL. Chronic infection and coronary artery disease. Cardiol Clin 2003;21:333-62. 36. Zhu J, Quyyumi AA, Norman JE, Csako G, Epstein SE. Cytomegalovirus in the pathogenesis of atherosclerosis: the role of inflammation as reflected by elevated C-reative protein levels. J Am Coll Cardiol 1999;34:1738-43. 37. Cairo F, Gaeta C, Dorigo W, Oggioni MR, Pratesi C, Pini Prato GP, et al. Periodontal pathogens in atheromatous plaques. A controlled clinical and laboratory trial. J Periodontal Res 2004;39:442-6. 38. Farman AG. Panoramic radiology and the detection of carotid atherosclerosis. Panoramic Imaging News 2001;1(2):1-6. Reprint requests: Allan G. Farman, BDS, PhD, DSc, MBA Department of Surgical and Hospital Dentistry The University of Louisville 501 South Preston Street Louisville, KY 40292 [email protected]