ABSTRACT: Coronary heart disease is one of the leading causes of morbidity and death in most countries. In the United States, coronary heart disease is responsible for one of every five deaths. In recent years, a number of studies have shown evidence indicating that periodontal disease may play an etiologic role in the pathogenesis of several systemic diseases, such as cardiovascular disease and preterm low birth weight. This article reviews the current evidence linking periodontal diseases with an increased risk for cardiovascular diseases (CVD) such as coronary heart disease (CHD). Proposed mechanisms for this link are also reviewed.
Cardiovascular disease (CVD) is the leading cause of death in the western society, and its pathobiological basis is atherosclerosis. World Health Organization statistics (World Health Report, 1995) show that cardiovascular diseases accounts for about 20 percent of deaths. In western countries, CVD were responsible for 50 percent of deaths (Beck et al., 1998). The American Heart Association estimated that approximately 1.1 million Americans would have a new or recurrent coronary heart attack in 1998 and concluded that coronary heart disease is the single largest killer in the United States (Arbes et al., 1999). Evidence from epidemiological studies has shown that smoking, high serum cholesterol level, hypertension, age, male gender, stress, history of diabetes and lower socioeconomic status are significant risk factors for the development of cardiovascular diseases (Mattila et al., 1998). Although all these classical risk factors can be indications of most CVD-associated deaths, they cannot account for all of the clinical and epidemiological features of the disease. There seems to be other risk factors that play an important role as well (Dorn et al., 1999).
Various infections have been reported as being associated with the development of both cerebral and myocardial infarctions and atherosclerosis process itself (Nieto, 1998; Valtonen et al., 1999; Chiu, 1999). Increasing evidence from epidemiological and experimental studies has indicated associations between atherosclerosis and chronic infections such as Chlamydia pneumoniae, Helicobacter pylori, HSV (Herpes Simplex Virus), and dental infection, suggesting that certain infections may play a role in the etiopathogenesis of atherosclerosis (Mattila et al., 1998; Zhou et al., 1996). Recently, epidemiological data from longitudinal studies strongly suggests that periodontal disease is an important risk factor for coronary heart disease (DeStefano et al., 1993; Mattila et al., 1989, 1995; Beck et al., 1996; Joshipura et al., 1996).
This article reviews the evidence that suggests periodontal disease as a significant risk factor in cardiovascular disease and also briefly reviews the possible pathogenic pathways that may explain this association.
EVIDENCE FROM THE LITERATURE
In a longitudinal study, DeStefano et al. analyzed coronary heart disease (CHD) mortality based upon the National Health and Nutrition Examination Survey I (NHANES I), which followed 9,760 subjects for 14 years. They demonstrated that subjects with periodontitis had a 25% increased risk of coronary heart disease compared to subjects with minimal periodontal disease, controlling for a large number of confounding variables including age, gender, race, education, marital state, blood pressure, total cholesterol level, diabetic status, alcohol consumption. The association was even more significant among men younger than 50 years of age, in which periodontal disease was associated with a 70% greater risk of future CHD (DeStefano et al., 1993). This study provides evidence for an association between periodontal disease and CHD and supports the findings of earlier case-control studies that showed an association between periodontal infections and acute myocardial infarction and atherosclerosis (Mattila et al., 1989, 1993).
In a most recent report of seven-year follow-up study on their earlier cases, Mattila et al. investigated 214 patients with diagnosed coronary heart disease who had undergone a dental examination and evaluation of the risk factors of CHD. As with their previous two studies, dental conditions was a significant predictor for further coronary heart events when controlled for the other common risk factors (Mattila et al., 1995). Taken together, these three studies by this research group have demonstrated consistent and significant association between dental infections and coronary heart disease.
Using combined data from the Normative Aging Study (NAS) and the Dental Longitudinal Study (DLS) sponsored by the Department of Veterans Affairs, Beck et al. conducted longitudinal analyses. Mean bone loss scores were measured in 1147 men at baseline and also during a follow-up 18 years later. Higher levels of alveolar bone loss at baseline were associated with a higher incidence of CHD, fatal CHD, and stroke, after adjusting for age and common established risk factors (Beck et al., 1996).
Joshipura et al. completed a six-year follow-up study of 44,119 male health professionals who had no reported coronary heart disease symptoms at baseline. In the entire study population, the association between the extensive loss of teeth at baseline and the incidence of coronary heart disease was demonstrated, but the association was limited to those who reported a history of periodontal bone loss. Among 6,619 men with periodontal disease, the multivariate relative risk was 1.67 for men with 10 or fewer remaining teeth after adjusting for classic coronary heart disease risk factors (Joshipura et al., 1996).
Genco et al. assessed the baseline alveolar bone level and monitored the cardiovascular status for up to ten years in 1,372 Native Americans of the Gila River Indian Community. They demonstrated that periodontal bone level was a strong predictor of cardiovascular disease for age group of 60 or younger with odds ratio of 2.68 after controlling for other factors such as gender and duration of diabetes (Genco et al., 1997).
Beck et al. started the Dental Atherosclerosis Risk in Communities (DARIC) study in 1996 as an ancillary study to the Atherosclerosis Risk in Communities study, which is a prospective study of the cause and clinical sequelae of atherosclerosis. Their preliminary data available from 3937 participants indicate that, after adjusting for potential confounding factors, periodontal diseases was associated with carotid intimal-medial wall thickness, a measure of subclinical atherosclerotic cardiovascular disease (Beck et al., 1999).
In 1999 Arbes et al. reported the result from a cross-sectional study on 5564 subjects 40 years of age and older, using data from the third National Health and Nutrition Examination Survey (NHANES III). After adjusting for sociodemographic variables and established risk factors for cardiovascular disease, the odds ratio of heart attack increased with increased periodontal attachment loss, with range of 1.4 to 3.8 (Arbes et al., 1999).
The studies reviewed suggested that the associations between periodontal conditions and coronary heart disease are remarkably consistent, in spite of different population samples and different parameters of periodontal disease used among these studies. In general, the incidence odds ratio falls between 1.5 and 2.5. In addition, studies using incident CHD events as an outcome indicated that the dental conditions preceded the heart conditions.
POSSIBLE MECHANISMS
The biological basis for the hypothetical association of cardiovascular disease and periodontal infections is presently under intensive investigation. There are several mechanisms that may link cardiovascular disease and periodontal disease. Periodontal disease is a chronic inflammatory reaction of periodontium to predominantly anaerobic gram-negative bacterial infections. These bacteria and bacterial products such as lipopolysaccharide will have ready access to underlying vasculature through the large surface area of pocket epithelium (Offenbacher et al., 1999).
The bacterial thrombus hypothesis is
a possible mechanism in which interplay between bacterial products and various hemostatic systems takes place. As discussed, infection has appeared to be a risk factor for atherosclerosis and cardiovascular events. Patients with periodontal disease have been shown to have higher levels of plasma fibrinogen and white blood cell counts (Kweider et al., 1993). Such increase in fibrinogen and WBC may promote both atheroslerosis and thrombosis formation which will lead to cardiovascular disease (Lowe, 1998).
Platelet aggregation can be caused by collagen and thrombin, as well as some microorganisms such as Streptococcus sanguis and Porphyromonas gingivalis (Herzberg et al., 1996). They also showed that these oral bacteria can induce aggregation of platelets through the binding of a specific surface protein which share sequence homology with a platelet-activation region of collagen. In addition, periodontal pathogens, P. gingivalis and P. intermedia, were found within atheromatous tissues and were also able to invade endothelial cells (Deshpande et al., 1998; Haraszthy et al., 1998). Lipopolysaccharide (LPS) or endotoxin, when presented as a systemic challenge, can elicit inflammatory cell infiltration into major blood vessels, vascular smooth muscle proliferation, vascular fatty degeneration, and intravascular coagulation (Beck et al., 1996). Taken together, these findings suggest that oral microorganisms present in the blood stream may serve as a thromboembolic trigger and may increase the risk for cardiovascular disease and thrombogenic events.
There is also the hypothesis of common genetic predisposition where some individuals with a genetically predetermined hyperinflammatory monocyte phenotype have a higher risk for both atherosclerosis and periodontal disease (Beck et al., 1996; Mattila et al., 1993). These hyperinflammatory monocytes may respond to a given microbial or LPS challenge with an abnormally high inflammatory response, as reflected in the release of high levels of pro-inflammatory mediators such as prostaglandin E2 (PGE2), interleukin 1b (IL-1b), and tumor necrosis factor a (TNF-a). Increasing evidence suggests that the LPS-monocyte-proinflammatory cytokines axis plays a critical role in infection-associated atherogenesis and thromboembolic events (Marcus et al., 1993; Seymour et al., 1998).
Bacterial LPS can have a significant vascular effect and trigger the release of IL-1b, TNF-a and thromboxane A2. These cytokines can then initiate platelet adhesion and aggregation and promote the formation of lipid-laden foam cells and the deposition of cholesterol within the intima. Evidence also demonstrated that these monocytic cytokines can be increased by low-density lipoprotein (LDL), thereby providing a further mechanistic link between dietary factors and the increased risk of cardiovascular disease (Beck et al., 1999). Overall, the presence of hyperinflammatory monocyte phenotype places certain individuals at high risk for both cardiovascular disease and periodontal disease, and the expression of this trait appears to be under both the environmental and genetic influence.
Recent studies (Slade et al., 2000; Loos et al., 1998; Ebersole et al., 1997) have demonstrated that periodontal infections are associated with elevated C-reactive protein (CRP), an acute phase protein and marker of inflammation. Elevation of serum CRP has been shown to be a risk factor for cardiovascular disease (Ridker et al., 1997). These findings raised another interest in current research on possible pathway through which periodontal disease can increase the risk for cardiovascular disease.
CONCLUSION
Strong evidence from research studies demonstrated that infection and inflammation are etiologic factor for atherosclerosis/cardiovascular disease, and the several studies also shed light on a more direct role for the oral infections, periodontal infection in particular, in the atherosclerotic events. The chronic nature of periodontal disease provides a rich source of subgingival microbial and host response products and effects over a long period of time.
An increasing body of evidence is pointing toward periodontal disease as a causal factor for heart disease. However, it needs more convincing data from further studies such as well-controlled intervention studies to substantiate the cause-and-effect relationship. The preliminary data from the on-going efforts by researchers appear to be promising.
If future studies establish the fact that periodontal disease is a true risk factor for cardiovascular disease and that periodontal treatment can reduce the risk of developing the systemic diseases, this will provide significant and positive implications for dental health professionals and for patient motivation and awareness. Thereby the importance of periodontal disease in public health will grow significantly and changes will be brought to the standard of care for physicians and to the insurance industry.
Dentists must emphasize the need for improved dental health the may reduce the risk of cardiovascular disease, especially for those individuals at high risk.
Dr. Henry H. Chang and Haihong Chen are post-doctoral candidates at Loma Linda University, School of Dentistry, Division of International Dentistry.
Oral Health welcomes this original article.
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