Discuss the current evidence suggesting a link between chronic periodontal inflammation and cardiovascular disease
The microflora of the oral cavity is rich, diverse and unique. Bacteria in the mouth can aggregate as a biofilm, which is a microcolony of up to 700 different bacterial families.
Chronic periodontal inflammation and cardiovascular disease
These colonies of bacteria are attached to non-shedding tooth surfaces on which the bacteria can proliferate, with dietary sources of nutrition provided from saliva. As plaque matures, the conditions favour the colonisation by gram negative anaerobic bacteria in the deeper plaque layers. This mature plaque extends subgingivally, where it is in close proximity to the vulnerable, non-keratinised junctional epithelium.
The accumulation of this plaque then results in disease. Gingivitis is characterised by inflammation of the gums, redness, swelling and bleeding on probing. This is a reversible condition. In comparison, periodontitis is an irreversible condition, characterised by loss of connective tissue attachment, alveolar bone loss, and there is true pocketing on probing. This pocket can extend from 4-12mm, and can harbour from 107 to 109 bacterial cells. Not everyone who has gingivitis will progress to periodontitis, only susceptible individuals whose plaque contains periodontal pathogens.
Clinically, patients with pockets of 4mm or more are diagnosed with periodontitis. Generally, mild periodontitis can be treated with scaling and root planing, whereas more severe periodontitis may need surgical intervention.
Cardiovascular disease refers to a group of diseases that involve the heart or blood vessels. It is a large group of diseases which includes coronary artery disease, peripheral vascular disease, stroke and atherosclerosis. CVD is a very common problem, accounting for 50% of deaths in the USA each year and 29% of deaths worldwide. Atherosclerosis is one of the main types of CVD and it affects one in four people, also contributing to 39% of deaths in the USA each year. Some of the risk factors for the development of CVD include smoking, stress, diabetes and low exercise, some of which are common to periodontitis.
Both periodontal disease and CVD have some characteristics in common, in that they are both common problems, they are both usually chronic and they both have multifactorial aetiologies. Over recent times, there have been several epidemiological studies that suggest that periodontal diseases may be an important risk factor for some cardiovascular diseases. Due to the high prevalence of both conditions, and the possible detrimental consequences of both, clarification of the association between periodontal diseases and CVD would be of great interest and value to both medical and dental professionals alike.4
The aim of this project is to review and evaluate some of the current literature available regarding the possible link between chronic periodontal disease and cardiovascular disease, and to look at some of the different mechanisms suggested for this link.
How these aims are to be achieved
The literature will be reviewed in a systematic order, and will be evaluated under the following headings:
* Suggested mechanisms proposed to explain the link between periodontal disease and CVD
· Different cardiovascular disorders and their possible association with periodontal disease.
The different cardiovascular disorders I will focus on are:
Ø Coronary artery disease
Ø Peripheral vascular disease
Review of the literature
Suggested mechanisms proposed to explain the link between periodontal disease and CVD
There have been varying mechanisms suggested for the possible association between periodontal disease and CVD. Recently, the one that appears to be gaining most strength is the role of inflammation.
The bacteria involved in periodontal disease, and their components, like lipopolysaccharide, can stimulate the release of enzymes and inflammatory products. Some of the inflammatory mediators released are interferon's (IFNs), interleukins (ILs), prostaglandins (PGE2), and acute phase proteins like tumour necrosis factor-a (TNF- a), C-reactive protein (CRP) and fibrinogen. The excessive production and uncontrolled activation of these inflammatory mediators will lead to excessive tissue damage.
According to Dave et al (2008), the role of inflammation in the pathogenesis of both periodontal disease and cardiovascular disease has taken on increased significance.
It has been shown that periodontal disease contributes to an increase in systemic inflammation, and this resultant systemic inflammation increases the risk of cardiovascular disease. Elevated markers for systemic inflammation are now considered recognised risk predictors of CVD.
Atherosclerosis, a disease of the arteries in which fatty plaques develop on their inner walls, is the underlying cause of many cardiovascular diseases affecting 1 in 4 persons. Many studies have indicated the link between periodontal disease and atherosclerosis.10+ Inflammatory processes play a major part in atherosclerosis, presumed to be involved from initiation of the atheroma to the final stages of plaque rupture.10
Endothelial cells, which are the innermost surface of the artery wall, do not allow the attachment of leucocytes in their normal state. However, this can change in inflammatory states, as circulating cytokines and bacteria can activate the endothelial cells, leading to expression of adhesion molecules; vascular cell adhesion molecules (VCAM) and intercellular adhesion molecules (ICAM), which allow leucocytes to bind to them.10 This is an early step in atherogenesis.
Therefore, factors which modulate the expression of adhesion molecules may be important in modulating the development of atherosclerosis. For example, studies have shown that nitric oxides (No's) ability to decrease endothelial activation may play a part in its anti-atherogenic and anti-inflammatory properties. NO is a free radical which can down regulate the expression of VCAM-1 by inhibiting NF-kB.15
On the other hand, C-reactive protein (CRP) is a protein that can up-regulate the expression of adhesion molecules. CRP plays a role in endothelial dysfunction and may prove the link between CVD and periodontal disease. CRP is linked to atherogenesis through the production of cytokines and promotes cell surface expression of ICAM-1.
Several studies have shown that periodontal pathogens and the resultant inflammatory response can systemically trigger pro-inflammatory cytokines and tissue-destructive mediators like CRP, TNF- a and PGE2.4,, For example, the study by Loos et al (2000), although a small study of 150 people, found that periodontal disease resulted in elevated levels of neutrophils, IL-6, and systemic CRP.18 They concluded that “these elevated inflammatory factors may increase inflammatory activity in atherosclerotic lesions, potentially increasing the risk for cardiac or cerebrovascular events.”
A much larger study by Wu et al. (2000), looking at 10,146 participants, also came to the same conclusion. They found that “poor periodontal health status is associated with elevated C-reactive protein”, and suggest that this may explain the link between periodontal disease and increased CVD risk.
The inflammation theory is also supported by Beck et al. (1996). They carried out a large cohort study, and they propose that the association between periodontal disease and CVD may be due to an inflammatory response trait that puts an individual at an increased risk for the development of both periodontal disease and atherosclerosis. They also suggest that once periodontal disease is established, it can provide a source of endotoxins and inflammatory cytokines that are able to initiate atherogenesis and thromboembolic events, as well as exacerbate them.21
Another potential mechanism for the association between periodontal disease and CVD is the direct effects of periodontopathic bacteria on host cells.13 It is hypothesised that oral bacteria can affect the CVS when they enter the blood stream, attaching to fatty plaques in the coronary arteries and contributing to clot formation. Intact bacteria can enter the blood stream through a myriad of paths, such as breaks in the epithelium caused by tissue damage.
There are a number of studies that have identified periodontal pathogens in atheromatous plaques and other cardiovascular specimens.,,
Haraszthy et al. (2000)22 examined 50 human specimens obtained during carotid endarterectomy for the presence of certain types of bacteria. They concluded from their findings that “periodontal pathogens are present in atherosclerotic plaques, where they may play a role in the development and progression of atherosclerosis leading to coronary vascular disease and other clinical sequelae”.22
A recent study by the American Heart Association found that human atherosclerotic plaque contains Actinobacillus Actinomycetemcomitans and Porphyromanas Gingivalis, and they conclude that “the bacteria could contribute to the vascular pathology either directly through their cytotoxicity or indirectly by inducing or exacerbating inflammation.”
An in vitro study by Giacona et al. (2004) found that when P.Gingivalis bacteria are taken up by macrophages, there is an increase in foam cell formation, which are the hallmark of early atherogenesis.
Another study worth mentioning was carried out by Nakamura et al. (2008), and also involves P. Gingivalis. They found that the lipopolysaccharide fraction of P. Gingivalis can produce increased expression of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells, facilitating the adhesion of mononuclear cells to them.
These results clearly suggest that a periodontal infection by P. Gingivalis can play a part in atherogenesis, by promoting the recruitment of monocytes to the vascular endothelium, through increased expression of cell adhesion molecules and by increasing the formation of foam cells.
Another possible mechanism suggested for the association between periodontal disease and CVD, but on which there are not as many studies available, are the changes to lipoprotein metabolism. During a period of infection or inflammation, such as periodontal disease, there are changes in lipoprotein metabolism that can be caused by the acute-phase response.4 The pro-inflammatory cytokines present can be pro-atherogenic and can result in an increase in low-density lipoprotein and decrease in high-density lipoprotein cholesterol. These events can make the vascular endothelium more susceptible to injury. As I have already discussed, as dysfunction of the endothelium is an early step in atherogenesis, this could suggest the association between periodontal disease and CVD.
A more recent hypothesis linking periodontal disease with CVD is due to cross-reactivity of self heat shock proteins (Hsp) with bacterial Hsp's. Heat shock proteins are produced by all cells in response to stress. The immune system may not be able to differentiate between self and bacterial-Hsp, thus cross-reactivity between the two may occur. This has been proposed to occur in blood samples of patients with atherosclerosis, in atherosclerotic plaques and in periodontal disease tissue. This could therefore support the hypothesis that cross-reactivity of the immune response to bacterial Hsp's may be a mechanism involved in the process of atherosclerosis.
Different cardiovascular disorders and their possible association with periodontal disease
Ø Coronary Heart Disease
Coronary Heart Disease (CHD) is probably the most important manifestation of atherosclerosis. According to the American Heart Association (2003), CHD is the biggest cause of mortality in Western countries, affecting 7 million Americans and accounting for 33% of all deaths annually in the U.S.
There are several studies that have linked infections like periodontitis to CHD,13 with some studies being stronger than others.
For example, a study by Meurman et al. (2003) found that patients with CHD had worse oral health status than those without CHD. However, the strength of the evidence for the causal relationship between the two, from such a study, is weak as the study did not adjust for things such as confounding risk factors.
On the other hand there have been studies that, after adjusting for confounding risk factors, did not find any significant associations between periodontitis and CHD.,
A prospective cohort study by Hujoel et al. (2000) looked at 8,032 adults to evaluate the risk of CHD in people with periodontitis, gingivitis, or no periodontal disease. Their study did not find any convincing evidence of a causal relationship between periodontal disease and CHD risk. However, the authors did mention in their conclusion that “a small causal association could not be ruled out”.32
Another study by Howell et al. (2001) also found no significant association between the two.33 However, this study had several limitations. For example, it was a self-reported study, so the accuracy of the data is questionable as no oral examinations were conducted on the participants. Some cases of periodontal disease may have been missed, and some cases reported may have been inaccurate.
In a recent study by Tubrizi et al. (2007), they investigated the oral health of ten pairs of monozygotic twins where one twin had CHD and the other did not. They found that the twin with CHD had higher percentages of bleeding on probing, reduced bone level and more pathological pockets. These findings showed that the twin with a history of CHD had worsened periodontal condition, suggesting that periodontitis and CHD are associated even when genetic factors are controlled.
A 14-year longitudinal study by DeStefano et al. (1993) found that periodontitis resulted in an increased risk of 25% for CHD, and an increase of 70% in men less than 50 years of age. A longitudinal study carries a lot of weight, as it allows for a causal relationship to be established if the proper confounding factors are adjusted.10 This study by DeStefano et al adjusted well for confounders, those being age, sex, race, education, poverty index, marital status, systolic blood pressure, diabetes, alcohol consumption, BMI and total cholesterol concentration.
A more recent study by the American Heart Association, with a follow up time of 35 years, found a significant association between periodontitis and CHD incidence among men less than 60 years of age, but no association in older men.
During this study, the participants were examined every 3 years, and the strength of the study is enhanced by the availability of repeated clinical and radiographic measures of periodontal disease over a long period, as opposed to other studies, such as the one by Howell et al already discussed 33, in which no measurements of periodontal disease were taken. Another important aspect of this study is that it controls for smoking, which can play an important role in both diseases.
Even though there are contradictions between the studies available, and the strength of the studies vary, it seems that the studies that show a positive association between periodontal disease and CHD outweigh and outnumber those that show no association between the two.
Ø Peripheral Vascular disease
Peripheral vascular disease (PVD), also known as peripheral arterial disease, involves obstruction of the blood vessels in the arms and legs. It can result from atherosclerosis, or inflammatory processes that lead to stenosis, an embolism, or thrombus formation. It can cause a lack of blood supply to the affected areas, and can result in pain at rest, intermittent claudication, and in extreme cases gangrene.
Whilst there have been many studies carried out to evaluate the risk of cardiovascular diseases like coronary heart disease, there are not many that evaluate the association between peripheral vascular disease and periodontal disease .
The first paper I found was a study by Mendez et al. published in 1998. This was a large prospective longitudinal study with a follow-up period of 25-30 years, and involved over 1000 participants. They found that men with periodontal disease had a two-fold increase in their risk of developing PVD, and concluded that “periodontal disease appears to be an independent, highly significant risk factor associated with PVD.” The study even adjusted for confounders like age, BMI, family history of heart disease and smoking.
In 2003, a study by Hung et al., involving a much larger number of participants, found a similar increase in the risk of developing PVD in patients who had periodontal disease. This prospective study looked at 45,136 people, who had no CVD at the start, over a 12-year follow-up time, and concluded that “tooth loss was significantly associated with PVD, especially among men with periodontal diseases.”
A more recent study by Chen et al. (2008) found that periodontitis increased the risk of having PVD 5-fold. However, this was a small case-control study, so the issue of causality cannot be confirmed by it. However, their results do support the previous epidemiological evidence37,38 suggesting a possible association between periodontitis and PVD, but further studies are needed to determine whether periodontal disease is a causal factor associated with PVD.
A stroke, also known as a cerebrovascular accident, involves the rapid loss of brain function as a result of a disturbance in the blood supply to the brain. This can be due to a blocked or burst blood vessel, resulting from ischaemia or haemorrhage, and can lead to the affected area of the brain being unable to function.
Stroke is the third leading cause of death in developed countries, after CHD and cancer.10 Some risk factors for stroke include hypertension, diabetes, high cholesterol and smoking. There have been a number of studies done to ascertain whether periodontal disease can be added to this list.
The general consensus amongst the studies I came across is that periodontal disease is associated with an increased risk of stroke, but the extent of this association is not yet known.
A retrospective study by Morrison et al. (1999) found a non-significant increase in the risk of fatal stroke in patients with periodontal disease. As this was a retrospective follow-up study, its accuracy is questionable as the outcomes had already happened.
In a prospective study by Wu et al. (2000), in which they analysed data from a large cross-sectional study, they found that periodontal disease was “a significant risk factor” for stroke. When analysing the different types of stroke, they found an increased risk for total and non-haemorrhagic stroke in patients with periodontal disease, but not for haemorrhagic stroke. While this study has many strengths, it also has some limitations, such as the fact that the likelihood of misclassification of the periodontal status is high, as the assessments were not very thorough. However, their findings are consistent with other studies I came across.
Joshipura et al. (2003) found that periodontal disease and stroke had a significant association. A possible downfall of this study though is that the periodontal disease was self-reported, so there is a doubt about the accuracy.
A more recent study by Grau et al. in 2004 found that periodontal disease is significantly associated with ischaemic stroke. A big advantage this study has over the previous one mentioned is that they carried out thorough clinical and radiographic examinations to evaluate periodontal disease, and they claim to be the first study to do so.
While the greater proportion of studies on this topic clearly support the hypothesis of an association between periodontal disease and stroke, a causal relationship cannot be proven from such studies, so much larger intervention studies are needed to prove or disprove the issue of causality.
After reviewing the literature, it is quite clear that there is currently a great interest in the possible link between periodontal disease and cardiovascular disease. Over the past couple of decades, there have been numerous studies carried out, some that show no association between the two, but the majority of which suggest that there is a positive correlation. The emerging association between periodontal disease and CVD is an exciting new area of research and has the potential to reap substantial health benefits with further knowledge.
There are several different mechanisms suggested for the association between periodontal disease and CVD. What became evident during my review is that the mechanism that is beginning to gain most strength is the role of inflammation. That is, the resultant systemic inflammation produced as a result of the indirect effect of periodontal bacteria increases the risk of CVD. Whatever the mechanism is, it is obvious that the relationship between periodontitis and CVD is shifting from a purely epidemiological association towards biological understanding of the underlying mechanisms.
When I looked at three different diseases; coronary heart disease, peripheral vascular disease and stroke, the same conclusion can be drawn up on all three. The greater proportion of studies do find a positive association between them and periodontal disease, but a causal relationship cannot be inferred from the studies done so far, so further studies are needed to determine this issue.
While the results for most studies on this topic are consistent, the studies are too few and show some biases and limitations to allow for a definitive conclusion. For example, there is no standard definition or measures for periodontal disease. A sample of cases reviewed all varied in how they measured the disease status. Also, there are many potential confounding risk factors that are common to both conditions that are not adjusted for in some studies. What is clear is that larger, well-designed, randomised clinical trials and intervention studies are needed before any definitive conclusions can be drawn.4
While it is unclear yet whether the association between periodontal disease and CVD is causal or coincidental, with further confounding research the potential public implications of true results could be substantial.
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