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An association between periodontal disease and peripheral vascular disease
An Association between Periodontal Disease and Peripheral Vascular Disease Manuel V. Mendez, MD, Thayer Scott, MPH, Wayne LaMorte, MD, PhD, MPH, Pantel Vokonas, MD, James O. Menzoian, MD, Raul Garcia, DMD, Boston, Massachusetts
BACKGROUND: Periodontal disease has been shown to be associated with increased risk of coronary heart disease. Because coronary heart disease and peripheral vascular disease (PVD) have similar pathophysiologies, we hypothesized that periodontal disease might be a risk factor for PVD. METHODS: Using the combined data from the Normative Aging Study and Dental Longitudinal Study of the US Department of Veterans Affairs, we examined the relationship between PVD and periodontal disease. Multivariate logistic regression analysis was used. RESULTS: Over the 25 to 30 years of follow-up, 80 of these initially healthy subjects developed PVD. Compared with controls (n 5 1,030), subjects with clinically significant periodontal disease at baseline had a 2.27 increment in the risk of developing PVD (95% confidence interval 1.32 to 3.9, P value 5 0.003). CONCLUSIONS: Periodontal disease emerged as a significant independent risk factor for PVD in a multivariate analysis that adjusted for other established risk factors. Am J Surg. 1998;176:153– 157. © 1998 by Excerpta Medica, Inc.
H
istorically, peripheral vascular disease (PVD) has received relatively little attention by epidemiologists. In contrast, a considerable amount of research has concentrated on risk factors for coronary heart
From the Section of Vascular Research (MVM), and Section of Surgical Research (TS, WL), Department of Surgery, Boston University School of Medicine; the Normative Aging Study (PV, RG), VA Outpatient Clinic, Department of Medicine, Boston University School of Medicine, and Department of Epidemiology and Biostatistics (PV), Boston University School of Public Health; the Section of Vascular Surgery (JOM), Boston University Medical Center; and Department of Health Policy and Health Services Research, Boston University Goldman School of Dental Medicine (RG), Boston, Massachusetts. The VA Normative Aging Study and VA Dental Longitudinal Study are supported by the VA HSR&D Service, US Department of Veteran Affairs. The studies are components of the Massachusetts Veterans Epidemiology Research and Information center. Dr. Garcia is recipient of a VA Career Development Award in Health Services Research from VA HSR&D Services. Requests for reprints should be addressed to James O. Menzoian, MD, Department of Surgery, Section of Vascular Surgery, Boston Medical Center, 88 East Newton Street, D-506, Boston, Massachusetts 02118. Presented at the 26th Annual Meeting of The Society for Clinical Vascular Surgery, Coronado, California, March 25–29, 1998.
© 1998 by Excerpta Medica, Inc. All rights reserved.
disease and stroke. Recently, the role of inflammation in the development and progression of atherosclerosis has attracted a great deal of interest. Since 1970, several reports have been published on the association between human coronary heart disease (CHD) and certain persistent bacterial and viral infections.1 Chronic inflammatory conditions, such as bronchitis and periodontal disease, have also been reported as independent risk factors for coronary heart disease (CHD) and stroke.2,3 Periodontal disease is a Gram-negative chronic infection of the tooth supporting structures in which alveolar bone resorption is a recognized hallmark for the severity of this chronic infection.4 In 1996, Beck et al2 reported that persons with clinically significant periodontal disease were at significantly elevated risk for subsequently developing CHD (1.5fold), fatal CHD (1.9-fold), and stroke (2.8-fold). This longitudinal study used data from more than 1,000 men in good health at baseline followed up for over 20 years.2 Because atherosclerosis is a common pathophysiologic mechanism for both CHD and PVD, we hypothesized that periodontal disease should also be an independent risk factor for the development of PVD.
METHODS The US Department of Veteran Affairs (VA) Normative Aging Study (NAS) is a closed panel longitudinal study that began in 1961 and followed up 2,280 men from the greater Boston area. These subjects ranged from 21 to 80 years of age at the time of entry, and were free of known chronic medical conditions. In 1968, a subgroup of 1,231 began receiving comprehensive oral examinations, including clinical and radiographic assessments of the periodontium. Follow-up evaluations were done at 3-year intervals. While all subjects were veterans, they were not VA patients and used medical and dental services available in the community. Assessment of PVD Baseline history and physical examination were performed on all subjects upon entry and at each triennial follow-up visit. Additional information was provided from hospital records. PVD was defined as one or more of the following: (1) intermittent claudication (IC); (2) extracranial cerebrovascular disease (ECD); (3) atherosclerosis (including aortic, renal, and mesenteric disease); and (4) arterial embolism and thrombosis. Diseases were entered into the database according to the 8th revision of the International Classification of Diseases (ICD-8). Determination of Other Cardiovascular Risk Factors The baseline examination of the NAS included a medical history, physical examination, and a variety of biochemical 0002-9610/98/$19.00 PII S0002-9610(98)00158-5
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TABLE I
TABLE II
Frequency of the Various Types of Peripheral Vascular Disease CONDITION Intermittent claudication Extracranial CVD Other atherosclerosis (aorta, mesenteric, renal) Arterial embolism or thrombosis
No. of Observations
ICD-8 Codes
60 14
443.2; 443.9 432–435.9; 437–437.9
9
440–440.9
2
444–444.9
CVD 5 cerebrovascular disease.
laboratory tests. Serum cholesterol was measured with the colorimetric method of Sperry. An examining physician measured blood pressure in each arm by using a standard mercury sphygmomanometer. The average systolic and diastolic blood pressure in both arms was used for analysis. Cigarette smoking status (current, former, and never) was determined, with current smokers defined as men who smoke one or more cigarettes daily. Total exposure to cigarettes over the subject’s lifetime was also calculated at the time of enrollment. Weight and height were measured and body mass index (BMI) was calculated as weight in kg divided by height in m2. Alcohol drinking habits were ascertained from responses to the Cornell Medical Index. The data were supplemented by information on cardiovascular illnesses abstracted from medical records. Other Vascular Conditions CHD was defined as nonfatal myocardial infarction, angina pectoris, or death from cardiac diseases. The criteria for myocardial infarction, angina pectoris, and stroke were those used in the Framingham Heart Study.5 Assessment of Oral Conditions We used a radiographic measure of periodontal disease status. The loss of tooth supporting alveolar bone was estimated from full mouth intraoral periapical radiographs exposed at baseline following methods and criteria previously reported.6 Mesial and distal tooth surface were read independently by a trained examiner and scored for alveolar bone loss in 20% gradations using a 5-point Schei ruler.4 Mean bone loss across all readable interproximal sites was calculated for each subject by using the midpoint of the alveolar bone loss intervals scored. Significant periodontal disease was considered present if the mean whole mouth alveolar bone loss was .20%. Data Analysis The periodontal disease exposure variable at baseline was used to dichotomize the cohort into a clinically significant periodontal disease group (.20% bone loss) and a clinically insignificant periodontal disease group (,20% bone loss). The disease outcome used was incidence of PVD, as defined above, and the total period of observation was over 25 years. Logistic regression was used to estimate the ageadjusted odds ratios between the two periodontal disease status groups (SAS, Cary, North Carolina). Multiple logis154
Risk Factor Status at Baseline in Those Who Develop PVD and Those Who Did Not VARIABLE n Age Body mass index (kg/m2) Diastolic BP (mmHg) Systolic BP (mmHg) Cholesterol (mg/dl) Family Hx. heart disease High school education or more Two 1 drinks of alcohol/day Current smoking Former smoking Packs of cigarette smoked/ life 3 1000 Periodontal disease
Non-PVD Group (Range)
PVD Group (Range)
1,030 80 42.7 (23–80) 44.2 (29–62) 25.6 (16–38) 26.9 (21–34) 77.1 (45–105) 77.6 (55–90) 123.6 (93–170) 123.7 (103–140) 204.7 (97–397) 218 (133–364) 9% 20% 58% 11.1% 33.6% 31.5%
53% 12.5% 43.7% 31.2%
4.6 21.6%
7.5 42.5%
PVD 5 peripheral vascular disease.
tic regression was used to calculate adjusted odds ratios for periodontal disease and all relevant vascular risk factors. Finally, backward selection was used to remove nonsignificant variables (P $0.05). The data were further analyzed in two additional models: (1) excluding from the non-PVD group any clinically manifest atherosclerotic disease by removing those patients with other vascular conditions such as CHD, aneurysmal disease and venous disease; and (2) excluding those subjects with extracranial cerebrovascular disease from the PVD group.
RESULTS Of the 1,231 men in the original Dental Longitudinal Study (DLS) cohort, complete data for the purposes of our analysis was available on 1,110 subjects. Over the 25 years of follow-up, a total of 80 initially healthy subjects developed PVD and 1,030 did not. The crude incidence of PVD in subjects with significant periodontal disease at baseline was 13.3%, and for those without significant periodontal disease, 5.4%, producing a crude relative risk (RR) of 2.46. The frequency of the conditions observed for each type of PVD is shown in Table I. A comparison of baseline risk factors for patients who developed PVD versus those who did not is presented in Table II. Periodontal Disease and PVD After adjusting only for age, subjects with significant baseline periodontal disease had 2.6-fold greater risk of developing PVD compared with those without significant periodontal disease (95% confidence interval 1.6 to 4.2; P 5 0.0001). Table III presents adjusted odds ratios (OR) for periodontal disease and other significant vascular risk factors. Even after adjusting for age, BMI, family history of heart disease, and smoking exposure, periodontal disease was significantly associated to the subsequent development of PVD (OR 5 2.27; 95% confidence interval 1.32 to 3.9;
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TABLE III Significant Risk Factors Associated with Peripheral Vascular Disease
Association with PVD Variables Periodontal disease Age Body mass index Family history of heart disease Lifetime packs smoked
Association with PVD (Excluding Other Vascular Conditions from the Non-PVD)*
Association with PVD (Excluding Stroke from Cases)†
OR (95% CI)
P value
OR (95% CI)
P value
OR (95% CI)
P value
2.07 (1.3–3.4) 1.006 (0.9–1.03) 1.14 (1.06–1.24) 2.25 (1.2–4.1) 1.05 (1.01–1.09)‡
0.004 0.65 0.0007 0.009 0.003
2.24 (1.3–3.8) 1.01 (0.98–1.04) 1.2 (1.08–1.3) 2.43 (1.25–4.7) 1.05 (1.01–1.1)
0.003 0.33 0.0001 0.008 0.008
2.27 (1.32–3.9) 1 (0.97–1.03) 1.16 (1.07–1.27) 2.25 (1.18–4.2) 1.04 (1.0–1.08)
0.003 0.95 0.0003 0.01 0.03
OR 5 odds ratio; CL 5 confidence intervals; * Non-PVD, n 5 545; † PVD, n 5 69; ‡ Packs life X 1,000; Adjustment for other significant vascular risk factors was done in a backward stepwise regression model that included age despite being a nonsignificant variable. Relationships after removing other vascular conditions from non-PVD group and after removing stroke subjects from the PVD group are shown.
TABLE IV Association of Established Cardiovascular Risk Factors with PVD Association with PVD (Excluding Other Vascular Conditions from the Non-PVD)*
Association with PVD Variables Periodontal Disease Age Body mass index Lifetime packs smoked Family history of heart disease Current smoking Former smoking Systolic blood pressure Diastolic blood pressure Serum cholesterol level Two or more drinks/day Education beyond high school
OR (95% CI)
P Value
OR (95% CI)
P Value
2.17 (1.2–3.8) 1.002 (0.9–1.03) 1.16 (1.06–1.27) 1.11 (1.003–1.1) 2.18 (1.13–4.1) 0.82 (0.35–1.9) 0.65 (0.29–1.4) 1 (0.96–1.02) 1.004 (0.96–1.05) 1.004 (1–1.01) 0.85 (0.38–1.9) 1 (0.5–1.6)
0.006 0.91 0.0006 0.03 0.01 0.64 0.29 0.61 0.86 0.1 0.69 0.94
2.28 (1.2–4.0) 1.01 (0.97–1.04) 1.2 (1.08–1.3) 1.06 (1–1.1) 2.51 (1.2–5.1) 0.93 (0.38–2.2) 0.6 (0.2–1.5) 0.99 (0.96–1.02) 1.01 (0.96–1.06) 1.006 (1–1.01) 0.64 (0.26–1.53) 0.96 (0.5–1.6)
0.009 0.49 0.0002 0.05 0.01 0.88 0.33 0.72 0.61 0.05 0.31 0.88
OR 5 odds ratio; CI 5 confidence intervals; * (n 5 545). Adjustment for other vascular risk factors was done regardless their significance status using multivariate analysis. PVD definition excluded stroke patients (n 5 69). Associations after removing other vascular conditions from the control group are shown.
P 5 0.003). Table IV presents the odds ratios of the association between periodontal disease and PVD after adjusting for all established vascular risk factors, including nonsignificant. Even in this larger model, the association between periodontal disease and PVD remained highly significant. In fact, the risk of developing PVD among those with significant periodontal disease was 2.2 times greater than for those with insignificant periodontal disease. Strength of Association with Stroke Patients Removed From PVD Group Other studies have documented associations between stroke and CHD.2,3 To evaluate how much of the association found between periodontal disease and PVD was contributed by stroke subjects, the category of ECD was removed from the PVD definition. The resultant group is formed primarily by patients with intermittent claudication (IC). Table III demonstrates that removing stroke subjects from the PVD group did not alter the relationship between periodontal disease and PVD.
Strength of Association with Other Vascular Conditions Removed from non-PVD Group Our initial approach to the analysis of the data was to compare the group within our PVD definitions versus all other subjects including patients with other PVD definitions (ie, aneurysmal disease, chronic venous insufficiency) and other clinically manifest atherosclerotic disease (CHD). To further test the association between periodontal disease and PVD, we repeated the analysis after removing other vascular conditions from the non-PVD group. Table IV shows that removing other vascular conditions from the non-PVD group did not substantially modify the relationship between periodontal disease and PVD after adjusting for other significant risk factors.
COMMENTS In this prospective study we found that otherwise healthy men with clinically significant periodontal disease at baseline had an approximate twofold increase in their risk of subsequent development of PVD. This association is independent of other well-established cardiovascular risk fac-
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tors. Two other interesting observations were made: (1) A family history of heart disease was identified as a significant risk factor for the development of PVD, an observation that is intuitive but has not been well documented; and (2) the strength of the association between periodontal disease and PVD is comparable with that of other cardiovascular risk factors such as family history of heart disease. Upon enrollment into the study, subjects who eventually develop PVD had baseline higher serum cholesterol levels, were more likely to have a family history of heart disease, were more likely to be current smokers, and had smoked more cigarettes over their lifetime. Twice as many of the PVD subjects fell within the clinically significant periodontal disease category. The rest of the covariates were distributed evenly between the two groups (Table II). Atherosclerosis is the underlying pathophysiologic process for both PVD and CHD. Risk factors for atherosclerosis have been determined primarily from studies focused on coronary atherosclerosis,5 but may differ in the extent to which they are associated with various manifestations of atherosclerosis, such as brain infarction, CHD, or IC.7 Recently, infection and chronic inflammatory conditions have been identified as risk factors for CHD.2,3,8 –13 This is consistent with the histopathologic evidence involving central components of the immune response (T cells, macrophages, and immune-regulatory cytokines) in atherosclerotic lesions.14 Infectious pathogens (eg, Chlamydia pneumoniae, Helicobacter pylori, and viral infections such as cytomegalovirus and herpesvirus) have been linked to atherosclerosis by at least 70 articles in the literature.1 In 1993, De Stefano and coworkers8 reported results on a prospective study in which 9,760 subjects had oral examinations at baseline, and showing that those with periodontal disease had a 25% increased risk of developing CHD compared with those with minimal periodontal disease. Other groups have reported similar findings in longitudinal studies.2,9 Recently, a cross-sectional study of older US veterans identified several oral health variables as risk indicators for CHD, such as having 1 to 14 teeth, low salivary levels of Streptoccocus sanguis, positive plaque benzoyl-DL-arginine-naphthylemide (BANA) test scores, gingivitis involving bleeding, and a complaint of xerostomia.10 Our study is the first to show an association between periodontal disease and PVD and further supports the concept that chronic inflammatory conditions have a significant role in clinically manifest atherosclerosis. It does not provide a biologic framework to explain the mechanism by which these phenomena occur. However, we can speculate about the potential mechanistic pathways linking periodontal disease and PVD. Periodontal disease, a chronic Gram-negative/anaerobic infection, may contribute to the atherosclerosis process through any one of several potential mechanisms: (1) direct vascular injury by pathogens involved in periodontal infection, like Porphyromonas gingivalis, which become blood borne after mechanical trauma like daily tooth brushing or flossing and may reside at sites of endothelial injury within the vessel wall; (2) the bacterial load within the gingival pockets may provide a large source of lipopolysaccharide from Gram-negative bacteria that reaches the 156
systemic circulation without any enterohepatic clearance, and could lead to chronic activation of circulating monocytes15 and/or expression of a range of membrane molecules such as class A scavenger receptor (SR-A)16 or CD68/macrosialin17 molecules implicated in experimental and natural atherogenesis; and (3) elevated titers of serum anti-heat shock proteins 65/60 antibodies, known to be induced by periodontal disease, may have a pathogenic role in atherosclerosis based on their cytotoxic activity toward stressed human endothelial cells.18,19 Regardless of the mechanisms involved, prolonged exposure to any of these factors may be the primary determinant for the development of PVD. These findings should alert practitioners to the potential importance of periodontal disease as a substantial modifiable risk factor for PVD. Our findings suggest that oral health and oral examinations may provide an important means of identifying patients at risk and developing targeted interventions for primary prevention.
CONCLUSION Based on these data, clinically significant periodontal disease appears to be an independent, highly significant risk factor associated with PVD. These results suggest that chronic inflammatory diseases, such as periodontal disease, have a significant role in the development or progression of atherosclerotic PVD.
REFERENCES 1. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997;350:430 – 436. 2. Beck J, Garcia R, Heiss G, et al. Periodontal disease and cardiovascular disease. J Periodontol. 1996;67:1123–1137. 3. Grau AJ, Buggle F, Ziegler C, et al. Association between acute cerebrovascular ischemia and chronic and recurrent infection. Stroke. 1997;28:1724 –1729. 4. Schei O. Alveolar bone loss as related to oral hygiene and age. J Periodontol. 1959;30:7–16. 5. Shurtleff D. Some characteristics related to the incidence of cardiovascular disease and death: Framingham Study, 18-year follow-up. Bethesda: US Department of Health, Education, and Welfare. USDHEW publication NIH 74-599; 1974. 6. Feldman RS, Alman JE, Chauncey HH. Design and analysis considerations for a longitudinal study of periodontal disease. J Clin Periodontol. 1986;13:506 –510. 7. Gordon T, Kannel W. Predisposition to atherosclerosis in the head, heart and legs. JAMA. 1972;221:661– 666. 8. DeStefano F, Anda RF, Kahn HS, et al. Dental disease and risk of coronary heart disease and mortality. BMJ. 1993;306:688 – 691. 9. Joshipura KJ, Rimm EB, Douglass CW, et al. Poor oral health and coronary heart disease. J Dent Res. 1996;75:1631–1636. 10. Loesche WJ, Schork A, Terpenning MS, et al. Assessing the relationship between dental disease and coronary heart disease in elderly US veterans. JADA. 1998;129:301–311. 11. Melnick JL, Hu CH, Burek J, et al. Cytomegalovirus DNA in arterial walls of patients with atherosclerosis. J Med Virol. 1994;42: 170 –174. 12. Melnick SL, Shahar E, Folsom AR, et al. Past infection by Chlamydia pneumoniae strain TWAR and asymptomatic carotid atherosclerosis. Am J Med. 1993;95:499 –504. 13. Ridker PM, Cushman M, Stampfer MJ, et al. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97:425– 428. 14. Hansson GK. Immune and inflammatory mechanisms in the development of atherosclerosis. Br Heart J. 1993;69:S38 –S41.
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15. Shapira L, Soskolne WA, Sela MN, et al. The secretion of PGE2, IL-1 beta, IL-6, and TNF alpha by adherent mononuclear cells from early onset periodontitis patients. J Periodontol. 1994;65: 139 –146. 16. Haworth R, Platt N, Keshav D, et al. The macrophage scavenger receptor type A (SR-A) is expressed by activated macrophages and protects the host against lethal endotoxic shock. J Exp Med. 1997;186:1431–1439. 17. van Velzen AG, da Silva RP, Gordon S, van Berkel TJC.
Characterization of a receptor for oxidized low-density lipoproteins on rat Kupffer cells: similarity to macrosialin. Biochem J. 1997;322: 411– 415. 18. Schett G, Metzler B, Kleindienst R, et al. Salivary anti-hsp-65 antibodies as a diagnostic marker for gingivitis and a possible link to atherosclerosis. Int Arch Allergy Immunol. 1997;114:246 –250. 19. Schett G, Xu Q, Amberger A, et al. Autoantibodies against heat shock protein 65 mediate endothelial cytotoxicity. J Clin Invest. 1995;96:2569 –2577.
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BACKGROUND: Periodontal disease has been shown to be associated with increased risk of coronary heart disease. Because coronary heart disease and peripheral vascular disease (PVD) have similar pathophysiologies, we hypothesized that periodontal disease might be a risk factor for PVD. METHODS: Using the combined data from the Normative Aging Study and Dental Longitudinal Study of the US Department of Veterans Affairs, we examined the relationship between PVD and periodontal disease. Multivariate logistic regression analysis was used. RESULTS: Over the 25 to 30 years of follow-up, 80 of these initially healthy subjects developed PVD. Compared with controls (n 5 1,030), subjects with clinically significant periodontal disease at baseline had a 2.27 increment in the risk of developing PVD (95% confidence interval 1.32 to 3.9, P value 5 0.003). CONCLUSIONS: Periodontal disease emerged as a significant independent risk factor for PVD in a multivariate analysis that adjusted for other established risk factors. Am J Surg. 1998;176:153– 157. © 1998 by Excerpta Medica, Inc.
H
istorically, peripheral vascular disease (PVD) has received relatively little attention by epidemiologists. In contrast, a considerable amount of research has concentrated on risk factors for coronary heart
From the Section of Vascular Research (MVM), and Section of Surgical Research (TS, WL), Department of Surgery, Boston University School of Medicine; the Normative Aging Study (PV, RG), VA Outpatient Clinic, Department of Medicine, Boston University School of Medicine, and Department of Epidemiology and Biostatistics (PV), Boston University School of Public Health; the Section of Vascular Surgery (JOM), Boston University Medical Center; and Department of Health Policy and Health Services Research, Boston University Goldman School of Dental Medicine (RG), Boston, Massachusetts. The VA Normative Aging Study and VA Dental Longitudinal Study are supported by the VA HSR&D Service, US Department of Veteran Affairs. The studies are components of the Massachusetts Veterans Epidemiology Research and Information center. Dr. Garcia is recipient of a VA Career Development Award in Health Services Research from VA HSR&D Services. Requests for reprints should be addressed to James O. Menzoian, MD, Department of Surgery, Section of Vascular Surgery, Boston Medical Center, 88 East Newton Street, D-506, Boston, Massachusetts 02118. Presented at the 26th Annual Meeting of The Society for Clinical Vascular Surgery, Coronado, California, March 25–29, 1998.
© 1998 by Excerpta Medica, Inc. All rights reserved.
disease and stroke. Recently, the role of inflammation in the development and progression of atherosclerosis has attracted a great deal of interest. Since 1970, several reports have been published on the association between human coronary heart disease (CHD) and certain persistent bacterial and viral infections.1 Chronic inflammatory conditions, such as bronchitis and periodontal disease, have also been reported as independent risk factors for coronary heart disease (CHD) and stroke.2,3 Periodontal disease is a Gram-negative chronic infection of the tooth supporting structures in which alveolar bone resorption is a recognized hallmark for the severity of this chronic infection.4 In 1996, Beck et al2 reported that persons with clinically significant periodontal disease were at significantly elevated risk for subsequently developing CHD (1.5fold), fatal CHD (1.9-fold), and stroke (2.8-fold). This longitudinal study used data from more than 1,000 men in good health at baseline followed up for over 20 years.2 Because atherosclerosis is a common pathophysiologic mechanism for both CHD and PVD, we hypothesized that periodontal disease should also be an independent risk factor for the development of PVD.
METHODS The US Department of Veteran Affairs (VA) Normative Aging Study (NAS) is a closed panel longitudinal study that began in 1961 and followed up 2,280 men from the greater Boston area. These subjects ranged from 21 to 80 years of age at the time of entry, and were free of known chronic medical conditions. In 1968, a subgroup of 1,231 began receiving comprehensive oral examinations, including clinical and radiographic assessments of the periodontium. Follow-up evaluations were done at 3-year intervals. While all subjects were veterans, they were not VA patients and used medical and dental services available in the community. Assessment of PVD Baseline history and physical examination were performed on all subjects upon entry and at each triennial follow-up visit. Additional information was provided from hospital records. PVD was defined as one or more of the following: (1) intermittent claudication (IC); (2) extracranial cerebrovascular disease (ECD); (3) atherosclerosis (including aortic, renal, and mesenteric disease); and (4) arterial embolism and thrombosis. Diseases were entered into the database according to the 8th revision of the International Classification of Diseases (ICD-8). Determination of Other Cardiovascular Risk Factors The baseline examination of the NAS included a medical history, physical examination, and a variety of biochemical 0002-9610/98/$19.00 PII S0002-9610(98)00158-5
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TABLE I
TABLE II
Frequency of the Various Types of Peripheral Vascular Disease CONDITION Intermittent claudication Extracranial CVD Other atherosclerosis (aorta, mesenteric, renal) Arterial embolism or thrombosis
No. of Observations
ICD-8 Codes
60 14
443.2; 443.9 432–435.9; 437–437.9
9
440–440.9
2
444–444.9
CVD 5 cerebrovascular disease.
laboratory tests. Serum cholesterol was measured with the colorimetric method of Sperry. An examining physician measured blood pressure in each arm by using a standard mercury sphygmomanometer. The average systolic and diastolic blood pressure in both arms was used for analysis. Cigarette smoking status (current, former, and never) was determined, with current smokers defined as men who smoke one or more cigarettes daily. Total exposure to cigarettes over the subject’s lifetime was also calculated at the time of enrollment. Weight and height were measured and body mass index (BMI) was calculated as weight in kg divided by height in m2. Alcohol drinking habits were ascertained from responses to the Cornell Medical Index. The data were supplemented by information on cardiovascular illnesses abstracted from medical records. Other Vascular Conditions CHD was defined as nonfatal myocardial infarction, angina pectoris, or death from cardiac diseases. The criteria for myocardial infarction, angina pectoris, and stroke were those used in the Framingham Heart Study.5 Assessment of Oral Conditions We used a radiographic measure of periodontal disease status. The loss of tooth supporting alveolar bone was estimated from full mouth intraoral periapical radiographs exposed at baseline following methods and criteria previously reported.6 Mesial and distal tooth surface were read independently by a trained examiner and scored for alveolar bone loss in 20% gradations using a 5-point Schei ruler.4 Mean bone loss across all readable interproximal sites was calculated for each subject by using the midpoint of the alveolar bone loss intervals scored. Significant periodontal disease was considered present if the mean whole mouth alveolar bone loss was .20%. Data Analysis The periodontal disease exposure variable at baseline was used to dichotomize the cohort into a clinically significant periodontal disease group (.20% bone loss) and a clinically insignificant periodontal disease group (,20% bone loss). The disease outcome used was incidence of PVD, as defined above, and the total period of observation was over 25 years. Logistic regression was used to estimate the ageadjusted odds ratios between the two periodontal disease status groups (SAS, Cary, North Carolina). Multiple logis154
Risk Factor Status at Baseline in Those Who Develop PVD and Those Who Did Not VARIABLE n Age Body mass index (kg/m2) Diastolic BP (mmHg) Systolic BP (mmHg) Cholesterol (mg/dl) Family Hx. heart disease High school education or more Two 1 drinks of alcohol/day Current smoking Former smoking Packs of cigarette smoked/ life 3 1000 Periodontal disease
Non-PVD Group (Range)
PVD Group (Range)
1,030 80 42.7 (23–80) 44.2 (29–62) 25.6 (16–38) 26.9 (21–34) 77.1 (45–105) 77.6 (55–90) 123.6 (93–170) 123.7 (103–140) 204.7 (97–397) 218 (133–364) 9% 20% 58% 11.1% 33.6% 31.5%
53% 12.5% 43.7% 31.2%
4.6 21.6%
7.5 42.5%
PVD 5 peripheral vascular disease.
tic regression was used to calculate adjusted odds ratios for periodontal disease and all relevant vascular risk factors. Finally, backward selection was used to remove nonsignificant variables (P $0.05). The data were further analyzed in two additional models: (1) excluding from the non-PVD group any clinically manifest atherosclerotic disease by removing those patients with other vascular conditions such as CHD, aneurysmal disease and venous disease; and (2) excluding those subjects with extracranial cerebrovascular disease from the PVD group.
RESULTS Of the 1,231 men in the original Dental Longitudinal Study (DLS) cohort, complete data for the purposes of our analysis was available on 1,110 subjects. Over the 25 years of follow-up, a total of 80 initially healthy subjects developed PVD and 1,030 did not. The crude incidence of PVD in subjects with significant periodontal disease at baseline was 13.3%, and for those without significant periodontal disease, 5.4%, producing a crude relative risk (RR) of 2.46. The frequency of the conditions observed for each type of PVD is shown in Table I. A comparison of baseline risk factors for patients who developed PVD versus those who did not is presented in Table II. Periodontal Disease and PVD After adjusting only for age, subjects with significant baseline periodontal disease had 2.6-fold greater risk of developing PVD compared with those without significant periodontal disease (95% confidence interval 1.6 to 4.2; P 5 0.0001). Table III presents adjusted odds ratios (OR) for periodontal disease and other significant vascular risk factors. Even after adjusting for age, BMI, family history of heart disease, and smoking exposure, periodontal disease was significantly associated to the subsequent development of PVD (OR 5 2.27; 95% confidence interval 1.32 to 3.9;
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TABLE III Significant Risk Factors Associated with Peripheral Vascular Disease
Association with PVD Variables Periodontal disease Age Body mass index Family history of heart disease Lifetime packs smoked
Association with PVD (Excluding Other Vascular Conditions from the Non-PVD)*
Association with PVD (Excluding Stroke from Cases)†
OR (95% CI)
P value
OR (95% CI)
P value
OR (95% CI)
P value
2.07 (1.3–3.4) 1.006 (0.9–1.03) 1.14 (1.06–1.24) 2.25 (1.2–4.1) 1.05 (1.01–1.09)‡
0.004 0.65 0.0007 0.009 0.003
2.24 (1.3–3.8) 1.01 (0.98–1.04) 1.2 (1.08–1.3) 2.43 (1.25–4.7) 1.05 (1.01–1.1)
0.003 0.33 0.0001 0.008 0.008
2.27 (1.32–3.9) 1 (0.97–1.03) 1.16 (1.07–1.27) 2.25 (1.18–4.2) 1.04 (1.0–1.08)
0.003 0.95 0.0003 0.01 0.03
OR 5 odds ratio; CL 5 confidence intervals; * Non-PVD, n 5 545; † PVD, n 5 69; ‡ Packs life X 1,000; Adjustment for other significant vascular risk factors was done in a backward stepwise regression model that included age despite being a nonsignificant variable. Relationships after removing other vascular conditions from non-PVD group and after removing stroke subjects from the PVD group are shown.
TABLE IV Association of Established Cardiovascular Risk Factors with PVD Association with PVD (Excluding Other Vascular Conditions from the Non-PVD)*
Association with PVD Variables Periodontal Disease Age Body mass index Lifetime packs smoked Family history of heart disease Current smoking Former smoking Systolic blood pressure Diastolic blood pressure Serum cholesterol level Two or more drinks/day Education beyond high school
OR (95% CI)
P Value
OR (95% CI)
P Value
2.17 (1.2–3.8) 1.002 (0.9–1.03) 1.16 (1.06–1.27) 1.11 (1.003–1.1) 2.18 (1.13–4.1) 0.82 (0.35–1.9) 0.65 (0.29–1.4) 1 (0.96–1.02) 1.004 (0.96–1.05) 1.004 (1–1.01) 0.85 (0.38–1.9) 1 (0.5–1.6)
0.006 0.91 0.0006 0.03 0.01 0.64 0.29 0.61 0.86 0.1 0.69 0.94
2.28 (1.2–4.0) 1.01 (0.97–1.04) 1.2 (1.08–1.3) 1.06 (1–1.1) 2.51 (1.2–5.1) 0.93 (0.38–2.2) 0.6 (0.2–1.5) 0.99 (0.96–1.02) 1.01 (0.96–1.06) 1.006 (1–1.01) 0.64 (0.26–1.53) 0.96 (0.5–1.6)
0.009 0.49 0.0002 0.05 0.01 0.88 0.33 0.72 0.61 0.05 0.31 0.88
OR 5 odds ratio; CI 5 confidence intervals; * (n 5 545). Adjustment for other vascular risk factors was done regardless their significance status using multivariate analysis. PVD definition excluded stroke patients (n 5 69). Associations after removing other vascular conditions from the control group are shown.
P 5 0.003). Table IV presents the odds ratios of the association between periodontal disease and PVD after adjusting for all established vascular risk factors, including nonsignificant. Even in this larger model, the association between periodontal disease and PVD remained highly significant. In fact, the risk of developing PVD among those with significant periodontal disease was 2.2 times greater than for those with insignificant periodontal disease. Strength of Association with Stroke Patients Removed From PVD Group Other studies have documented associations between stroke and CHD.2,3 To evaluate how much of the association found between periodontal disease and PVD was contributed by stroke subjects, the category of ECD was removed from the PVD definition. The resultant group is formed primarily by patients with intermittent claudication (IC). Table III demonstrates that removing stroke subjects from the PVD group did not alter the relationship between periodontal disease and PVD.
Strength of Association with Other Vascular Conditions Removed from non-PVD Group Our initial approach to the analysis of the data was to compare the group within our PVD definitions versus all other subjects including patients with other PVD definitions (ie, aneurysmal disease, chronic venous insufficiency) and other clinically manifest atherosclerotic disease (CHD). To further test the association between periodontal disease and PVD, we repeated the analysis after removing other vascular conditions from the non-PVD group. Table IV shows that removing other vascular conditions from the non-PVD group did not substantially modify the relationship between periodontal disease and PVD after adjusting for other significant risk factors.
COMMENTS In this prospective study we found that otherwise healthy men with clinically significant periodontal disease at baseline had an approximate twofold increase in their risk of subsequent development of PVD. This association is independent of other well-established cardiovascular risk fac-
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tors. Two other interesting observations were made: (1) A family history of heart disease was identified as a significant risk factor for the development of PVD, an observation that is intuitive but has not been well documented; and (2) the strength of the association between periodontal disease and PVD is comparable with that of other cardiovascular risk factors such as family history of heart disease. Upon enrollment into the study, subjects who eventually develop PVD had baseline higher serum cholesterol levels, were more likely to have a family history of heart disease, were more likely to be current smokers, and had smoked more cigarettes over their lifetime. Twice as many of the PVD subjects fell within the clinically significant periodontal disease category. The rest of the covariates were distributed evenly between the two groups (Table II). Atherosclerosis is the underlying pathophysiologic process for both PVD and CHD. Risk factors for atherosclerosis have been determined primarily from studies focused on coronary atherosclerosis,5 but may differ in the extent to which they are associated with various manifestations of atherosclerosis, such as brain infarction, CHD, or IC.7 Recently, infection and chronic inflammatory conditions have been identified as risk factors for CHD.2,3,8 –13 This is consistent with the histopathologic evidence involving central components of the immune response (T cells, macrophages, and immune-regulatory cytokines) in atherosclerotic lesions.14 Infectious pathogens (eg, Chlamydia pneumoniae, Helicobacter pylori, and viral infections such as cytomegalovirus and herpesvirus) have been linked to atherosclerosis by at least 70 articles in the literature.1 In 1993, De Stefano and coworkers8 reported results on a prospective study in which 9,760 subjects had oral examinations at baseline, and showing that those with periodontal disease had a 25% increased risk of developing CHD compared with those with minimal periodontal disease. Other groups have reported similar findings in longitudinal studies.2,9 Recently, a cross-sectional study of older US veterans identified several oral health variables as risk indicators for CHD, such as having 1 to 14 teeth, low salivary levels of Streptoccocus sanguis, positive plaque benzoyl-DL-arginine-naphthylemide (BANA) test scores, gingivitis involving bleeding, and a complaint of xerostomia.10 Our study is the first to show an association between periodontal disease and PVD and further supports the concept that chronic inflammatory conditions have a significant role in clinically manifest atherosclerosis. It does not provide a biologic framework to explain the mechanism by which these phenomena occur. However, we can speculate about the potential mechanistic pathways linking periodontal disease and PVD. Periodontal disease, a chronic Gram-negative/anaerobic infection, may contribute to the atherosclerosis process through any one of several potential mechanisms: (1) direct vascular injury by pathogens involved in periodontal infection, like Porphyromonas gingivalis, which become blood borne after mechanical trauma like daily tooth brushing or flossing and may reside at sites of endothelial injury within the vessel wall; (2) the bacterial load within the gingival pockets may provide a large source of lipopolysaccharide from Gram-negative bacteria that reaches the 156
systemic circulation without any enterohepatic clearance, and could lead to chronic activation of circulating monocytes15 and/or expression of a range of membrane molecules such as class A scavenger receptor (SR-A)16 or CD68/macrosialin17 molecules implicated in experimental and natural atherogenesis; and (3) elevated titers of serum anti-heat shock proteins 65/60 antibodies, known to be induced by periodontal disease, may have a pathogenic role in atherosclerosis based on their cytotoxic activity toward stressed human endothelial cells.18,19 Regardless of the mechanisms involved, prolonged exposure to any of these factors may be the primary determinant for the development of PVD. These findings should alert practitioners to the potential importance of periodontal disease as a substantial modifiable risk factor for PVD. Our findings suggest that oral health and oral examinations may provide an important means of identifying patients at risk and developing targeted interventions for primary prevention.
CONCLUSION Based on these data, clinically significant periodontal disease appears to be an independent, highly significant risk factor associated with PVD. These results suggest that chronic inflammatory diseases, such as periodontal disease, have a significant role in the development or progression of atherosclerotic PVD.
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