Kaumudi Joshipura, BDS, MS, ScD • Christine Seel Ritchie, MD, MSPH
ABSTRACT The objective of this review is to assess the strength of evidence relating periodontal disease and cardiovascular disease. Cardiovascular disease typically encompasses atherosclerosis (including coronary heart disease, peripheral arterial disease, and ischemic stroke), hemorrhagic stroke, congestive heart failure, hypertension, and rheumatic heart disease. This review focuses on atherosclerosis. Periodontal disease and cardiovascular disease may be causally linked or could be explained by common risk factors. Many potential pathways for the relationship have been postulated. This article evaluates the overall body of evidence, according to the following standard causal inference criteria: strength of the association, dose-response relationship, time sequence, consistency, specificity, biologic plausibility, and independence from confounding. Each criterion is reviewed as it relates to the existing literature. The overall strength of evidence for causal criteria for the relation between periodontal disease and cardiovascular disease is as follows: specificity is not important and is not established here, the magnitude and consistency of the association is stronger for stroke, there is some initial evidence for dose response, consistency is low for coronary heart disease, time sequence has been established with more evidence for stroke, and there is definitely biologic plausibility. Independence from confounding is also stronger for ischemic stroke and peripheral arterial disease. Because the underlying pathogenesis of atherosclerosis is common across the diseases, it is likely that, should additional studies show consistent associations, periodontal disease may be an important independent causal risk factor for cardiovascular disease.
Cardiovascular disease (CVD) encompasses several diseases: atherosclerotic CVD (including coronary heart disease [CHD], peripheral arterial disease [PAD], and ischemic stroke), hemorrhagic stroke, congestive heart failure, hypertension, rheumatic heart disease, and congenital heart defects. This article will focus on reviewing the evidence relating periodontal disease and CVD arising from atherosclerosis (CHD, PAD, and ischemic stroke).
Inflammation is now recognized as playing a key role in the pathogenesis of atherosclerosis. Inflammatory cells and cytokines are not only important in the initiation of plaque formation in the blood vessel wall but also in the maintenance and rupture of the plaque and subsequent thrombotic complications. Triggers of inflammation include smoking, diabetes, and infectious agents.1,2
Several possible pathways for the relationship between periodontal disease and CVD have been postulated (Figure 1). Periodontal disease may increase systemic levels of inflammatory mediators and thus potentially contribute to the inflammation-associated atherosclerotic process.3 Periodontal pathogens may also disseminate into the systemic circulation and localize in atheromas.4 Alternatively, individuals with periodontal disease and CVD may share common behaviors or have common host responses to inflammation (implying a noncausal relationship). For example, those most likely to practice poor dental care may be most likely to have other behaviors that accelerate CVD (eg, smoking, decreased physical activity). Alternatively, sequelae of periodontal disease (ie, tooth loss) may lead to dietary changes, such as decreased intake of fruits and vegetables/dietary fiber, that could subsequently affect the risk for CVD and other diseases. Also, those who are genetically susceptible to systemic inflammation may demonstrate increased oral inflammation in the form of gingivitis or periodontal disease as well as increased risk of CVD. Because of this complexity, it is difficult to assess whether oral disease actually contributes to increased risk of CVD (as a causal relationship) or whether oral disease and CVD share common risk factors (Figure 1). This article attempts to review the evidence to date to understand the strength of the evidence and to gain some insight into possible causality of the relationship.
CAUSAL INFERENCE CRITERIA
It seems likely that there could be a combination of common risk factors (Figure 1) that would explain some of the association between periodontal disease and CVD as well as some causal pathways. To assess the possible existence of a causal component, the major prospective studies are reviewed in the context of the criteria for causality proposed by Hill.5 Some of these criteria have been challenged or have evolved over time; however, the basic criteria, still considered a standard approach for assessing causality, are defined individually and applied to the pertinent literature.5,6 These criteria include strength of association, dose-response relationship, time sequence, consistency, specificity, and biologic plausibility. Coherence and plausibility have been combined into the criterion of biologic plausibility because the differences between the two are very subtle.6 Also, the criterion of experiment was not assessed since there is no direct evidence to date from clinical trials and it is not possible to randomly allocate people to periodontal disease. Lastly, the criterion of analogy was excluded because, as Rothman argues, "scientists can find analogies everywhere," and "the absence of such analogies only reflects lack of imagination or lack of evidence."7
Some epidemiologists have proposed alternative criteria for causality. Rothman defines a causal mechanism as a set of factors that are jointly sufficient to induce a binary outcome event, and that are minimally sufficient (ie, under the omission of just one factor the outcome would change).8 This definition highlights the potential complexity of causality but provides less structure for evaluating the effect of one condition on another outcome. For this article as in the earlier review,9 the relationship between periodontal disease and CVD in the context of Hill's criteria will be evaluated, recognizing the inherent limitation in any set of criteria used to assess causality.
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