Periodontitis as a risk factor for Cardiovascular diseases


As discussed earlier in “periodontal medicine”, periodontal infection, including gingivitis and chronic periodontitis, 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 adult population 1. Over the last 2 decades, several studies have reported epidemiological associations between periodontitis and cardiovascular disease 2-5. A survey that evaluated the association between periodontal and cariovasular diseases in 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 OR, of 3.8 (95 percent confidence interval, or CI, 1.5 to 9.7) compared with 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 6.

The Cardiovascular diseases have a complex etiology which includes set of genetic and environmental factors. The genetic factors include age, 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.

Atherosclerosis and coronary heart diseases:

Before discussing the relationship between periodontitis and coronary heart disease lets first try to understand how atheroma develops in an artery. The stages in the development of atherosclerosis involves a series of events that include development of fatty streak, progression to complex plaque and plaque rupture 7.

What is Atherosclerosis?

Atherosclerosis is a multifaceted, progressive, inflammatory disease that affects mainly large and mediumsized 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 disease 8.

Atheroma formation:

It is now well documented that first step in formation of an atheroma is most likely endothelial injury. After endothelial injury the surface adhesion molecules in the endothelial cells are up-regulated which lead to monocytes adhesion.  The adherence of monocytes to endothelium through the expression of MCP-1(Monocyte chemoattractant protein-1). These monocytes recruited from the blood stream then enter the vessel wall (intima layer) and become macrophages. These activated macrophages secrete various growth factors and cytokines which lead to smooth muscle proliferation in blood vessel wall. The cytokines secreted by activated macrophages further stimulate endothelial cells. These macrophages in the vessel wall accumulate  low density lipoproteins (LDL) in oxidised or modified form. These low density lipoproteins can undergo progressive oxidation. With formation of lipid peroxidades and accumulation of cholesterol esters, the result is formation of “Foam cells”.  Modified LDL’s are chemoattractants for monocytes which leads to further accumulation of these cells and thereby leading to formation of foam cells. At this stage this structure is called “Fatty streak”.

This fatty streak now becomes a complex fibrous plaque having a lipid core, calcification and deposition of extracellular matrix proteins. This complex structure, with 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-beta 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 remodels 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 CHD:

Periodontal diseases might affect heart disease through the mechanism of oral bacteria, bacterial toxins and induced inflammatory mediators entering the blood stream and contributing to chronic, systemic vascular challenge 9-10. 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 contribute to swelling and thickening of the arteries 11.

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.

Following is the description of few well accepted mechanisms of periodontitis associated cardiovascular diseases,

Direct bacterial effects on platelets:

The platelet aggregation associated proteins (PAAP) are collagen-like cell surface antigen containing the sequence KPGEPGK58. This sequence forms a structural motif common in all known platelet-interactive domains of collagens. Two oral bacteria Porphyromonas gingivalis and Streptococcus sanguis have been found to express this virulence factor in vitro and in vivo 19-20. Platelet aggregating strains (Agg+) of Streptococcus sanguis are found to induce aggregation of human platelets in vitro 21.

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

Porphyromonas gingivalis (that is considered as one of the important putative periodontal pathogens) can invade aortic and heart endothelial cells via its fimbriae 22.

Effects of pro-inflammatory mediators:

Inflammatory cells and the inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin- 1 beta (IL-1β) and prostaglandin E2 (PGE2) play a key role in human coronary heart disease and atherosclerosis 23. There is an up regulation of mediators in vascular tissues. C-reactive protein and fibrinogen levels are elevated 24-26Macrophages incubated in vitro with Porphyromonas gingivalis and low density lipoprotein take up bacteria  intracellularly and are capable of transforming into foam cells 27.

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 28Heat 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 29. Antibodies cross-react with periodontal bacteria and human Heat Shock Proteins (HSPs). Antibodies developed against Porphyromonas gingivalis HSP 60 cross react with human HSP because of the structural homology that exists between the two30-31.

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

Although the mechanism by which microbial overload in periodontal tissue leads to cardiovascular vasculature involvement is quite complex, Offenbacher et al. (1999) proposed a working model of periodontitis associated atherosclerosis 32They explained the following mechanism of association periodontal microbial overload and atherosclerosis,

  • Periodontal infection usually involves organisms like porphyromonas gingivalis, bacteroides forsythus, actinobacillus actinomycetemcomitans and others.
  • These organisms produce various virulent factors because of which the host immune response is activated.
  • It leads to recruitment of inflammatory cells like PMN’s and macrophages in that area.
  • Interactions between host immune cells and invading micro-organisms lead to 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, up-regulation of cellular receptors for monocyte recruitment, enhanced ox-LDL uptake and thus formation of more and more foam cells.
  • As this process continuous there is stenosis of artery lumen and rupturing of plaque from arterial wall leads to thrombotic event.

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

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

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 heart valves and cause other serious complications if it is not treated quickly with antibiotics. Certain oral bacteria are known as causative agents associated to infective endocarditis 33. Oral bacteria Streptococcus viridans, is responsible for about 50% of all bacterial endocarditis cases. Other common culprits include Staphylococcus aureus and enterococcus. Staphylococcus aureus can infect normal heart valves, and is the most common cause of infectious endocarditis in intravenous drug users. Other causative microorganisms for IE include enterococci, which are occasionally found in the oral cavity, or gram-negative HACEK micro‑organisms (Haemophilus species, Actinobacillus actinomycetemcomitans, Cardio bacterium 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 originate from periodontal infections. During routine dental procedures like scaling and root planing, dental extraction etc. these organisms can get entry into the systemic circulation and can populate the endocardium or the cardiac valves. Transient bacteraemia is well documented following tooth extraction 34 and following treatments for periodontal disease such as gingivectomy 35, supra- and subgingival scaling 36, ultrasonic scaling 37  and subgingival irrigation 38. Oral microorganisms such as Porphyromonas gingivalis and Streptococcus sanguis have been identified in atherosclerotic plaque 39-40.

So, in these patients the prophylactic antibiotic treatment is mandatory 41-42. American heart association in 1997 proposed recommendations for antibiotic prophylaxis for the patients having cardiac involvement.  Following is the list of cardiac conditions associated with endocarditis.

Cardiac conditions associated with endocarditis 43:

Endocarditis prophylaxis recommended

High-risk category

  • Prosthetic cardiac valves, including bioprosthetic and homograft valves
  • Previous bacterial endocarditis
  • Complex cyanotic congenital heart disease (e.g., single ventricle states, transposition of the great arteries, tetralogy of Fallot)
  • Surgically constructed systemic pulmonary shunts or conduits

Moderate-risk category

  • Most other congenital cardiac malformations (other than above and below)
  • Acquired valvular dysfunction (e.g., rheumatic heart disease)
  • Hypertrophic cardiomyopathy
  • Mitral valve prolapse with valvular regurgitation and/or thickened leaflets

Endocarditis prophylaxis not recommended

Negligible-risk category (no greater risk than the general population)

  • Isolated secundum atrial septal defect
  • Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residua beyond 6 mos)
  • Previous coronary artery bypass graft surgery
  • Mitral valve prolapse without valvular regurgitation
  • Physiologic, functional, or innocent heart murmurs
  • Previous Kawasaki disease without valvular dysfunction
  • Previous rheumatic fever without valvular dysfunction
  • Cardiac pacemakers (intravascular and epicardial) and implanted defibrillators.

Common dental treatments where according to American heart association the antibiotic prophylaxis is recommended are,

Dental procedures and endocarditis prophylaxis 43

Endocarditis prophylaxis recommended*

  • Dental extractions
  • Periodontal procedures including surgery, scaling and root planing, probing, and recall maintenance
  • Dental implant placement and reimplantation of avulsed teeth
  • Endodontic (root canal) instrumentation or surgery only beyond the apex
  • Subgingival placement of antibiotic fibers or strips
  • Initial placement of orthodontic bands but not brackets
  • Intraligamentary local anesthetic injections
  • Prophylactic cleaning of teeth or implants where bleeding is anticipated

Endocarditis prophylaxis not recommended:

  • Restorative dentistry**(operative and prosthodontic) with or without a retraction cord***
  • Local anesthetic injections (non-intra-ligamentary)
  • Intra-canal endodontic treatment ; post placement and buildup
  • Placement of rubber dams
  • Postoperative suture removal
  • Placement of removable prosthodontic or orthodontic appliances
  • Taking of oral impressions
  • Fluoride treatments
  • Taking of oral radiographs
  • Orthodontic appliance adjustment
  • Shedding of primary teeth

*Prophylaxis is recommended for patients with high- and moderate-risk cardiac conditions.

**This includes the restoration of decayed teeth (filling cavities) and the replacement of missing teeth.

***Clinical judgment may indicate antibiotic use in selected circumstances that may create significant bleeding.


Prophylactic regimens for dental, oral, respiratory tract, or esophageal procedures43*:

Situation Agent


Standard general prophylaxis Amoxicillin  Adults: 2.0 g ; children: 50 mg/kg orally 1 h before procedure
Unable to take oral medications Ampicillin  Adults: 2.0 g IM or IV ; children : 50 mg/kg IM or IV within 30 min before procedure
Allergic to penicillin Clindamycin  Adults: 600 mg; children: 20 mg/kg orally 1 h before procedure
Cephalexin or Cefadroxil**  Adults: 2.0 g; children; 50 mg/kg orally 1 h before procedure
Azithromycin or Clarithromycin Adults: 500 mg; children: 15 mg/kg orally 1 h before procedure.
Allergic to penicillin and unable to take oral medications Clindamycin  Adults : 600 mg ; children : 20 mg/kg IV within 30 min before procedure
Cefazolin  Adults: 1.0 g; children: 25 mg/kg IM or IV within 30 min before procedure.
IM indicates intramuscularly, and IV, intravenously.*Total children’s dose should not exceed adult dose.**Cephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (urticaria, angioedema, or anaphylaxis) to penicillins.


Prosthetic valve endocarditis (PVE):

It is an endovascular, microbial infection occurring on parts of a valve prosthesis or on reconstructed native heart valves 44. It is a serious complication of cardiac valve replacement, is reported to occur in from 1% to 9.4% of patients 45-49. Prostheses made from metal, pyrolyte or other materials do not allow adherence of microorganisms as long as they are free from thrombotic material. Infections of mechanical prostheses 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 are should be given antibiotic prophylaxis before starting dental treatments which lead to transient bacteraemia as given by American heart association. The microbiology of PVE is very different 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 risk factors common to both diseases 50 , with tobacco use as the main confounding factor 51. Smoking is a significant risk factor both in cardiovascular disease and periodontitis 52-55. A history of smoking has been reported as an important confounder in studies of the association between cardiovascular diseases and chronic periodontitis and when accounted for the odds of an association between the two conditions is drastically reduced 56-57. 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 58-59 . The endotoxins produced by these micro-organisms, along with inducing the production of pro-inflammatory cytokines also induce production of acute-phase proteins in the liver, such as C-reactive protein. These proteins can form deposits in damaged blood vessels, with the consequent activation of phagocytes and release of nitrous oxide, contributing to the formation of atheromas 60.

CRP has been shown to be not only a prognostic indicator of acute coronary syndromes, but also, a predictor of future coronary events. Perhaps the greater importance is the demonstration that CRP concentrations predict MI and stroke 61-63 . So, it becomes important to identify those conditions that contribute to CRP level elevations that may have significant prognostic and treatment implications in patients with cardiovascular disease. Studies done on microbial aspect showed an association between periodontitis and AMI in which periodontal destruction was correlated with the presence of periodontal pathogens. In particular, Pg might be considered a potential risk indicator for AMI 64

Know more………..

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 65. 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 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 66 . Furthermore, the peak CRP values at around 48 hours after the onset powerfully predict outcome after myocardial infarction 67-69 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 70. 


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