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Circulation. 2004;109:1076-1078
doi: 10.1161/01.CIR.0000118643.41559.E2
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(Circulation. 2004;109:1076-1078.)
© 2004 American Heart Association, Inc.

Focused Perspectives

Dental Disease, Coronary Heart Disease and Stroke, and Inflammatory Markers

What Are the Associations, and What Do They Mean?

Gordon D.O. Lowe, MD, FRCP, FFPH

Section of Vascular Medicine, University of Glasgow, United Kingdom.

Correspondence to Prof G.D.O. Lowe, University Department of Medicine, Royal Infirmary, 10 Alexandra Parade, Glasgow, G31 2ER, UK. E-mail gdl1j{at}clinmed.gla.ac.uk


Key Words: Focused Perspectives • coronary disease • inflammation • risk factors

In addition to "classical" risk factors for coronary heart disease (CHD) and stroke, "emerging" risk predictors (which may also play roles in pathogenesis) include measures of chronic infections and of chronic, low-grade activation of inflammation and of hemostasis.1,2 As all dental healthcare professionals know (but probably fewer medical practitioners and their patients), the oral cavity is a major site of chronic infection and inflammation, particularly periodontal disease. In recent years there has been increasing interest in the "periodontal-systemic connection" between dental health parameters and the risks of cardiovascular disease, respiratory disease, diabetes mellitus, osteoporosis, and adverse pregnancy outcomes.3 Given that poor oral health, coronary heart disease, and stroke are major worldwide health problems, their associations are potentially important. In particular, two practical questions are of mutual interest to dental and medical healthcare practitioners and their patients. First, should dental health scores be used (in addition to classical risk factors) to predict an individual’s risk of CHD and stroke? Second, does treatment of poor dental health reduce such risk?

See p 1095

Answering the first question requires a rigorous assessment of epidemiological studies that have examined the associations between dental health parameters, CHD and stroke. The initial reports of positive associations, by Mattila et al from Finland, came from case-control studies of myocardial infarction4 and coronary atherosclerosis.5 Similar findings have been reported from other case-control studies of myocardial infarction6,7 and stroke8 and from cross-sectional studies of myocardial infarction,4 stroke,9 and cardiovascular disease (CHD, stroke, or claudication).10 Although in general these reported associations remained statistically significant after adjustment for major confounders such as age, sex, smoking habit, and socioeconomic status,10 the recognized limitations of case-control studies and the possibility of selective publication bias mandate caution when interpreting these results.

A further confounder of the association between dental health parameters, CHD, and stroke is their mutual association with markers of inflammation. After the initial publication of Mattila et al,4 a case-control study observed that patients with periodontal infections had significant elevations of plasma fibrinogen and white blood cell count, leading to the hypothesis that periodontal disease might increase risk of CHD in part by inducing a systemic proinflammatory, prothrombotic state.11 A subsequent cross-sectional study observed that total tooth loss (of which the two commonest causes were periodontal disease and dental caries) was also associated with some markers of activated inflammation and hemostasis (including C-reactive protein in men).10 Because total tooth loss abolishes periodontitis, such data suggested two alternative hypotheses. First, total tooth loss may reflect a constitutional (perhaps genetic) predisposition to severe inflammatory reactions following an inflammatory stress (such as smoking and/or periodontal infection). The association between tooth loss, CHD, and stroke might therefore reflect a common influence of "proinflammatory" constitutional states both on the need for tooth extraction after periodontitis and on the likelihood of clinical events after arterial plaque inflammation (induced by agents including smoking, lipids, and plaque infections—including infection with periodontal pathogens12). Second, total tooth loss resulted in altered nutritional status, such as reduced intake of citrus fruit and vitamin C, which might increase risks of both inflammation and cardiovascular disease.10 A third hypothesis, that edentulous persons wearing dentures at night might develop a systemic proinflammatory, prothrombotic state as a result of chronic Candida albicans infection, was not supported by the data.10

Prospective longitudinal studies are less susceptible to bias than case-control and cross-sectional studies. Over the last 10 years, nine such studies of the association of dental health parameters (including measures of periodontal disease and of tooth loss) with risk of CHD and/or stroke have been reported.13,14 A recent meta-analysis showed modest, but statistically significant, increases in cardiovascular risk associated with dental health parameters.14 It has been noted that many of these studies have been secondary analyses of studies that were not designed to test the association of dental health parameters and risks of CHD and stroke, and that several of these reports used questionnaires to define dental disease, leading to misclassification and dilution of the estimates of association.14–16 On the other hand, no prospective study report has performed multivariate analysis including both measures of dental disease, and measures of activated inflammation and hemostasis in the assessment of risk of CHD and stroke. This is a limitation not only in assessing the associations of dental health parameters with risk of cardiovascular disease but also in assessing the associations of markers of inflammation and hemostasis with risk of cardiovascular disease.2

In this issue, Janket et al17 report a study that advances this field in three ways. First, they compared a recently developed dental health score (the Asymptotic Dental Score [ADS], which used asymptotic weights to increase precision) with the original Total Dental Index (TDI, which used an arbitrary weighting scheme), used by Mattila et al.4 The authors observed a significantly stronger association of the ADS (compared with the TDI) with angiographically confirmed CHD in a case-control study. This finding supports an emerging consensus14–16 that the more precise the dental health score, the stronger are its associations with CHD and stroke in epidemiological studies, and hence the likelihood of a true biological relationship.

Second, Janket et al17 report that the more precise ADS also showed stronger associations in general with markers of activated inflammation and hemostasis, triglyceride, and total cholesterol/HDL ratio than the TDI. This finding supports an increasing body of data that poor dental health is associated with both "classical" and "emerging" risk predictors for CHD and stroke.

Third, the report of Janket et al17 compares the associations of their dental score (ADS) with the traditional Framingham Heart Score in discrimination of CHD cases and controls. A prediction model including the ADS, C-reactive protein, HDL cholesterol, and fibrinogen offered similar predictive value to the Framingham Heart Score. When the ADS was removed from the model, its predictive ability fell, suggesting that the dental score contributed to CHD prediction in addition to known biochemical predictors.

Although Janket et al17 conclude that their new dental score may be useful in screening persons without overt CHD to detect increased risk of CHD and stroke, caution is required in extrapolating from their case-control study of persons with overt CHD to the general population. Current national and international guidelines rightly emphasize the importance of using classical risk predictors (age, sex, smoking habit, diabetes, blood pressure, total cholesterol/HDL ratio) for prediction of CHD and stroke, and also provide evidence-based recommendations for lifestyle advice, reductions in blood pressure and cholesterol, and control of diabetes to reduce cardiovascular risk.1 Further studies are required to evaluate the additive predictive value of emerging risk predictors including dental health scores and markers of activated inflammation and hemostasis (and also to evaluate their potential additive roles in pathogenesis as potential causal risk factors).1,2 Practical limitations of comprehensive dental scores in risk prediction include the time and cost of a skilled dental healthcare professional to perform them and the reluctance of many in the general population to undergo such a procedure (which involves some time and discomfort) as part of a health screen. Nevertheless, dental healthcare professionals and investigators will doubtless promote their interests in this field, as will laboratory scientists and investigators with interests in blood tests2 and other laboratory measures for prediction of CHD and stroke. Further evaluation of all such "emerging" risk predictors for cardiovascular disease could usefully follow the example of the Fibrinogen Studies Collaboration,18 which pools and analyzes all available individual data from prospective studies.

In conclusion, the answer to the first question (Should dental health scores be used in addition to classical risk factors to predict an individual’s risk of CHD and stroke?) is "We don’t know." The paper by Janket et al17 points us in the direction of using more sensitive dental scores in future epidemiological studies, where time and resources permit. On the other hand, these time and resource constraints will severely limit the use of such scores in screening of healthy persons for cardiovascular risk. For the second question (Does treatment of poor dental health reduce such risk?), the answer is also "We don’t know." Further studies should include the following: the effect of treatment of periodontitis on markers of activated inflammation and hemostasis; the associations of proinflammatory genetic polymorphisms19 with dental disease, as well as with CHD and stroke; and, if possible (given the impracticality of randomized studies), prolonged observational studies of dental status (preferably defined with sensitive scores), inflammatory and hemostatic markers and risks of CHD and stroke. Meanwhile, periodontal disease obviously merits prevention and treatment as a health problem in itself, and it is also prudent to ensure adequate nutrition in edentulous persons.10,20


*    Footnotes
 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.


*    References
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 *References
 

  1. Lowe GDO, Danesh J, eds. Classical and emerging risk factors for cardiovascular disease. Semin Vasc Med. 2002; 2: 229–445.
  2. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003; 107: 499–511.[Free Full Text]
  3. Proceedings of The Periodontal-Systemic Connection: a State-of-the-Science Symposium. Ann Periodontol. 2001;6:1–231.
  4. Mattila K, Nieminen M, Voltonen V, et al. Association between dental health and acute myocardial infarction. BMJ. 1989; 298: 779–782.[Medline] [Order article via Infotrieve]
  5. Mattila KJ, Valle MS, Nieminen MS, et al. Dental infections and coronary atherosclerosis. Atherosclerosis. 1993; 103: 205–211.[CrossRef][Medline] [Order article via Infotrieve]
  6. Genco RJ, Wu TJ, Grossi S, et al. Periodontal microflora related to the risk for myocardial infarction: a case control study. J Dent Res. 1999; 78: 457. Abstract.
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  8. Grau A, Buggle F, Ziegler C, et al. Association between acute cerebrovascular ischaemia and chronic and recurrent infection. Stroke. 1997; 28: 1724–1729.[Abstract/Free Full Text]
  9. Loesche WJ, Schork A, Terpenning MS, et al. The relationship between dental disease and cerebral vascular accident in elderly United States veterans. Ann Periodontol. 1998; 3: 161–174.[Medline] [Order article via Infotrieve]
  10. Lowe GDO, Woodward M, Rumley A, et al. Total tooth loss and prevalent cardiovascular disease in men and women: possible roles of citrus fruit consumption, vitamin C, and inflammatory and thrombotic variables. J Clin Epidemiol. 2003; 56: 694–700.[CrossRef][Medline] [Order article via Infotrieve]
  11. Kweider M, Lowe GDO, Murray GD, et al. Dental disease, fibrinogen and white cell count; links with myocardial infarction? Scott Med J. 1993; 38: 73–74.[Medline] [Order article via Infotrieve]
  12. Haraszthy VI, Zambon JJ, Trevisan M, et al. Identification of periodontal pathogens in atheromatous plaques. J Periodontol. 2000; 71: 1554–1560.[CrossRef][Medline] [Order article via Infotrieve]
  13. Danesh J. Coronary heart disease, Helicobacter pylori, dental disease, Chlamydia pneumoniae, and cytomegalovirus: meta-analyses of prospective studies. Am Heart J. 1999; 138: S434–S437.[CrossRef][Medline] [Order article via Infotrieve]
  14. Janket SJ, Baird A, Chuang S, et al. Meta-analysis of periodontal disease and risk of coronary heart disease and stroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003; 95: 559–569.[Medline] [Order article via Infotrieve]
  15. Beck J, Offenbacher S. The association between periodontal diseases and cardiovascular diseases: a state-of-the-science review. Ann Periodontol. 2001; 6: 9–15.[CrossRef][Medline] [Order article via Infotrieve]
  16. Genco RJ, Trevison M, Wu T, et al. Periodontal disease and risk of coronary heart disease. JAMA. 2001; 285: 40–41.[Free Full Text]
  17. Janket SJ, Qvarnstrom M, Meurman JH, et al. Predicting coronary heart disease utilizing dental health parameters. Circulation. 2004; 109: 1095–1100.[Abstract/Free Full Text]
  18. Fibrinogen Studies Collaboration. Collaborative meta-analysis of prospective observational studies of plasma fibrinogen and cardiovascular disease. Eur J Cardiovasc Prev Rehabil. In press.
  19. Brull DJ, Serrano N, Zito F, et al. Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol. 2003; 23: 2063–2069.[Abstract/Free Full Text]
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Related Article:

Asymptotic Dental Score and Prevalent Coronary Heart Disease
Sok-Ja Janket, Markku Qvarnström, Jukka H. Meurman, Alison E. Baird, Pekka Nuutinen, and Judith A. Jones
Circulation 2004 109: 1095-1100. [Abstract] [Full Text]



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