Ahmed REVIEW and ARTICLE Tanwir

Association of Periodontal Pathogenesis and Cardiovascular Diseases: A Literature Review Umair Ahmeda/Farzeen Tanwirb Purpose: To present a short review of recent literature available on the association of periodontal and cardiovascular diseases (CVD) and the role of peridontal disease as a risk factor to exacerbate CVD. Materials and Methods: A thorough search of articles was carried out on the databases PUBMED and MEDLINE on the association of periodontal and cardiovascular diseases (CVD). The selected literature included review articles, observational and case-control studies as well as randomised control trials. While selecting articles, priority was placed on papers published within the last 12 years. A brief description of periodontal diseases, atherosclerosis, underlying pathophysiology and oral bacteria has been included. Results and Conclusion: There is growing evidence of the association of periodontal diseases and CVD, as reviewed by the epidemiological studies. The in vitro studies also highlight a potential link between oral bacteria and atherosclerosis. Thus, there is urgent need for proper case controls and efficient interventional trials to analyse how such interventions can produce a positive outcome on cardiovascular diseases. Some recent interventional trials have shown that periodontal treatment can decrease markers of systemic inflammation. The relationship between periodontal diseases and CVD deserves further research because of its consequences for public health. Key words: atherosclerosis, cardiovascular disease, C-reactive protein oral bacteria, periodontal diseases Oral Health Prev Dent 2015;13:21-27 doi: 10.3290/j.ohpd.a32823


ardiovascular diseases (CVD) have been the leading cause of death in the United States for more than a hundred years (AHA Scientific Statement, 2013). They have serious health implications in most countries of the world and are regarded as the most frequent systemic problem affecting the general public (Lloyd-Jones et al, 1999). There are many risk factors associated with CVD, including tobacco use, alcohol consumption, hypertension, high cholesterol, unhealthy diets and obesity. As the number of risk factors increase, the likelihood of contracting CVD also increases. The majority of these risk factors are ‘modifiable’ risk factors and altering lifestyle events can drastically reduce the a

Research Assistant, Department of Periodontology, Ziauddin University, Karachi, Pakistan. Performed literature review, wrote and proofread manuscript, contributed to discussion.


Director of Post Graduate Studies and Research, Associate Professor and Head of Department of Periodontology, Ziauddin University, Karachi, Pakistan. Idea, hypothesis, study design, proofread manuscript, contributed to discussion and literature review.

Correspondence: Dr. Umair Ahmed, Department of Periodontology, Ziauddin University, Postal Address: 4/B, Shahrah-e-Ghalib, Clifton, Karachi 75600, Pakistan. Tel: +92-345.315-1831, Fax: +92-35862940. Email: [email protected]

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Submitted for publication: 13.06.12; accepted for publication: 01.08.13

risk of CVD. Stopping smoking, regular exercise and changing to a healthy diet can significantly cut down the risk of CVD. Amongst the non-modifiable risk factors are age, gender, family history and ethnic origin. Periodontal disease is an inflammatory disease of the periodontal tissues, which enclose and reinforce the tooth structure. In individuals with good periodontal health, a very shallow space known as the gingival sulcus is maintained around the circumference of the tooth surface by the gingival tissue. In a diseased state, microorganisms present in the gingival sulcus actuate the inflammatory process. This causes deepening of the gingival sulcus which gradually develops into a periodontal pocket. A series of events thus follows, beginning with gingivitis, apical migration of gingival attachment and loss of connective tissue and alveolar bone. It has been suggested that such inflammatory processes of the periodontal tissues may directly or indirectly influence the genesis of systemic diseases such as CVD. Several studies have established epidemiological links between periodontal diseases and CVD, establishing the association between these two different diseases (Lockhart et al, 2012).


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DEFINITIONS Cardiovascular diseases (CVD) or ‘total cardiovascular diseases’ include rheumatic fever/rheumatic heart disease, hypertensive diseases, ischemic (coronary) heart disease, pulmonary heart disease and diseases of pulmonary circulation, other forms of heart disease, cerebrovascular disease (stroke), atherosclerosis, other diseases of arteries, arterioles, and capillaries, diseases of veins, lymphatics, and lymph nodes not classified elsewhere as well as other and unspecified disorders of the circulatory system. When data is available, congenital cardiovascular defects are also included (AHA, 2013). Atherosclerosis is a systemic disease process in which fatty deposits, inflammation, cells and scar tissue build up within the walls of arteries. It is the underlying cause of the majority of clinical cardiovascular events (AHA, 2013). Periodontal diseases include gingivitis and periodontitis. These inflammatory diseases involve the tissues that surround and support teeth in the mouth. The process usually begins with inflammation of the gums (gingivitis) and subsequently progresses to periodontitis. Periodontitis is a local inflammatory process triggered by bacterial insults, which brings about destruction of the periodontal tissues (Noack et al, 2001).

PATHOPHYSIOLOGY AND MECHANISMS Possible underlying mechanisms to elucidate the association of periodontal pathogenesis and CVD have been postulated.

Endothelial dysfunction An interesting hypothesis suggested in some studies is that oral bacteria or their metabolic products directly affect the endothelium by stimulating the formation of atherosclerotic plaques (Haraszthy et al, 2000; Fiehn et al, 2005; Nakano et al, 2006; Aimetti et al, 2007). Furthermore, atheromatous samples collected from variable vascular locations contained oral bacteria or their products. In contrast, some studies have not validated any such findings (Cairo et al, 2004; Elkaim et al, 2008). The initiating factor in the progression of atherosclerosis is endothelial dysfunction. A randomised controlled trial (RCT) of aggressive periodontal treatment reflected marked progress of blood-


flow–mediated dilation, pointing to an association of periodontal diseases with dysfunction of endothelium as a marker of early plaque formation in subjects affected by moderate to severe periodontal disease (Tonetti et al, 2007).

Indirect mechanisms and the molecular immune response (molecular mimicry) Periodontal diseases can also indirectly affect CVD by influencing potential CVD risk factors, such as low-density lipoprotein (LDL) serum levels and glucose metabolism. This has been shown by relevant observational studies linking periodontal diseases and glucose metabolism (Grossi et al, 1998; Losche et al, 2000) and serum total cholesterol (Wu T et al, 2000; Katz J et al, 2002; Joshipura et al, 2004). It has been hypothesised that serum concentrations of LDLs, very low-density lipoproteins (vLDLs) and triglycerides are elevated in periodontal diseases. These groups of lipids enter the endothelial vasculature easily and are prone to modification and adherence to the existing atherosclerotic lesion. A study by Losche et al (2000) hypothesised that patients with chronic periodontitis showed elevated levels of total cholesterol and serum LDL compared to control cases. In a study carried out by Nibali et al (2007), increased serum levels of LDL and decreased high-density lipoprotein levels were recorded in patients with severe periodontitis. The results also included increased leukocyte counts, indicating low-grade systemic inflammation. Although the underlying mechanism is not fully understood, it is postulated that it may be due to the effect of periodontal diseases on endothelial function or on the inflammatory process. Another interesting hypothesis that links periodontal disease with CVD is that of molecular immune response or ‘molecular mimicry’. This hypothesis states that oral bacterial products along with inflammatory mediators induce the endothelial vasculature to produce certain immune factors against the bacterial heat-shock proteins (HSP) (Seymour et al, 2006). This response is thought to occur when the immune system perceives foreign and autogenous HSPs to be similar, thus leading to the cross reaction of autoantibodies T- and B-cells, the ‘autoimmune reaction’ (Kohm et al, 2003). This cross-reactive autoantibody reaction to HSPs has been identified as a link between periodontal diseases and CVD. This immune reaction may potentiate further inflammation, thus enhancing athero-

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sclerotic plaque formation. HSPs are expressed by both eukaryotic and bacterial cells as an outcome of different forms of stress (mechanical stress, infection, oxygen radicals).

Systemic inflammation Another hypothesis on the putative link between periodontal diseases and CVD involves systemic inflammation. Inflammation causes an increase in the level of circulating cytokines, which in turn actively contributes towards damaging the endothelial vasculature, thereby bringing about atherosclerosis. Extensive studies have confirmed the production of these pro-inflammatory cytokines in periodontal diseases (Preshaw and Taylor, 2011). It has been hypothesised that the combined effects of these cytokines contribute to chronic inflammation; however, the exact role of this cytokine network in pathogenesis still remain unclear. Some epidemiological studies have linked cardiovascular risk with elevated cytokine levels (interlukin-1 [IL-1], interlukin-6 [IL-6], monocyte chemoattractant protein-1 [MCP-1] and tumor necrosis factor alpha [TNF-α]), fibrinogen and also acute phase proteins, particularly C-reactive protein (CRP) (Ridker et al, 2000a,b,c). CRP is a type-I acute-phase protein which is produced by the liver in response to inflammatory stimuli (Saito et al, 2003). Such stimuli include infection, trauma and hypoxia. There appears to be an association between periodontal diseases and CRP levels, in which CRP levels contribute to CVD with a possible intermediary role in the pathophysiology of CVD. Buhlin et al (2009) conducted a study in which 68 cases of advanced periodontal disease were compared to 48 periodontally healthy controls. Periodontal disease was affiliated with elevated CRP levels, IL-8, glucose and fibrinogen. In another study, patients having periodontal disease were treated with scaling, root planing and flurbiprofen. It was seen that CRP levels decreased one year after therapy (Ebersole et al, 1997). It has also been shown that CRP plasma levels can be better indicators of future CVD events than serum LDL levels, thus stressing the role of inflammation in the progression of atherosclerosis (Ridker et al, 2002). CRP is also believed to play a more direct role in the atheromatous plaque development. CRP promotes foam cell formation by causing aggregation of monocytes at the arterial wall and enhances LDL uptake via macrophages. This is the initial stage of atherosclerosis known as the ‘fatty streak’

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(Libby, 2002). However, a detailed mechanism by which CRP influences the development of atheroma formation has yet to be described. Bacterial lipolysaccharide (LPS) also contributes to atherosclerosis by modifying lipid metabolism (Stoll et al, 2004). The impact of systemic inflammation contributing to the progression of atherosclerosis is further amplified by the interplay of other risk factors as well.

Periodontal pathogens and bacteraemia The role of periodontal pathogens and bacteraemia as a proposed hypothesis linking CVD and periodontal diseases is discussed in the following section. Relevant studies have established the potential relationship of periodontal diseases and CVD. Holmlund et al (2006) conducted a study in Sweden to investigate the extent of periodontal disease in relation to hypertension and myocardial infarction (MI) in a pool of 4254 patients. The incidence of periodontitis was significantly linked to hypertension (prevalence 16%; P < 0.0005) independent of age and to MI (prevalence 1.7%, P < 0.03) in the middleage group (40 to 60 years). The number of periodontal pockets and the remaining number of teeth were among other parameters used. The study supported the hypothesis that periodontal health is linked to CVD in a dose-dependent fashion. Janket et al (2003) conducted a meta-analysis of periodontal diseases as a risk factor for future CVD events. The study revealed an overall 19% increased risk of such systemic diseases in patients suffering from periodontitis. The risks were greater (44%) in individuals under the age of 65. Bahekar et al (2007) conducted a meta-analysis on the prevalence of periodontitis linked to an elevated risk of coronary heart disease (CHD). The meta-analysis showed that individuals with periodontitis had a 1.14-times higher risk of developing CHD and that the prevalence of CHD was higher in patients who had periodontitis. The study thus found that the occurrence of CHD was higher in cases of periodontitis. In another meta-analysis conducted by Mustapha et al (2007), periodontitis with increased bacterial systemic exposure was strongly linked to CHD events, unlike those subjects without periodontitis. Such studies indicate that periodontal diseases do affect cardiovascular health. Cueto et al (2005) performed a case-control study hypothesising a possible link between periodontal pocket depth/loss of clinical attachment and myocardial infarction. The correla-


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tion of periodontal disease and acute MI was significantly higher in the unmodified (P < 0.001) as well as the modified analyses (P < 0.005). However, some studies have not used probing pocket depths and attachment levels but instead alveolar bone loss as the standard definition of periodontitis (Persson et al, 2003; Engebretson et al, 2005; Geismar et al, 2006; Rech et al, 2007).

THE ROLE OF ORAL BACTERIA IN CVD The oral cavity of a newborn infant does not contain bacteria. It is only after some time that it is rapidly colonised by microorganisms. Interestingly, by the time adulthood is reached, the oral cavity hosts more than one billion bacteria. With pertinence to atherosclerosis, the region in the oral cavity with the highest saturation of microbial flora is the periodontal pocket. In the form of oral biofilm, the microbial flora has close anatomical access to the vasculature of the periodontium, thus contributing to the extra-oral spread of bacteria to sites such as the heart (Nanci and Bosshardt, 2006). In periodontitis, there is dilation of the periodontal vasculature and an increase in viable surface area, which promotes bacteraemia (Parahitiyawa et al, 2009). The bacterial pathogens enter the bloodstream to eventually reach the endothelium, starting a chain of events beginning with endothelial dysfunction, progressing to inflammation and finally atherosclerosis. In a study conducted by Forner et al (2006), individuals with poor oral hygiene are more prone to develop bacteraemia during periodontal procedures because of an elevated bacterial load. They stated that after 30 minutes, bacteraemia was detected in 4 out of 20 individuals, one after chewing, one after toothbrushing and two after scaling. It is postulated that bacteraemia during the course of oral infection may result in bacterial invasion of endothelial vasculature. A study carried out by Giacona et al (2004) reflects on the direct influence of oral bacteria on the endothelium. It has been shown that strains of Porphyromonas gingivalis trigger their uptake via macrophages to stimulate foam-cell formation in the presence of LDL in vitro. Various strains of oral bacteria (including Streptococcus mutans, Streptococcus sanguinis, Aggregatibacter actinomycetemcomitans and P. gingivalis) have been found in heart-valve specimens (Nakano et al, 2009). However, studies by Espinola et al (2002) and Honda et al (2005) have shown that the role of different strains of bacteria in the progres-


sion of atherosclerosis may possibly be due to the influence of total microbial load and not just to any single microbial entity. Danesh et al (1997) also examined the role of infections, finding evidence that certain oral infections caused by Cytomegalovirus, Cytomegalovirus pneumonia, Helicobacter pylori and periodontal pathogens are linked with CVD. In a study by Haraszthy et al (2007), 50 samples of human carotid atheromas were analysed and periodontal pathogens were identified (direct evidence). 30% of the specimens were affirmative for Tannerella forsythia, 26% were positive for P. gingivalis, A. actinomycetemcomitans was positively identified in 18%, while 14% were affirmative for Prevotella intermedia. According to some studies, species of streptococci have been linked to acute coronary syndrome (ACS) (Li et al, 2000; Herzberg et al, 2005). Renvert et al (2006) performed a case-control study to evaluate the role of periodontal pathogens and cumulative bacterial load in the progression of an inflammatory process leading to acute coronary syndrome (ACS). A total of 161 patients diagnosed with ACS were compared to 161 cases. The total periodontal bacterial load was higher in patients diagnosed with ACS (mean difference: 17.4 × 105; standard deviation: 10.8; 95% confidence interval: 4.2 to 17.4; p < 0.001) and significantly so for a majority of periodontal species such as P. gingivalis and T. forsythia. Some studies have shown that increased antibody titres to bacteria involved in periodontitis exist in patients with cardiovascular diseases (Meurman et al, 2003; Mustapha et al, 2007). Further direct evidence was provided by animal studies on mice (Kuramitsu et al, 2001). That study showed that infections caused by P. gingivalis have systemic implications with calcifications of aortic atherosclerotic plaques. It was also observed that increasing the time of exposure to the pathogen stimulates the amount of calcification further. Such studies highlight the presence of periodontal pathogens in atherosclerotic plaques, although the exact underlying mechanisms remain unclear. One hypothesis suggests that oral bacteria contribute to endothelial dysfunction by direct invasion of the endothelial vasculature. Endothelial dysfunction is associated with elevated coagulative characteristics, cell adhesion and pro-inflammatory cytokines, all of which have been shown to be stimulated by P. gingivalis (Roth et al, 2006; Roth et al, 2007). Komatsu et al (2012) studied the role of E-Selectin (a cell adhesion molecule on the endothelium that induces inflammatory events) in assisting P. gingi-

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valis to adhere to human umbilical vein endothelial cells (HUVECs). This was the first study done to explore the adhesion of ‘activated’ endothelial cells by P. gingivalis. The inflammatory cytokine TNF-α triggers the activation of these HUVECs. After activation, E-selectin mediates the adhesion between the activated endothelial cells and OmpAlike proteins Pgm6 and Pgm7 found in P. gingivalis. Bacterial invasion of the endothelial cells was also shown to cause apoptosis or programmed cell death by elevated levels of P. gingivalis (Roth et al, 2007). Hence, oral bacteria such as P. gingivalis cause endothelial dysfunction through pro-inflammatory changes and causing apoptosis. The abovementioned studies demonstrate that periodontal microorganisms invade the endothelial vasculature. However, it still remains uncertain whether they directly influence atherosclerosis or affect already-compromised endothelium.

PERIODONTAL INTERVENTION AGAINST ATHEROSCLEROTIC VASCULAR DISEASES It is yet to be established whether periodontal treatment strategies alter the progression of atherosclerotic vascular diseases. Therapeutic strategies to combat periodontal diseases include mechanical debridement, especially of subgingival locations of the tooth, and at-home oral hygiene methods which include brushing and flossing. Some studies have hypothesised that periodontal treatment may reduce pro-inflammatory mediators. Studies conducted by Iwamoto et al (2003), D’Aiuto et al (2004) and Montebugnoli et al (2005) showed reduction in the levels of CRP, TNF-α and IL-6 after employing periodontal treatment strategies such as scaling, root planing and antibiotic therapy. Lockhart et al (2012) have done an elaborative review on the relationship of periodontal diseases and atherosclerotic vascular disease. The study, which is a scientific statement of the American Heart Association (AHA), reviewed numerous publications to present a systematic review on this potential relationship. It states that ‘Observational studies to date support an association between PD and ASVD independent of known confounders. They do not however support a causative relationship. Although periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction in short-term studies, there is no evidence that they prevent ASVD or modify its outcomes’ (AHA Scientific Statement, 2013). The paper con-

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cludes that consistent and thorough studies are required on different periodontal treatment modalities employed during intervention in order to assess the link with atherosclerosis and CVD in general. Some interventional studies were designed to analyse the results of periodontal therapy/intervention on cardiovascular diseases. ‘Periodontal Intervention and Vascular Events’ (PAVE) was a multicentre study conducted by the joint collaboration of five centres (State University of New York at Buffalo, University of North Carolina at Chapel Hill, Boston University, Oregon Health and Science University, and University of Maryland) from the period of January 2003 to June 2005. This study aimed to formulate and launch a large-scale clinical trial on periodontal therapy in cardiovascular risk patients. Offenbacher et al (2009) published the results of this multicentre PAVE pilot study. The pilot trial was carried out at five integrated cardiac-dental offices. After 6 months of periodontal therapy involving scaling and root planing, a significant decrease in mean probing depths and pocket depths of 4 to 5 mm were observed. However, the use of ITT (intent to treat) analysis exhibited no marked influence on serum high-sensitivity C-reactive protein (hs-CRP) levels. In contrast, secondary analysis indicated that integration of periodontal interventional care vs no interventional treatment demonstrated a marked reduction in the percentage of patients with elevated levels of hs-CRP (levels >3 mg/l) after 6 months. The study emphasised the role of obesity in such periodontal intervention studies and CVD. It suggested that obesity increased CRP levels and thus interfered with the desired outcome of periodontal intervention in reducing CRP levels. The study also highlighted interesting modalities which can be adopted to design future RCTs to further study the role of periodontal pathogenesis/intervention and CVD. Beck et al (2008) performed a study on the incidence of serious adverse events (SAE) during the PAVE pilot trial. Cardiovascular adverse events occurred with similar incidence (23 vs 24, p = 0.85) in the community control group and the group that received periodontal interventional treatment.

CONCLUSION There is growing evidence of the association of periodontal diseases and CVD as reviewed by the epidemiological studies. The in vitro studies also indicated a potential link between oral bacteria and atherosclerosis. Thus, there is urgent need for prop-


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er case controls and efficient interventional trials to analyse how such interventions can produce a positive outcome on cardiovascular diseases. Some recent interventional trials have shown that periodontal treatment can decrease markers of systemic inflammation. The findings by Lockhart et al (2012) have provided insight into the design and methodology of further studies and prospective clinical trials to establish the benefits of periodontal therapy on CVDs. It would be worthwhile to study the relationship between periodontal diseases and CVD further because of its consequences for public health.

ACKNOWLEDGEMENTS The authors would like to thank Ms. Faiza Kazi for her valuable contribution in editing the language content of this article.

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Association of periodontal pathogenesis and cardiovascular diseases: a literature review.

To present a short review of recent literature available on the association of periodontal and cardiovascular diseases (CVD) and the role of peridonta...
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