Our systematic review and meta-analysis evaluating the relationship between periodontal disease, including gingivitis, bone loss, and missing teeth, suggests that periodontal disease is an independent, though relatively weak, risk factor for CHD. Our analyses provide the most current measure of the association between periodontal disease and CHD, and suggest that various measures of periodontal disease confer approximately a 24–35% increase in risk of CHD.
Our study focuses on prospective studies conducted among the general population rather than combining data from referral centers or cohorts with known CHD, which allows for evaluating cause/effect relationships and for generalizing our results to other populations. Also, given that these are very large populations followed for CHD, a very common cause of morbidity and mortality in North America and Europe, it is unlikely that knowledge of periodontal disease biased the ascertainment of CHD. Thus, our meta-analysis results suggest either a biological link or unknown confounding with periodontal disease serving as a marker for subsequent CHD. While we believe our findings provide a more current measurement of the association between periodontal disease and CHD than prior systematic reviews and meta-analyses, it is notable that our findings are similar to older meta-analyses that have shown summary relative risks in the 1.15 to 1.19 range.14,15
There are several limitations of our review. First, we relied on each study’s definition and diagnosis of CHD. As stated above, there is no indication that bias in ascertaining outcome played a role in our findings, due to the prospective nature of the included studies. It is more plausible that exposure misclassification resulted in under-estimation of the true risk associated with periodontal disease. This is particularly likely in studies relying on self report of periodontal disease. Another limitation is incomplete adjustment for all Framingham risk factors in some of the studies. However, in a subgroup analysis of the good quality studies with adjustment for all Framingham risk factors, an independent association between periodontal disease and CHD was identified. Another limitation of our review is the relatively low number of studies evaluating the relationship, although the total number of subjects enrolled in these studies was large (approximately 227,000). Finally, each of the studies evaluated periodontal disease differently, although most involved a dental examination.
We believe our review is strengthened by only including studies in which the exposure of periodontal disease was determined systematically at the beginning of the study. Furthermore, we evaluated the importance of periodontal disease in the general population rather than in populations selected for coronary artery disease which, by design, represent survival cohorts and address secondary rather than primary prevention. Although we did not systematically review literature evaluating this relationship among individuals with prevalent CHD, studies among those cohorts have also shown an association between periodontal disease and CHD.26–28
These studies support our findings, but are limited by the issues discussed above, and their results may not be generalizable to the healthy adult population.
We also identified several case control26,28–30
studies that evaluated the association between CHD and various measures of periodontal disease; most have shown a strong positive association after adjustment for many or all Framingham risk factors, as well as socioeconomic status.32–35
The consistency of these studies with our findings lends support to the identified relationship between periodontal disease and CHD.
There are several biological mechanisms by which periodontal disease might be etiologically associated with CHD. First, studies have suggested that periodontal disease represents a chronic infection resulting in a chronic inflammatory state.8
This hypothesis is supported by many studies showing fibrinogen, CRP, serum amyloid A and Von Willebrand factor elevations in association with periodontal disease.11,13,18,36–38
Notably, periodontal treatment studies have shown improvements in measures of systemic inflammation such as CRP and serum IL-6 with treatment.39
Recently, a randomized controlled trial conducted among individuals with periodontal disease showed that intensive periodontal treatment resulted in improvement of endothelial function 6 months after therapy.40
A second biological consideration is the intermittent bacteremia associated with periodontal disease and its possible role either in the chronic inflammatory state or more directly on endothelial tissue surfaces.41
For example, in one study, 80% of carotid endarterectomy specimens were positive for one or more PCR assays of various oral pathogens.41
In addition, data from the prospective ARIC study have shown that carotid artery intima-media wall thickness was associated with severe periodontal disease;42
others have shown this as well.43
While not statistically significant, data from a sub-sample of the ARIC study showed a relationship between periodontal disease and coronary artery calcification by CT (relative risk 1.51; 95% CI 0.54–4.23) after 2–4 years of follow-up.44
Third, some studies have shown increased platelet activation in vivo in association with periodontal disease, which could contribute to plaque instability and thrombosis.45
Fourth, studies conducted among animals have shown an association between atheroma formation and exposure to periodontal pathogens.46
Periodontal disease has also been implicated as a risk factor for stroke23,47,48
as well as carotid atherosclerosis.49,50
Several of the studies evaluating this outcome were conducted among cohorts included in this review and showed relative risks for stroke in association with periodontal disease in the range of 1.2 to 3.0.14,23,51
In addition, a relationship has been shown among individuals with peripheral vascular disease and periodontal disease, as well as tooth loss.22,52
Furthermore, data from angiography studies have shown a relationship between the extent of atherosclerosis and the degree of periodontal disease.35
Finally, several studies have shown a relationship between oral health and total mortality.18,20,53
These data support the role of periodontal disease in generalized atherosclerosis and support our finding of an association between periodontal disease and CHD.
If periodontal disease is not causally related to CHD, our data suggest it may be a marker of risk. This hypothesis implies that unexplained confounding by a factor associated with both periodontal disease and CHD explains the relationship. The most likely known contenders include: smoking, diet, diabetes and socio-economic factors.54–56
However, almost all of the studies included in our review adjusted for all of these factors and still identified increased risk. In fact, three good quality studies20,22,25
from two cohorts and one fair quality study18
with adjustment for the traditional Framingham risk factors, plus alcohol and measures of socioeconomic status, identified significant elevations of risk. Some investigators have hypothesized that genetic susceptibility to a strong inflammatory response mediates both CHD and periodontal disease.
To clarify the link between CHD and periodontal disease will require a consistent body of evidence from longitudinal studies with standardized measures of periodontal disease and careful follow-up. The ideal longitudinal study would start in childhood and account very carefully for socioeconomic status since this CHD risk factor could confound the identified relationship. From a public health perspective, if further studies consistently identify periodontal disease as a risk factor for CHD and treatment studies show benefit, the implications are significant since periodontal disease is mostly avoidable and treatable when not prevented. In addition, good preventive dental care has multiple other benefits, particularly on quality of life. Furthermore, identifying individuals at higher risk for CHD than predicted by traditional risk factors could facilitate treatment of risk factors known to decrease CHD events in high-risk individuals, such as those with hyperlipidemia.
To definitively establish an etiological link between periodontal disease and CHD will require randomized controlled trials in which individuals are randomized to treatment versus usual care of periodontal disease and followed carefully for CHD. However, there are important ethical considerations as well as feasibility issues related to a randomized trial of an intervention known to be of benefit for reasons other than the question under study. Notably, however, such a trial is underway in a cohort of individuals with prevalent CHD.57,58
If randomized treatment trials for primary prevention are planned, it is important to consider that short-term trials may not definitively answer the etiologic question as it is plausible that long-term exposure to periodontal disease might be more predictive of subsequent CHD. Thus, the best intervention trial would be one that began in early childhood rather than adult life. In its absence, however, if benefit were shown in an adult primary prevention treatment trial, the potential impact on public health and specifically CHD might be significant given the high prevalence of periodontal disease in the population and the common problem of CHD.