Influence of the Periodontium on Cardiovascular Disease
Influence of the Periodontium on Cardiovascular DiseasePr. Thomas E. Rams - DDS, Professor and Chairman, Department of Periodontology and Professor of Oral Biology, Associate Dean for Advanced Education and Research, Temple University School of Dentistry.
Pr. Eugene J. Whitaker - Dentistry and Oral Biology, and Director of Oral Biology Research Laboratory, Temple University School of Dentistry.
ABSTRACTThe results of several recent cross-sectional and longitudinal human epi-demiologic studies have demonstrated a statistical link between the occurrence of destructive periodontal disease in the oral cavity and an increased risk of cardiovascular disease. Several theories have been advanced to explain the association of the two diseases. However, it is not presently known if periodontitis plays an etiologic role in the patho-genesis of cardiovascular disease or whether the relationship is merely a statistical correlate for an undetermined risk factor common to both dis-eases. The strength and limitations of the available data from major stud-ies are discussed, along with potential clinical implications for dental practitioners.
INTRODUCTIONUntil recently, the most widely recog-nized link between the status of the peri-odontium in the oral cavity and cardio-vascular disease was related to the key role played by inflamed gingival tissues in the pathogenesis of subacute infec-tive endocarditis. Chewing, oral hygiene procedures, trauma, and various dental therapies have an increased potential in the presence of gingival inflammation to seed viridans streptococci and peri-odontal pathogens (i.e., Actinobacillus actinomycetemcomitans) from subgingi-val dental plaque biofilms into the bloodstream and increase the risk of subacute infective endocarditis in indi-viduals with pre-existing valvular heart conditions.1 Subactute infective endo-carditis thus represents a type of "dental focal infection" where systemic dissemi-nation of certain pathogenic oral microorganisms via transient bac-teremias leads to clinical disease at a non-oral body site.2
More recently, emerging research data has implicated destructive periodontal disease as a risk factor in other types of heart conditions, most notably, acute myocardial infarction and coronary heart disease. This paper will provide a critical review of major studies reported to date on this issue and their possible implications for dental practitioners.
Finland StudiesMattila et al.3 in Finland in 1989 first sug-gested a relationship between oral health status and acute myocardial infarction ("heart attack"). Using a case-control study design, 100 consecutive persons admitted for hospitalization for acute myocardial infarction were com-pared to age, gender, and place-of-resi-dence matched control subjects ran-domly selected from the Helsinki, Finland community. Oral health status was evaluated using a newly created "total dental index", which provided a cumulative score ranging from a mini-mum of zero (good oral health status) to a maximum of ten (poor oral health sta-tus) based on the number of dental caries (scored on a 0-3 scale), the num-ber of 4-5 mm and ³ 6 mm probing depths, or presence of suppuration (scored on a 0-3 scale), the number of radiographic periapical lesions and/or vertical bone defects (scored on a 0-3 scale), and presence of pericoronitis (scored as 1 if present). Other conven-tional cardiovascular risk factors evaluat-ed on the patient groups included serum total cholesterol concentrations, serum triglyceride concentrations, serum high density lipoprotein cholesterol concen-trations, serum C peptide concentra-tions, history of infections, smoking habits, hypertension, diabetes, age, and socioeconomic status. Patients with acute myocardial infarction yielded sig-nificantly higher total dental index scores than the community control subjects. Multiple stepwise logistic regression analysis using conventional risk factors and the total dental index as indepen-dent variables confirmed the association between the total dental index and acute myocardial infarction to be statistically significant (P = 0.004), even when age, total cholesterol, tryglycerides, hyperten-sion, diabetes and smoking were taken into account. Hence, the authors con-cluded that "dental caries or periodontal disease, or both, is more common among patients with acute myocardial infarction than among controls matched for age and sex".3
A second cross-sectional investigation by Mattila et al.4 used a "pantomography index", which scored the total number of radiographic periapical lesions, caries, vertical bony defects, and furcation involvements. Pantomography index scores, age, and serum triglyceride lev-els were significantly correlated in multi-variate analysis with the degree of coro-nary atherosclerosis in 88 males exam-ined with diagnostic coronary angiogra-phy, even after controlling for total cho-lesterol, HDL cholesterol, smoking, hypertension, body mass and socioeco-nomic status. These findings again impli-cated the oral health status as a possi-ble determinant for cardiovascular pathology.
A third study involving the total dental index was a 7-year follow-up longitudinal investigation of 182 males and 32 females with a previous history of myocardial infarction.5 Baseline total dental index scores were found to be a significant predictor of new coronary events over the subsequent 7-year time period. This study provided a time sequence relationship further implicating oral health status as a risk factor for sub-sequent heart disease.
However, inherent shortcomings in the total dental index and the pantomogra-phy index as surrogate measures of oral health status severely limits interpreta-tion of all of the above study findings. Since the various types of oral pathology (i.e., caries, periodontitis, periapical lesions) found on clinical or radiographic examination are not differentiated by either index, it is not clear what the rela-tive contribution of periodontal disease vs. dental caries (or periapical lesions and/or pericoronitis) is in relationship to the assessed cardiovascular conditions. Thus, studies using total dental index or pantomography index scores do not specifically implicate periodontal disease as a risk factor in acute myocardial infarction or coronary heart disease. An overall ill-defined poor oral health status is instead reflected in high total dental index and high pantomography index scores rather than specific dental dis-eases. Additionally, the arbitrary 0-10 scale used in the total dental index has not been biologically validated to date or shown to be reproducible in calibration studies. Thus, by using the total dental index or the pantomography index, the The National Health and Nutrition Examination Survey I (NHANES-I) and its epidemiological follow-up study over the following 14 years involved a population-based evaluation of the systemic and oral health of a representative sample of American adults aged 25-74 years at baseline. DeStefano et al.6 related base-line dental examination data for 9,760 subjects with their subsequent median 14-year incidence of death or hospitaliza-tion due to coronary heart disease, and total mortality. Persons identified with periodontitis at the baseline oral exami-nations were found to exhibit a 25%excess risk for developing coronary heart disease over the following 14 year period as compared to individuals with minimal periodontal disease, even after statistical adjustments were made for potentially confounding risk factors such as age, gender, race, education, marital status, systolic blood pressure, total cholesterol levels, body mass, diabetes, physical activity, alcohol consumption, poverty and smoking. The effect of oral status on subsequent cardiovascular outcome was most pronounced in males younger than 50 years of age at baseline, where peri-odontitis-affected younger males had a 72% excess risk of subsequent coronary heart disease as compared to younger males with periodontal health and gin-givitis.6
The large subject sample size represen-tative of USA adults, the standardized oral and medical evaluations, the longitu-dinal study design, and the statistical analysis carried out by DeStefano et al.6 are strengths of the investigation. However, the periodontal classification of subjects was only broadly made into the categories of "no disease", "gingivitis", "periodontitis" (which was determined solely on probing depth values), and "no teeth". No measurements of periodontal attachment loss were recorded in the oral examinations, no differentiation was made between early, moderate and advanced forms of periodontitis, and no assessments of furcation involvements were carried out. Thus, the clinical methodology used in the DeStefano et al. analysis provided periodontal data that is incomplete and subject to misclassifica-tion and misinterpretation. Interestingly, the excess risk of coronary heart disease associated with periodontitis was of a similar magnitude as that associated with subjects with no teeth at baseline, where no ongoing periodontal infection was possible. This would indicate that either edentulous subjects possess increased risk of coronary heart disease due to residual effects of previous periodontitis when teeth were present, or that other unrelated and to date unidentified risk factors exist.
VA Normative Aging StudyAnother longitudinal database examined for periodontal-cardiovascular relation-ships was from the combined outcomes of the VA Normative Aging Study and Dental Longitudinal Study.7 Incidence data over an 18-year period for coronary heart disease and fatal heart attack for 1,147 males with no history of coronary heart disease at baseline was related to baseline periodontal status, which was assessed by mean whole-mouth inter-proximal alveolar bone height measured with a 5-point Schei ruler and worst clini-cal probing depth values. When compar-ing persons classified with "Hi" amounts of bone loss ( > 20% mean bone loss score) vs. those classified with "Lo" bone loss ( ² 20 mean bone loss score), the multivariate incidence odds ratios adjust-ed for age and other recognized risk fac-tors for cardiovascular disease were 1.5 for the relationship between "Hi" alveolar bone loss at baseline and subsequent total coronary heart disease, and 1.9 between "Hi" alveolar bone loss and fatal coronary heart disease. This indicates an approximate two times greater risk for a fatal coronary heart event over an 18-year period in persons with pre-exisiting marked alveolar bone loss vs. persons with minimal periodontal disease or peri-odontal health. Analysis of clinical prob-ing data showed that persons with all of their teeth demonstrating a worst probing depth > 3 mm at baseline experienced a 3.6 times greater odds of developing coronary heart disease over the following 18-year period as compared to subjects with all probing depths ² 3 mm.7
The strength of the study are the stan-dardized medical evaluations, the entry criteria of systemically-healthy study sub-jects followed longitudinally for disease incidence, and the magnitude of the odds ratios (3.6) demonstrating a rela-tionship between probing data and development of coronary heart disease. Bone loss measurements were taken from non-standardized radiographs using visual assessments of broad gradations (20% increments) of bone loss, which are more difficult to calibrate. Unfortunately, no clinical periodontal attachment loss assessments, which are a "gold standard" for identification of periodontal break-down, were made with clinical probing measurements carried out in the study.
Elderly US Veterans StudyA cross-sectional study of 320 males > 60 years of age assessed history of coronary heart disease relative to peri-odontal status, which included measure-ment of clinical periodontal attachment loss.8 Coronary heart disease was found to be 2.9 times more prevalent in older dentate persons with only 1-14 teeth vs. those with 15-28 teeth. Interestingly, the 1-14 tooth subject group with coronary heart disease exhibited a significantly higher proportion (81% vs. 59-62%) of teeth with clinical periodontal attachment loss of > 4 mm than individuals with 15- 28 teeth. Elevated BANA test scores from interproximal plaque samples, which screen for typsin-like enzyme activ-ity most likely to be derived from the peri-odontal bacterial pathogens Porphyromonas gingivalis, Bacteroides forsythus or Treponema denticola, were two times more likely to be found in sub-jects affected by coronary heart disease.
Possible Biologic Mechanisms of ActionDespite the limitations of the major stud-ies detailed above, there appears to be a statistical link established between the status of periodontal tissues and heart dis-ease by them and additional reports.9 This association needs to be clarified by addi-tional studies which more accurately clas-sify persons with periodontitis and better capture the degree and extent of peri-odontal disease breakdown in study sub-jects relative to their cardiovascular status. However, a plausible biologic mechanism explaining the apparent statistical associa-tion of the two disease conditions has not been established, and is essential to determine if any type of causal inference is to be made between the periodontal disease and heart disease. At present, three basic theories have been advanced. First, it has been proposed that transient bacteremias from inflamed gingival tis-sues introduce pathogenic microorgan-isms from subgingival dental plaque biofilms into the bloodstream, where they induce pathologic damage to blood ves-sels and promote clot formation.10 Supporting this dental focal infection hypothesis are the intriguing findings that the major bacterial pathogen in adult peri-odontitis, Porphyromonas gingivalis, pos-sesses a platelet-aggregation capability unique among subgingival plaque microorganisms11, 12, and is a common inhabitant of atheromatous plaques removed from carotid arteries13, and thus possibly also in coronary arteries. In this model, microbial infection associated with periodontitis lesions would contribute to coronary heart disease and act as an adjunctive etiologic factor to other estab-lished risk factors after the metastatic spread of the plaque organisms into the bloodstream via transient bacteremias. The second theory suggests that persons jointly affected by periodontitis and coro-nary heart disease exhibit a genetically-determined hyperinflammatory immune response to bacterial challenge.7,9 Abnormally elevated secretion of pro-inflammatory and tissue damaging media-tors such as prostaglandin E2 and inter-leukin 1b from peripheral blood mono-cytes in hyperinflammatory phenotype-positive individuals are proposed to account for the increased risk for both periodontitis and coronary heart dis-ease.7,9 Thus, a host susceptibility trait common to both periodontitis and heart disease would be operational.
In the third theory, an infectious etiolog-ic agent common to both periodontitis and coronary heart disease has been proposed. Slots14 has pointed out that certain herpesviruses, particularly cytomegalovirus and Epstein-Barr virus, may be recovered from both periodonti-tis lesions in the oral cavity and dis-eased coronary arteries. It is suggested that perhaps herpesviruses may inde-pendently give rise to both periodontal disease and cardiovascular disease. Thus, no cause-effect relationship between periodontal disease and heart disease would exist if both conditions are etiologically associated with a com-mon infectious agent.
Conclusions and Implications for Dental ProfessionalsThe weight of evidence from large-scale epidemiologic studies supports the notion that persons with periodontitis also appear to possess a greater risk of developing coronary heart disease. This association presently exists only at a statistical level, with no firm explanations established which account for the joint disease rela-tionship. Thus, a causal relationship where-by periodontal disease contributes to the etiology of coronary heart disease has not been scientifically documented to date. Dental practitioners should be aware of these findings to more intelligently inter-act with inquiring patients. However, pre-sent data do not support the premise that periodontal therapy or any other oral intervention has any impact on reducing the risk of coronary heart disease. Rather, patients with periodontitis should be urged to maintain medical surveillance of their cardiovascular status, and work on controlling or reducing all known risk fac-tors associated with coronary heart dis-ease, including periodontal infections.
- Pallasch, T.J. & Slots, J.: Antibiotic prophylaxis and the medically compromised patient. Periodontology 2000 10:107-138, 1996.
- Rams, T.E. & Slots, J.: Systemic manifestations of oral infections. In: Slots, J. & Taubman, M.A. (eds.), Contemporary Oral Microbiology and Immunology. Mosby Year Book: St. Louis, 1992, p.500-510.
- Mattila, K.J., Niemminen, M.J., Valtonen, V.V., Rasi, V.P., Kesaniemi, Y.A., Syrjala, S.L., Jungell, P.S., Isoluoma, M., Hietaniemi, K., Jokinen, M.J. & Huttunen, J.L.: Association between dental health and acute myocardial infarction. British Medical Journal 298:779-981, 1989.
- Mattila, K., Valle, M.S., Nieminen, M., Valtonen, V.V. & Hietaniemi, K.L.: Dental infections and coronary ath- erosclerosis. Atherosclerosis 103:205-211, 1993.
- Mattila, K.J., Valtonen, V.V., Nieminen, M. & Huttunen, J.K.: Dental infection and the risk of new coronary events: prospective study of patients with documented coronary artery disease. Clinical Infectious Diseases 20:588-592, 1995.
7. Beck, J., Garcia, R., Heiss, G., Vokonas, P.S. & Offenbacher, S.: Periodontal disease and cardiovas- cular disease. Journal of Periodontology 67:1123- 1137, 1996.
- Loesche, W.J., Schork, A., Terpenning, M.S., Chen, Y- M., Dominguez, B.L. & Grossman, N.: Assessing the relationship between dental disease and coronary heart disease in elderly U.S. veterans. Journal of the American Dental Association 129:301 311, 1998.
- Beck, J.D. & Offenbacher, S.: Oral health and systemic disease: periodontitis and cardiovascular disease. Journal of Dental Education 62:859-870, 1998.
- Hertzberg, M.C., MacFarlane, G.D., Liu, P. & Erickson, P.R.: The platelet as an inflammatory cell in periodontal diseases: interactions with Porphyromonas gingivalis. In: Genco, R., Hamada, S., Lehner, T., McGhee, J. & Mergenhagen, S. (eds.), Molecular Pathogenesis of Periodontal Disease. American Society for Microbiology: Washington, DC, 1994, p. 247-255.
- Pham, K., Rams, T.E., Feik, D., Whitaker, E.J., Scott, C.F. & Colman, R.W.: Aggregation of human platelets by Porphyromonas gingivalis. Journal of Dental Research 77(Special Issue A):124, abstract 148, 1998.
- Haraszthy, V.I., Zambon, J.J., Trevisan, M., Shah, R., Zeid, M. & Genco, R.J.: Identification of pathogens in athromatous plaques. Journal of Dental Research 77(Special Issue A): 666, abstract, 1998.14. Slots, J.: Casual or non-casual relationship between periodontal infection and non-oral disease? Journal of Dental Research 77:1764-1765, 1998.