Periodontitis as a risk factor for cardiovascular diseases

Periodontal infection is found worldwide and is among the most prevalent human microbial diseases.  It has been mentioned that severe generalized periodontal disease is present in 8% to 13% of the world’s total adult population 1. The roles of infection and inflammation in atherosclerosis have become increasingly apparent. Over the last three decades, several studies have reported epidemiological associations between periodontitis and cardiovascular diseases (Table 38.1) 2-5. On the other hand, some studies have shown a weak or no association between periodontitis and cardiovascular diseases 6-8. However, at present, most of the research is in favor of direct or indirect association of periodontitis and cardiovascular diseases. A survey that evaluated the association between periodontal and cardiovascular diseases in the third National Health and Nutrition Examination Survey or NHANES III, found that the odds of having a history of heart attack increased with the severity of periodontal disease. The highest severity of periodontal disease in the population was associated with an odds ratio (OR), of 3.8 [95 percent confidence interval (CI) 1.5 to 9.7] as compared to no periodontal disease, after adjusting for age, sex, race, poverty, smoking, diabetes, high blood pressure, body mass index and serum cholesterol levels. Thus, this cross-sectional study confirmed the association seen in other cross-sectional studies, as well as in case-control studies, and also showed a direct relation­ship between heart disease and increasing levels of periodontal disease 9.

The cardiovascular diseases have a complex etiology which includes a set of genetic and environmental factors. The genetic factors include genetic markers for hypertension, diabetes, marked obesity, lipid metabolism, fibrinogen levels and platelet P1 polymorphism. The environmental risk factors include diet, physical inactivity, stress, cigarette smoking, socioeconomic status, chronic infections, use of non-steroid anti-inflammatory drugs and possible endothelial cell injury.

Table 38.1 Some landmark longitudinal studies of association between periodontal diseases and coronary artery diseases

Some landmark longitudinal studies of association between periodontal diseases and coronary artery diseases and other thrombo-embolic events


Study Design & Subjects


Data collection

Results & observations

De Stefeno et al. 1993 12

9,760 subjects. Cohort that participated in the National Health and Nutrition Examination Survey I

Coronary artery disease


Russell periodontal index, number of decayed and missing teeth In this study the subjects were matched for age, blood pressure, diabetes, and partially adjusted for smoking. Results showed that subjects with periodontitis had 25% increased risk of coronary heart disease with relative risk of 1.72, in males under 50 years of age.

Mattila et al. 1995 13

Follow up study on 214 subjects (182 males, 32 females) at 7-year follow-up

Fatal and nonfatal  Coronary artery disease


Total dental index Results demonstrated that total dental index demonstrated a statistically significant difference between cases and controls. Adjust­ments were made for smoking, diabetes, hypertension, socioeconomic status, previous MI, body mass index (BMI), and serum lipids

Beck et al. 1996 14

1,147 males enrolled from the normative ageing study and the dental longitudinal study

Coronary heart disease (CHD) and stroke

Radiographic interproximal alveolar crestal heights Study evaluated the alveolar crestal bone hight and incidences of CHD and stroke. Results showed alveolar bone loss at baseline associated with fatal CHD with relative risk of 1.9 (1.10, 3.43), after adjusting for age, smoking, systolic blood pressure, and diabetes.

Joshipura et al. 1996 15

44,119 male health professionals followed up over 6 years

Coronary artery disease

Self-reported periodontal disease and self-reported number ofteeth Those who reported periodontal disease and less than 10 teeth at baseline had a relative risk of Coronary artery disease of 1.67. Adjust­ment was made for smoking, physical activity, hypertension, cholesterol, family history of CAD, dietary and alcohol intake.

Genco et al. 1997 16

1,372 Native Americans followed up for 10 years; population has a low level of smoking

Electrocardio- graphic     evidence of  loss cardiovascular disease (CVD)

Alveolar bone level and tooth loss Study demonstrated a relative risk of 2.68 for developing cardiovascular disease in subjects 60 years of age having periodontal disease. Adjustments were done for diabetes, age, gender, cholesterol, BMI, smoking, and hypertension.

Morrison et al. 1999 17

A retrospective cohort study using participants in the 1970-1972 Nutrition Canada Survey (NCS). Self-reported CHD (n = 10,368) and cerebrovascular disease (CVD) (n = 11,251)

Fatal coronary heart disease and stroke

Gingivitis (mild-severe) periodontitis Adjusted for age, sex, diabetes status, serum total cholesterol, smoking, hypertensive status, and province. Results showed a statistically significant association between periodontal disease and risk of fatal CHD. Rate ratios (RR) of 2.15 and 1.90 for severe gingivitis and edentulous status, respectively.

Wu et al. 2000 18

Association between periodontal disease and cerebrovascular accidents (CVA).  9962 adults (25-74 years) who participated in the First National Health and Nutrition Examination Survey and its follow-up study

Incident non-hemorrhagic stroke

Russell periodontal index was recorded for gingivitis, periodontitis and edentulous Results showed periodontitis as a significant risk factor for total CVA and, in particular, non hemorrhagic stroke. The relative risks for incident non hemorrhagic stroke were 1.24 (0.74-2.08) for gingivitis, 2.11 (1.30-3.42) for periodontitis, and 1.41 (0.96-2.06) for edentulousness.

Atherosclerosis and coronary heart diseases

Before discussing the relationship between periodontitis and coronary heart disease, let’s first try to understand how atheroma develops in an artery. The stages in the development of atherosclerosis involve a series of events that include the development of fatty streak, progression to complex plaque and plaque rupture 14.

What is Atherosclerosis?

Atherosclerosis is a multifaceted, progressive, inflammatory disease that affects mainly large and medium-sized arteries. It is characterized by the formation and build-up of atherosclerotic plaques that consist of a well-defined structure of lipids, necrotic cores, calcified regions, inflamed smooth muscle cells, endothelial cells, immune cells and foam cells; consequently, atherosclerosis is associated with cardiovascular diseases 15.

Atheroma formation:

It is now well documented that first step in the formation of an atheroma is most likely, the endothelial injury. After the endothelial injury…………………..123

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This fatty streak, now becomes a complex fibrous plaque, having a lipid core, calcification, and deposition of extracellular matrix proteins. This complex structure, with an accumulation of fibrous tissue, is attached to the vessel wall. Certain growth factors like, platelet derived growth factor and cytokines like IL-1, transforming growth factor-β from endothelial cells and monocytes, stimulate smooth muscle cells to produce interstitial collagen. The activated T-cells may stimulate the macrophages to secrete metalloproteinases, which remodel the fibrotic plaque. Ultimately, a dense fibrotic cap covers the atheroma.

Now, if this fibrotic cap becomes thin and ruptures, there is activation of clotting system” leading to thrombus formation which clinically precipitates as myocardial infarction.

Proposed pathways linking periodontal diseases to coronary heart disease (CHD)

Periodontal diseases might affect heart disease through various mechanisms including direct involvement of oral bacteria,  indirectly by bacterial toxins, and by inducing inflammatory mediators that enter the bloodstream and contributing to chronic, systemic vascular challenge 16, 17. Bacterial DNAs of periodontal pathogens such as Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Aggregatibacter actinomycetemcomitans and Campylobacter rectus have been detected in stenotic coronary artery plaque samples 18. The DNA of these microorganisms has also been detected in aneurysm walls and aneurysmal thrombus tissues 19, 20. Another possibility is that the inflammation caused by periodontal disease induces inflammatory cell infiltration into major vessels, vascular smooth muscle proliferation, vascular fatty degeneration, and increasing plaque build-up, which contributes to swelling and thickening of the arteries 21. Following is the description of some well-accepted mechanisms of periodontitis associated cardiovascular diseases,

Effect on platelets:

It has been found that bacteria may promote platelet aggregation directly or indirectly. Platelets participate in the immune response against infection. Oral bacteria may affect platelet function by three mechanisms.  The first mechanism involves platelet activation by the immune system. The immune response against bacteria in the oral cavity may stimulate platelet aggregation. The second mechanism involves the activation of platelets by bacterial products and the third mechanism involves direct attachment of bacteria to platelets resulting in their activation 22.

The in vitro studies [reviewed in Kerrigan and Cox (2010) 23] have demonstrated that many Streptococci species, particularly belonging to viridans group, S. sanguinis (formerly known as Streptococcus sanguis), S. gordonii, S. mutans, and S. mitis may promote platelet aggregation. The platelet aggregation by bacteria is mediated by various surface proteins such as platelet aggregation associated protein (PAAP) of S. sanguinis 24, adhesions such as SspA and SspB in S. gordonii 22, serine-rich glycoproteins designated SrpA and GspB/Hsa in S. sanguinis   25 and S. gordonii  26, respectively, as well as glucosyltransferases 27. The PAAP are collagen-like cell surface antigen containing the sequence KPGEPGK. This sequence forms a structural motif, common in all known platelet-interactive domains of collagens. Two oral bacteria P. gingivalis and S. sanguis have been found to express this virulence factor in vitro and in vivo  28, 29. Platelet aggregating strains of S. sanguis are found to induce aggregation of human platelets in vitro 30. The vesicles associated with the P. gingivalis cell surface have also been shown to induce platelet aggregation 31. Thus, these bacteria may promote platelet aggregation in coronary arteries.

Invasion and/or uptake of bacteria in endothelial cells and macrophages:

P. gingivalis (that is considered as one of the important putative periodontal pathogens) can invade aortic and heart endothelial cells via its fimbriae 32. P. intermedia 33 and S. mutans 34 have also been shown to invade and persist within the aortic endothelial cells, in vitro. The invasive strains of P. gingivalis have been shown to induce their uptake by macrophages and enhance foam cell formation, in the presence of LDL, in vitro 35. The ability of these bacteria to survive in the intracellular environment may allow the……………..


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Effects of pro-inflammatory mediators:

It has been well established that during host-microbial interactions in periodontal diseases, various pro-inflammatory cytokines are released which may enter the systemic circulation and affect other organ systems. Furthermore, it has been found that inflammatory mediators such as, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and prostaglandin E2 (PGE2) play a key role in human coronary heart disease and atherosclerosis 39. These cytokines promote cholesterol accumulation in monocytes and smooth muscle proliferation, which presumably results in thickening of vessel walls 40, 41. Epidemiological studies have shown that increased levels of cytokines (IL-1, IL-6, TNF-α, and MCP-1), and acute-phase proteins such as C-reactive protein (CRP) and fibrinogen 42-44 are associated with cardiovascular risk. These mediators of inflammation are upregulated in the blood vascular system during active periodontal destruction 45-47. IL-1β, which is secreted by cells of the monocyte-macrophage lineage when stimulated by bacterial LPS has been shown to impede fibrinolysis but facilitates coagulation and thrombosis 48. These mechanisms individually or combinedly may facilitate atherosclerosis.

Autoimmune response:

It has been shown that endotoxins of plaque microorganisms are capable of penetrating the gingival tissues and entering into the blood stream, in amounts sufficient to bring about a systemic LPS-specific antibody response 49. Heat shock proteins (HSP) are produced by a wide variety of bacteria and human cells under a variety of stressful or harsh conditions such as high temperature, infection, inflammation, and mechanical stress 50. The bacterial HSPs are also known as GroEL 51.  These are highly conserved proteins and many periodontal pathogens express HSPs that are homologous to human HSPs 52. Due to their homogenous nature, the antibodies produced against periodontal bacteria may cross-react with human HSPs. GroEL proteins and homologues have been identified in several oral bacteria including P. gingivalis, A. actinomycetemcomitans, F. nucleatum, P. intermedia, T. denticola, and S. mutans [reviewed by Goulhen et al. (2003) 53]. It has been shown that antibodies developed against P. gingivalis HSP60, cross-react with human HSP because of the structural homology that exists between the two 54, 55. Another study demonstrated that GroEL from P. gingivalis, F. nucleatum, and A. Actinomycetemcomitans was recognized by serum antibodies in patients with periodontal disease 56.

A positive association between elevated levels of antibodies to human HSP60 with the severity of coronary artery disease 57 and atherosclerosis 58 has been demonstrated. Furthermore, periodontal treatment has been shown to significantly reduce the levels of anti-P. gingivalis GroEL antibodies in patients with moderate to advanced periodontal disease, while the mean levels of antibodies to human HSP60 remained unchanged 59. These findings were supported by Buhlin  et al. (2009) 60.

It should be noted that cardiovascular risk factors such as, hypertension and hypercholesterolemia, enhance the expression of HSP by endothelial cells, thereby resulting in progression of early fatty streak lesions to more severe and irreversible atherosclerotic alterations.

Our current understanding of the association between periodontitis and coronary heart disease

It has been observed that bacteria entering the systemic circulation from periodontal sites may contribute to the development of atherosclerosis. The non-surgical periodontal therapy has been shown to cause transient bacteremia which causes initial, transient elevation in inflammatory and pro-thrombotic mediators and an overall decrease of endothelial function 61. Furthermore, following completion of the treatment, a reduction in the inflammatory markers, both, at local and systemic levels have been observed 62. The periodontal infection may indirectly facilitate atherosclerosis by the endotoxins and cytokines that enter the circulation.

Although the mechanism by which microbial overload in periodontal tissue leads to cardiovascular vasculature involvement is quite complex, Offenbacher et al. (1999) 63 proposed a working model of periodontitis associated atherosclerosis (Figure 38.1). They explained the following mechanism of the association between periodontal microbial overload and atherosclerosis,

  • Periodontal infection usually involves organisms like P. gingivalis, T. forsythia, A. actinomycetemcomitans and others.
  • These organisms produce various virulence factors, because of which the host immune response is activated.
  • It leads to the recruitment of inflammatory cells like, PMNs and macrophages in that area.
  • Interactions between the host immune cells and invading microorganisms lead to the production of reactive oxygen intermediates, which cause increased oxidative stress.
  • Now, these reactive oxygen intermediates which include oxidized low-density lipoproteins (ox-LDL) and products of arachidonic acid metabolism (Isoprostanes), reach the systemic circulation.
  • These products on reaching the site of atheroma, stimulate various functions like smooth muscle proliferation, upregulation of cellular receptors for monocyte recruitment, enhanced ox-LDL uptake and thus formation of more and more foam cells.
  • As this process continues, there is stenosis of artery lumen and rupturing of plaque from arterial wall leads to a thrombotic

Figure 38.1 The working model of periodontitis-atherosclerosis syndrome (PAS) proposed by Offenbacher et al.(1999) .

Association of periodontitis with cardiovascular diseases (Offenbacher et al 1999)


Another working model of the potential mechanism of role of periodontal infectious agents in atherosclerosis has been proposed by Fong (2002) 64. The author explained the direct and indirect mechanisms of the potential role of periodontal bacteria in the development of atherosclerosis (Figure 38.2). The direct mechanism involves the ingress of bacteria and their products in the systemic circulation and their participation in the formation of atherosclerotic plaque. This mechanism is supported by the findings that in carotid endarterectomy samples, common periodontal pathogens have been found in the arterial plaques 65, 66. The indirect mechanism involves vascular injury and atheroma formation due to systemic inflammatory mediators. The levels of systemic inflammatory markers have been found to be increased in patients with active periodontal destruction 45, 67-70. These mediators may facilitate the development of atherosclerosis.

Figure  38.2  The working model of periodontitis  as a  risk factor  for coronary  heart disease  proposed by  Fong et al.  (2002) .

working model of  periodontitis  as  a  risk  factor  for  coronary  heart  disease  proposed  by  Fong et  al.

Infective endocarditis

Bacterial endocarditis is an infection of the inner surface of the heart or the heart valves, caused by bacteria, usually found in the mouth, intestinal tract or urinary tract. It can seriously damage the heart valves and cause other serious complications if it is not treated quickly with antibiotics.

Certain oral bacteria are known to be the causative agents associated with infective endocarditis 3. Oral bacteria Streptococcus viridans is responsible for about 50% of all bacterial endocarditis cases. Other common culprits include Staphylococcus aureus and enterococcusStaphylococcus aureus can infect normal heart valves and is the most common cause of infectious endocarditis in intravenous drug users. Other causative microorganisms for infective endocarditis include enterococci, which are occasionally found in the oral cavity, or Gram-negative HACEK microorganisms (Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella, and Kingella), some of which, especially A. actinomycetemcomitans and Eikenella corrodens, are putative periodontal pathogens.

The bacteria implicated in bacterial endocarditis have been shown to………………


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Valvular heart diseases

Prosthetic valve endocarditis (PVE) is an endovascular, microbial infection occurring on parts of a valve prosthesis or on reconstructed native heart valves 78. It is a serious complication of cardiac valve replacement, reported to occur in 1% to 9.4% of patients 79-83. Prosthesis made from metal, pyrolytic carbon or other materials do not allow adherence of microorganisms as long as they are free from the thrombotic material. Infections of mechanical prosthesis generally originate from the sewing cuff or from thrombi located near the sewing ring downstream in recirculation areas. Inflammatory periprosthetic leaks, ring abscesses, and invasion of the infective process into the adjacent tissue are common findings.

These patients should be given antibiotic prophylaxis before starting dental treatments which can lead to transient bacteremia. The microbiology of PVE is very differen6t from that of native valve endocarditis (NVE). Streptococci and enterococci occur less frequently, while staphylococci, bacteria of the HACEK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikinella, and Kingella), and fungi are found more frequently in cases of PVE.

Myocardial Infarction

As already discussed, the periodontal infections have direct and indirect effects on systemic conditions, directly by microbes and their products and indirectly by chemical mediators or pro-inflammatory cytokines. According to the most widely established hypothesis, the relationship between acute myocardial infarction and periodontitis depends on the risk factors, common to both the diseases 84, with tobacco use as the main confounding factor 85. Smoking is a significant risk factor both in cardiovascular disease and periodontitis 86-89. A history of smoking has been reported as an important confounder in studies of the association between CVD and chronic periodontitis 8, 90 . It has also been proposed that periodontal pathogens or their lipopolysaccharides are systemically disseminated via the blood flow and directly infect the vascular endothelium, producing an atherosclerotic lesion and subsequent myocardial ischemia 15, 91. The endotoxins produced by these micro-organisms, along with inducing the production of…………………


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Know more…….

Myocardial infarction and C-Reactive protein:

CRP is a plasma protein involved in the acute phase response. CRP, named for its capacity to precipitate the somatic C-polysaccharide of Streptococcus pneumoniae, was the first acute-phase protein to be described and is an exquisitely sensitive systemic marker of inflammation and tissue damage 97. The specific ligand was later found to be phosphocholine. It is an important marker of disease activity. CRP has been found to interact with various other ligands, activate the classical complement pathway, stimulate phagocytosis and bind to FcγR immunoglobulin receptors.

Plasma CRP is produced only by hepatocytes, predominantly under transcriptional control by the cytokine IL-6. Although, other sites of local CRP synthesis and possibly secretion have also been suggested. The plasma half-life of CRP is about 19 hours and is constant under all conditions of health and disease.

Tissue necrosis is a potent acute-phase stimulus, and following myocardial infarction, there is a major CRP response, the magnitude of which reflects the extent of myocardial necrosis 98. Furthermore, the peak CRP values at around 48 hours after the onset, powerfully predict the outcome after myocardial infarction 99-101 and compelling experimental evidence now suggests that the CRP response not only reflects tissue damage in this context but may also contribute significantly to the severity of ischemic myocardial injury 102.



The epidemiological data has provided us with the evidence that periodontal diseases may act as a risk factor for cardiovascular diseases. Furthermore, intervention studies have demonstrated that periodontal therapy can reduce the systemic markers of inflammation and may promote systemic health. However, the exact mechanism, how the periodontal infections can act as a risk factor for or contribute causally to cardiovascular diseases is still not clear.  The recent consensus report on periodontitis and atherosclerotic cardiovascular diseases has recommended that patients with moderate to severe periodontitis should be informed that periodontal infections act as a risk factor for cardiovascular diseases and that the patients with more than one cardiovascular risk factors should undergo a medical evaluation of the risk factors 103. Because of extensive research going on in this field, more clarity in the mechanisms involved in the association of periodontal diseases to cardiovascular diseases is expected in future. 


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