William Hunter, an English physician in the early 20th century, brought to our attention that the bacteria in the oral cavity are a source of infection for the entire body.1 Today, there is a great deal of interest surrounding oral infection in relationship to systemic illness, with a focus on periodontal disease as a risk factor for certain systemic disorders. In a US national survey conducted between 1988 to 1991, 54% of children between 5 and 17 years of age were caries free in the permanent dentition; 90% of adults over 18 years of age were dentate; and 30% had retained all their teeth.2,3 Therefore, the future will see an aging population retaining more teeth, and these teeth will be at risk for periodontitis. The relationship between periodontal disease and systemic health has become the focus of increased attention on the part of researchers, health professionals, and the public, and this attention is likely to grow in the future.
This article reviews the link between periodontal disease and coronary artery disease (CAD), with a discussion of the mechanisms involved and challenges for the future.
CORONARY ARTERY DISEASE
CAD remains a major cause of morbidity and mortality in the western world. Recognized risk factors for CAD include serum cholesterol concentration and lipid profile, obesity, diabetes, smoking, physical inactivity, hypertension, and genetics.4,5 Males over 40 years of age and postmenopausal women have an increased risk.4-6 Recently, there has been significant interest regarding the role of viral and bacterial infections as risk factors for CAD.7-9
Atherosclerosis is the underlying cause of CAD and cerebrovascular disease. The atherosclerotic process primarily targets the intima of the arteries supplying the heart and brain (coronary arteries and carotid arteries), but is not limited to those vessels. The result is a narrowed lumen, and diminished blood flow and oxygen supply. Occlusion occurs by two mechanisms: narrowing of the artery by atherosclerotic plaque formation, and smooth muscle proliferation. When the myocardial oxygen demand increases, blood flow through the arteries supplying the heart cannot increase proportionally, and there is a decreased oxygen supply. This leads to ischemia, and if prolonged, infarction followed by myocardial cell death. Arterial occlusion can occur because of endothelial damage of the blood vessels and platelet and fibrinogen deposition on the damaged wall. The resulting plaques may rupture, and the embolus may occlude a coronary artery and lead to a myocardial infarction (MI).
Men are more prone to the clinical manifestations of coronary arteriosclerosis than are premenopausal women. The reason for this may be that estrogen down-regulates the production of cytokines, especially platelet-derived growth factor that stimulates smooth muscle proliferation in the intima. This process can contribute to development of an atheroma.10
Smoking, another risk factor, seems to cause an increase in fibrinogen levels, activates factor VII, and stimulates platelets. Hypertension is shown to be a weak risk factor,11 whereas diabetes increases the risk of silent MI.12
Figures 1 and 2. The formation of a fibrin thrombus and the contribution of endotoxin and lipopolysaccharide. The areas in blue indicate where periodontal disease affects the clothing cascade.
It has been shown that elevated serum lipid levels, in particular low density lipoprotein (LDL) cholesterol is associated with an increased risk of CAD.13,14 LDL is a macromolecular complex which consists of cholesterol and triglycerides bound to proteins, and which circulate freely in plasma. HDL protects against atherogenesis through at least two mechanisms. First, it removes excess cholesterol from peripheral tissues, such as blood vessels, and moves it back to the liver through a process known as reverse cholesterol transport. Once cholesterol is in the liver it can be excreted from the body in bile. Therefore higher levels of HDL allow more excretion of excess cholesterol. Second, HDL may inhibit the migration of monocytes through endothelial cells, thereby halting further oxidation of LDL. In addition, HDL is associated with various proteins that are believed to have antioxidant effects.15 Most of the LDL cholesterol is removed by the liver, but a small amount of excessive LDL cholesterol is ingested by scavenger macrophages that may migrate into arterial walls where the cholesterol contributes to the development of atherosclerotic plaques.16 Specific adhesion molecules expressed on the surface of vascular endothelial cells mediate leukocyte adhesion to the endothelial cell. LDL cholsterol is trapped in the fibrin meshwork of a thrombus. In autopsy studies, the structure and extent of atherosclerotic lesions vary greatly. Some lesions are soft and lipid-filled while others are calcified or contain smooth muscle cells and fibrocytes. In a MI, the softer lesions with thinner caps tend to become complex, rupture, and cause occlusion of the artery.13,14
For the sequence of atherosclerosis as described by Nieminen et al,17 see Table 1.
Stage I of the lesion occurs between 0 to 10 years when the endothelium of blood vessels first becomes damaged. Platelets then aggregate on the damaged wall. Another contributing factor is the deposition of lipids in the smooth muscle of the intima. As this plaque expands, it projects into the lumen of the vessel. This projection allows for turbulent flow within the vessel and thus further platelet deposition and clot formation.
Stage II occurs between 10 to 20 years. The atheroma matures and further organizes.
Stage III occurs after 20 to 30 years when complicated calcified plaques are seen. Clinical symptoms include unstable angina pectoris and acute MI as a consequence of thrombotic occlusion.
Libby18 and Weissberg19 have described the changing concepts in atherogenesis and causes of atheroma as a modifiable process. They suggested that atherogenesis in humans develops over decades. Early lesion formation may even occur in adolescence. Lesion progression depends on genetic predisposition, gender, and certain well-recognized risk factors.
PERIODONTAL DISEASE AND CAD
Periodontal disease in its various forms is one of the most common disorders affecting mankind. The signs include inflammation, pocket formation, resorption of alveolar bone, and ultimately tooth loss. It is believed that the quantity and virulence of the plaque microorganisms, as well as the intensity of the host inflammatory response, will determine the progression and severity of the disease. The clinical course of periodontal disease can be modified by a number of factors, including diabetes mellitus, cigarette smoking, hormonal influences, and certain genetic disorders.20-22
Periodontal disease has risk factors in common with CAD, including smoking, diabetes mellitus, and low socioeconomic status.23 The question that must be posed is, what is the link between these two diseases? Is the link causal, or casual? Finnish investigators who first implicated Chlamydia pneumoniae as a risk factor for myocardial infarction24 also recognized the connection between dental disease and cardiovascular disease.11,12 They utilized two measures of dental disease: radiographic examination and a clinical examination (total dental index, TDI). In the Finnish population, high TDI scores reflected mostly the periodontal aspects of dental infection. After controlling for cardiovascular disease, the TDI demonstrated a significant association with cardiovascular disease.16 Later studies confirmed the association between periodontal disease and CAD.25-31
The interaction between bacterial products and various homeostatic mechanisms is currently believed to be the link between these disorders.14,32-34 The products of bacteria found in the subgingival plaque, particularly endotoxin associated with Gram negative bacteria, have access to the vasculature in the gingival connective tissue. A patient with moderate to severe generalized periodontitis will have a large surface area of ulcerated subgingival epithelium. Thus, it has been suggested that there is sufficient surface area for exchange between bacteria and bacterial products on the root surface and the vasculature present in chronically inflamed gingival connective tissue.23 Hence, there are three main pathways that may account for the link between periodontal disease and CAD22:
(1) Subgingival microorganisms are the source of transient but repeated episodes of bacteremia. As a result of these bacteremias, bacterial organisms are deposited on the lining of fatty streaks or atheromas found on endothelial walls.35 Investigators have found DNA from C pneumoniae, cytomegalovirus, and Actinobacillus actinomycetemcomitans in atheromas removed at autopsy8,32,33. The role of Porphyromonas gingivalis in atheromas has been suggested by Nassar et al36 and Sojar.37 P gingivalis binds to and invades endothelial cells, and the fimbriae are shown to be involved in this process.
(2) Systemically elevated levels of inflammatory mediators that are the result of inflammation of the periodontal tissues. The inflammatory cells in the gingiva produce large amounts of these pro-inflammatory mediators, which gain access to the systemic circulation.
(3) A combination of pathways 1 and 2.
Different researchers have suggested mechanisms that may contribute to the linkage of periodontal disease and cardiovascular disease. For many of these studies there is no clear distinction between a strictly microbial mechanism and a strictly inflammatory mechanism.
Hertzberg et al33 used a rabbit model and found that bacterial endotoxins affect endothelial integrity and accelerate platelet aggregation when animals were infused with Streptococcus sanguis. There was accelerated platelet aggregation and a dose-dependent change in the electrocardiogram, blood pressure, and heart rate and cardiac contractility, which were consistent with what is seen with a MI.
Many investigators28,34,38-42 have reported that endotoxin and lipopolysaccharides released by bacteria are potent activators of different inflammatory reactions. These factors, released from Gram negative bacteria, stimulate monocytes to secrete pro-inflammatory cytokines such as tumor necrosis factor and interleukin 1, and prostaglandin E2 and thromboxanes, which initiate platelet adhesion and aggregation. These pro-inflammatory cytokines promote the formation of lipid-laden foam cells and the deposition of cholesterol in the intima. It has been suggested that platelet-derived growth factor increases smooth muscle proliferation of the blood vessels, leading to the thickening of the vessel wall. Such thickening predisposes to atheroma formation.23 Lipopolysaccharides also cause endothelial damage, activate thrombocytes, inhibit tissue plasminogen activation, increase thromboxane A2, and decrease lipoprotein lipase activity.43-46 Lipopolysaccharides form complexes with various lipoproteins, especially oxidized LDL cholesterol, which stimulates monocytic secretion of cytokines and thereby creates a cycle of up-regulation.28,47
Furthermore, patients with acute MI and a poor dental status have an increased level of Factor VIII activity compared with patients with a MI and a good dentition. This clotting factor is associated with an increase in thrombogenicity.48
Endotoxin from Gram negative bacteria have been reported by Matilla and colleagues (1995)49 to induce the release of Von Willebrand’s Factor (VWF) from vascular endothelial cells. This link between periodontal disease and VWF results in activation of the clotting cascade.
Lourbakos et al50 studied the effects of the enzymes known as cysteine proteinases (also known as gingipains) produced by P gingivalis on coagulation. They found that the enzymes induced platelet aggregation with an efficiency comparable with thrombin.
A study done by Kweider et al32 reported that patients with periodontal disease have higher plasma fibrinogen levels and white blood cell counts compared with patients without periodontal disease. Such elevated levels may promote atherosclerosis and thrombus formation.
One of the responses to a systemic insult of endotoxin and lipopolysaccharide is an increase in circulating C-reactive protein. This marker has been shown to be a predictor of MI and stroke. C-reactive protein is thought to form deposits in injured blood vessels.28 A study by Noack et al51 found that there were statistically significant increases in C-reactive protein levels in subjects with periodontal disease as compared with healthy individuals. They suggested that this positive correlation between C-reactive protein and periodontal disease might be a possible underlying pathway in the association between periodontal disease and cardiovascular disease.
To summarize the mechanisms discussed above, the direct effects of periodontal infections are those mediated by bacteria and/or their products directly on host tissues. The indirect effects involve generation of an inflammatory response, activation of mononuclear and other cells, with increased production of pro-inflammatory mediators35 (Tables 2 and 3).
The inflammatory response could also potentially contribute to autoimmune events related to bacterial heat shock proteins and heat shock proteins in the individual’s coronary vessel wall.32 Heat shock proteins are found in all species, and the amino acid sequences are conserved between species. This creates a potential for cross-reactions to occur between bacteria and the host. Human tissues, including the endothelial cells lining vessel walls produce heat shock proteins in response to stressors such as hypertension and exposure to lipopolysaccharides. Those host heat shock proteins, in addition to bacterial heat shock proteins, can produce cell damage.52-54 Different human tissues produce heat shock proteins, including the endothelium lining the vessel wall.35
Figures 1 and 2 present the interplay of the mechanisms that have been discussed.
A question arises concerning what to tell patients regarding the association of periodontal disease and CAD. It is fair to inform patients that evidence suggests a relationship, and that periodontal therapy will help maintain the dentition in health and comfort, but it is premature to claim a cardiovascular-protective effect of treatment. It is important to remember that not all studies have been supportive. Howell et al55 suggested that self-reported periodontal disease is not an independent predictor of subsequent cardiovascular disease in middle-aged to elderly men. In addition, Hujoel et al56 did not find convincing evidence of a causal association between periodontal disease and coronary heart disease risk. Larkin also disputed this association.57
Future long-term studies need to establish the relationship between preventive periodontal therapy and the reduction of CAD risk. While a number of studies have shown a relationship between periodontal disease and CAD, (with the link being bacterial infection, bacteremia, and production of inflammatory mediators), these studies have not identified the relative contribution of periodontal disease to CAD in relation to other risk factors such as smoking, high cholesterol levels, and diabetes. A study reported by Genco in 1997 concerning native Americans in the Gila River Indian Community suggested that periodontal disease was a stronger risk factor for CAD than hypertension, cholesterol, age, gender, or smoking.58 In this study population, however, smoking was not common, and could not be evaluated as a contributing factor. He found that only diabetes showed a stronger association with the development of CAD than periodontal disease. The risk of myocardial infarction was 2.7 times higher in the individuals with periodontal disease versus those without periodontal disease.33
Much research remains to be performed. Studies focusing on women are needed because most reported studies have a disproportionate percentage of men. In addition, as noted, intervention studies are needed to determine to what extent treatment of periodontal disease will decrease the occurrence of cardiovascular disease or reduce morbidity and mortality once cardiovascular disease is established. Furthermore, treatment studies will need to identify optimal interventional strategies for treating periodontal disease, ie, as an infectious disease; hence anti-infective therapy, anti-adherent therapy through prevention of plaque accumulation and development of the biofilm, or anti-inflammatory therapy, in which the focus is prevention of the hyperinflammatory state that characterizes progression of periodontal disease.
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Dr. Patel is a former general practice resident at the University of Illinois at Chicago. She is currently practicing in Mechanicsville, Maryland.
Dr. Messieha is the director of the General Practice Residency program at the Chicago College of Dentistry and Medical Center at the University of Illinois. He is also the head of the division of General Dentistry, and a clinical assistant professor of both Oral Medicine and of Anesthesiology.