Gregory J. Seymour, BDS, MDSc, PhD, FRCPath, FFOP(RCPA), FRACDS(Perio)
Pauline J. Ford, BDentSt, BDSc
Erica Gemmell, BSc, PhD
Kazuhisa Yamazaki, DDS, PhD
ABSTRACT There is increasing evidence that chronic infections are associated with cardiovascular diseases. A number of hypotheses have been put forward to explain these associations, including common susceptibility, systemic inflammation, direct infection of the blood vessels, and cross-reactivity or molecular mimicry between bacterial and self-antigens. In terms of common susceptibility, a person who is susceptible to progressive periodontal disease is also susceptible to atherosclerosis, but the periodontal disease does not cause the atherosclerosis. In recent years much research has been focused on the role of systemic inflammation and the increase in circulating cytokines and inflammatory mediators. These cytokines and mediators can lead to direct endothelial damage and ultimately to atherosclerosis. A number of studies have shown that periodontal bacteria can directly invade the endothelium and thereby lead to inflammation in the blood vessel wall resulting in atherosclerosis. In terms of molecular mimicry, it is proposed that because of the homology between bacterial GroEL antigens and human heat shock protein (HSP), the local immune response to the periodontopathic bacteria cross-reacts with self-HSP expressed on the endothelium leading to vascular inflammation and hence atherosclerosis. There is increasing evidence in support of this hypothesis; however, none of these possible mechanisms are mutually exclusive, and it is likely that in different people different mechanisms may explain the link between periodontal infection and cardiovascular disease.
There is increasing evidence that chronic infections are associated with cardiovascular diseases (CVDs). These infections include Helicobacter pylori, Chlamydia pneumoniae, cytomegalovirus, and, more recently, periodontopathic bacteria such as Porphyromonas gingivalis. Although a large number of potential mechanisms have been postulated, the mechanism by which these infections associate with CVDs is still unclear. A number of hypotheses nevertheless exist, including common susceptibility, systemic inflammation with increased circulating cytokines and inflammatory mediators, direct infection of the blood vessels, and, finally, cross-reactivity or molecular mimicry between bacterial and self-antigens. This final hypothesis is gaining support and will be discussed in this review.
Common susceptibility involves a genetically determined phenotype,which leads to a greater risk of both atherosclerosis and infection. In this hypothesis, in the presence of periodontal pathogens, a susceptible person develops periodontal disease. This same person would also be susceptible to atherosclerosis, but, in this model, the periodontal disease does not cause the atherosclerosis (Figure 1).
The second hypothesis is that of systemic inflammation and increased circulating cytokines and inflammatory mediators. In this hypothesis, inflammation leads to an increase in the levels of circulating cytokines, which in turn damage the vascular endothelium and ultimately result in atherosclerosis (Figure 2). The circulating cytokines of interest include C-reactive protein (CRP), Interleukin-1, Interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-a), and prostaglandin.
The highest relative risk for myocardial infarction was found to be the levels of CRP together with the ratio of total cholesterol to high-density lipid.1 CRP is a powerful marker of vascular risk and there is some evidence for a direct role in vascular dysfunction and atherogenesis. It is produced by the liver and is stimulated by TNF-a and IL-6, leading to a decrease in nitric oxide availability and an increase in angiotensin 1 receptors. It binds to low density lipids, increasing their uptake by macrophages and hence an increase in foam cell formation. For these reasons,CRP has been postulated as a major mechanism for atherosclerosis.
MEASURES OF ENDOTHELIAL DYSFUNCTION
Endothelium dysfunction can be measured by a number of available techniques. The most common is flow-mediated dilatation. Pulse-wave analysis and pulse pressure have also been used to look at endothelial dysfunction.
Flow-mediated dilatation measures the capacity of the arteries to dilate in response to altered flow. Basically, a blood pressure cuff with 300 mm of mercury is applied for 5 minutes. It is then released and the diameter of the artery is measured by ultrasound. The percent increase in diameter after release is a measure of the elasticity of the artery. In healthy subjects, a 7% to 10% increase in the diameter of the artery is expected. In diabetics, in whom there is a vascular defect, there would only be a 4% to 6% increase. Unfortunately, flow-mediated dilatation is technically demanding, costly, and painful. Nonetheless, it has been shown that flow-mediated dilatation is decreased in severe periodontal disease and that this is associated with high levels of CRP.2
Pulse-wave analysis measures heart rate, blood pressure (systolic, diastolic, pulse), large artery elasticity, small artery elasticity, and systemic vascular resistance. This technique is clinically feasible, and abnormal results are predictive of CVD. The results are abnormal in hypertension, diabetes, early renal disease, and rheumatoid arthritis. The defects are reversible with angiotensin-converting enzyme inhibitors and statins. Wilson and Jenkins showed that pulse-wave analysis correlates with flow-mediated dilatation.3 Preliminary data indicate that with treatment of periodontal disease, there is not only a decrease in the CRP but also an increase in small artery elasticity.
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