Periodontal Disease, Inflammation, and Cardiovascular Disease



Periodontal Disease, Inflammation, and Cardiovascular Disease


Douglas Thompson, DDS, FAAMM, ABAAHP

Gregori M. Kurtzman, DDS, MAGD, FPFA, FACD, FADI, DICOI, DADIA, DIDIA



Introduction

Periodontal disease is one of the most prevalent diseases affecting humans and is a chronic inflammatory disease that affects the gum (gingival) tissue and the bone supporting the teeth. If left untreated, periodontal disease can lead to tooth loss due to loss of the supporting bone. Recent studies suggest that one out of every two adults aged 30 years and older has periodontal disease. Research has also shown that periodontal disease is associated with multiple health conditions, including cardiovascular and renal issues, diabetes, osteoporosis, and pulmonary disorders, to name a few.

Data from the 2009 and 2010 National Health and Nutrition Examination Survey (NHANES) reported that over 47% of the sample, representing 64.7 million adults, had periodontitis, distributed as mild (8.7%), moderate (30.0%), and severe periodontitis (8.5%). Adults aged 65 years and older presented with moderate or severe periodontitis 64% of the time.1 Prevalence was highest in Hispanics (63.5%) and non-Hispanic blacks (59.1%), followed by non-Hispanic Asian Americans (50.0%), and lowest in non-Hispanic whites (40.8%). A twofold increase in prevalence was reported between the lowest and highest levels of socioeconomic status, whether defined by poverty or education.2 Periodontal disease is also reported to be higher in men (56.4%) than women (38.4%) and positively associated with increasing age. Additionally, we observe a higher prevalence rate with current smokers (64.2%), those living below the federal poverty level (65.4%), and those with less than a high school education (66.9%).


Periodontal Disease and Oral Biofilm


What Is Periodontal Disease and What Causes It?

Periodontal disease is an inflammatory process initiated by oral bacteria, yeast, viruses, their byproducts, and the host immunoinflammatory response to them. This response results in inflammation and ultimately bone loss around the teeth. Every person has a unique host response generated from their combined innate (genetic) and acquired (environmental) risk factors. Innate (genetic) risk factors are things you cannot change such as ethnicity, gender, and age. Acquired (environmental) risk factors are alterable things such as smoking, nutrition, stress management, sleep quantity and quality.

This polymicrobial disease can be slowly progressing or quite aggressive. It is also episodic in nature based on the varying health of the immune system. Therefore, periodontal disease is biofilm induced but host modulated. Our traditional focus has been on controlling this disease to prevent bone loss and ultimately tooth loss. Today, we have additional concerns. Oral bacteria, yeast, and viruses contained in dental plaque were long ignored for any effects outside the oral cavity and the connection to systemic effects have been poorly understood. Recently, research has been strong connecting a link between oral health and systemic disease, with 200 possible connections.3

Plaque is a community of microorganisms found on the tooth surface or within the sulcus (periodontal pocket) which are embedded in a matrix of polymers of host and bacterial origin. This is a more complex bio-environment than previously recognized and has been retermed biofilm as a result.4,5
Over 700 different species of bacteria naturally reside in the mouth. Most are considered innocuous, but some of these microorganisms have been identified as pathogenic. This aggregation of bacteria work together as a community, producing specific proteins and enzymes utilizing oral fluids as the vector for transmission.6 It has been long demonstrated that these microbial communities can display enhanced pathogenicity (pathogenic synergism). Additionally, unlike planktonic (free-floating) bacteria those in biofilms restrict penetration of antimicrobial agents and are less susceptible to antimicrobials applied locally or administered systemically.7,8 To summarize, bacteria in these complex biofilms act and react differently than bacteria that are planktonic in nature, which complicates management and treatment.


Oral Biofilm Formation and Effects

The bacterial community composition in the biofilm is very diverse. Variations in the many species can be detected and may be different from site to site in the same patient. With biofilm maturation, the microbial composition changes from one that is primarily gram-positive and streptococcus-rich to a structure filled with gram-negative anaerobes.9

Formation of the biofilm includes a series of steps that begins with the initial colonization of the pellicle through adsorption of bacterial molecules creating an adhesive on the tooth surface. Other diverse bacterial species co-adhere using bacterial receptors creating diversity and have both synergistic and antagonistic biochemical interactions among the inhabitants. The bacteria continue to divide until a three-dimensional mixed-culture biofilm forms that is specially and functionally organized with polymer production leading to development of an extracellular matrix. This matrix is a key structural aspect of the biofilm offering the inhabitants protection from external factors. As the biofilm thickens and becomes more mature, anaerobic bacteria are able to live deeper within the biofilm, further protecting them from the oxygen-rich environment within the oral cavity.

The early biofilm is able to withstand frequent mechanisms on oral bacterial removal such as chewing, swallowing, and salivary fluid flow. Early biofilm colonizers are also able to survive in the high oxygen concentrations present in the oral cavity. This initial biofilm is always present orally, forming immediately after oral cleansing by the patient.

The understanding of how complex oral biofilm and dentists’ management of it has evolved as science has demonstrated that “plaque” is not as innocuous as previously thought. We now understand that what is contained in the oral biofilm, and how its components interact, has far reaching (systemic) actions that affect multiple areas including cardiac, pulmonary, renal, diabetes, colon, and a variety of other areas of the body. In fact, periodontal pockets and atheromatous plaques of cardiovascular disease patients can present similarities in the microbial diversity, indicating possible bacterial translocation between periodontal pockets and coronary arteries.10

Today, we evaluate, discuss, and treat patients differently than we used to based on a more complete understanding of oral biofilms and its systemic connection. We are now able to improve their dental and periodontal health, prevent oral conditions that may negatively affect systemic health, and aid in improving systemic conditions that may be complicated or worsened by the oral biofilms. Part of that change in care is mutual understanding of oral biofilms and the systemic connection with our medical colleges and involvement by all in managing total patient health care. However, what connection(s) to the systemic system are known and how does that occur?


The Systemic Connection

Harmful strains of bacteria in the oral biofilm can enter the bloodstream during the inflammatory response and can travel to other areas of the body. Increasing evidence indicates patients with periodontal disease have a much higher risk of developing cardiovascular and other systemic issues than those individuals who take preventive measures to eliminate and control the biofilm in their mouths.11 Below is a review of some of the systemic effects that have been associated with oral biofilm, before examining the cardiovascular connection.


Diabetes

Diabetes is a significant public health problem, affecting 29.1 million patients (9.3% of the US population), with an estimated 8.1 million (27.8%) patients going undiagnosed.12 Patients with diabetes have twice the risk for periodontal disease than those without the metabolic disorder. In addition, periodontal disease is more prevalent, progresses more rapidly, and is often more severe in patients with type I or type II diabetes.13,14 Periodontal disease has been classified as the sixth most common complication of diabetes and is a strong, well-established risk factor for severe periodontal disease. Patients with periodontal infections have worse glycemic control over time and thus have greater difficulty managing their diabetes. Much of the dysglycemia is related to inflammation and insulin resistance. Treatment of periodontitis appears to improve glycemic control.15 Therefore, control of the periodontal infection and associated biofilm should be part of the standard treatment for the diabetic patient.


Pulmonary Disease

Periodontal biofilm is a reservoir of bacteria and a source of lower airway infections, especially in older patients or those who are debilitated. Oral biofilm can inoculate the respiratory tract when aspirated. Severity of the disease is correlated with the pathogenicity of the bacteria in the biofilm. Periodontal pathogens and cariogenic bacteria increase risk factors for aspiration pneumonia.


The highest risk patients for respiratory infection (bronchitis and pneumonia) are medically compromised patients with or without respiratory disease who are unable to perform adequate oral homecare. Patients with removable dental prosthetics (dentures) are particularly prone to aspiration of the oral biofilm accumulating on the prosthesis. Evaluation of 328 articles published over an 11-year period reported linking oral hygiene to oral health care-associated pneumonia or respiratory tract infection in elderly people. The authors reported, “There is sufficient evidence that mechanical oral hygiene practices reduce the progression or occurrence of respiratory diseases in high-risk elderly people in nursing homes or hospitals. Mechanical oral hygiene practices may prevent the death of about 1 in 10 elderly residents of nursing homes from health care-associated pneumonia.”16

Proper oral homecare is critical in preventing these oral infections by minimizing the potential of aspirating biofilm into the pulmonary system. One author reported, “Oral hygiene intervention significantly reduced occurrence of pneumonia in institutionalized subjects.”17 Frequent tooth brushing and preoperative use of 0.12% chlorhexidine mouthrinse or gel reduced nosocomial respiratory tract infections.18 It has also been demonstrated that use of low-concentration peroxides in custom trays has a positive effect on oral biofilms, reducing the bacterial load and decreasing pathogenic material that may be aspirated. This may be a more predictable approach in elderly patients who lack manual dexterity to perform oral homecare with a toothbrush. Those patients with removable prosthetics, dentures, also need to keep them clean to keep oral biofilm down on the appliances as this biofilm may be aspirated leading to pulmonary issues as outlined above.19


Prostate Disease

Prostate-specific antigen (PSA), an enzyme created in the prostate normally secreted in very small quantities, has been reported to be secreted at much higher levels in men with periodontal disease.20 Inflammation of the prostate or presence of infection or being affected by cancer demonstrates elevated PSA levels. Elevated PSA levels are a classic indicator of prostate cancer.21 Research has demonstrated that men with indicators of periodontal disease and prostatitis have higher levels of PSA than men who do not have periodontal disease.22


Colon Cancer

Colon cancer is responsible for 50,000 deaths annually in the United States. Yet, the link to an oral connection and periodontal disease via biofilm is just becoming known in recent years. The bacterium Fusobacterium nucleatum, found in the mouth and in periodontal biofilm, has a role in periodontal disease. This bacterium has also been shown to colonize the gut and attach to cells in the colon, triggering a sequence that can lead to colon cancer. It has been reported that patients with periodontal disease have much higher levels of F. nucleatum then those with normal periodontal status.23,24 Although a possible association was found between oral infections and colon cancer, a cause-and-effect relationship has not been found. Published studies show how F. nucleatum can speed the accumulation of cancer cells.25,26 Minimizing F. nucleatum by controlling the oral biofilm may lower the risk for those who are at increased risk of developing colorectal cancer.


Pancreatic Cancer

Annually 30,000 people die from pancreatic cancer in the United States. Pancreatic cancer risk factors include cigarette smoking and chronic pancreatitis. But the role of inflammation from periodontal disease may promote this cancer.27 The Harvard School of Public Health and Dana-Farber Cancer Institute researchers found that periodontal disease may be associated with an increased risk of cancer of the pancreas. Additionally, research shows men with periodontal disease had a 63% higher risk of developing pancreatic cancer compared with those reporting no periodontal disease.28


Preterm Pregnancy

Inflammation of the periodontal tissues due to the formation of biofilm increases dramatically during the course of a normal pregnancy.29 Evidence has linked an association between the presence of periodontitis and preterm delivery and low birth weight infants. Oral bacteria have been identified in fetal membranes. Biofilm inflammatory molecules can enter the circulatory system and cross the placenta to reach the fetal membranes and cause preterm delivery. Lipopolysaccharides from cell walls of periodontal pathogens can trigger production of prostaglandins and a periodontal infection can lead to the release of these prostaglandins into the circulatory system. Translocation of periodontal bacteria to the fetus occurs via the placenta, which stimulates the release of prostaglandins.30 These prostaglandins stimulate oxytocin production, which can initiate preterm labor and result in lower birth weight babies.


Cardiovascular Disease

Periodontal disease and the cardiovascular connection provides the strongest cause and effect with oral biofilm. Unfortunately, this connection has been ignored or misunderstood by dentists and physicians alike until recent literature has provided evidence of that connection.

CVD, an umbrella term for heart and blood vessel conditions, such as atherosclerosis, coronary heart disease, stroke, and myocardial infarction, is the result of a complex set of genetic and environmental factors.31 It is commonly accepted that genetic factors including age, lipid metabolism, obesity, hypertension, and diabetes have a direct connection to CVD and its severity. But environmental risk factors also play a key component and include socioeconomic status, exercise, stress, diet, smoking, and chronic infections. Classic risk factors such as hypertension, hypercholesterolemia, and cigarette smoking may only account for one-half to two-thirds
of the incidence of CVD.32 There is increasing evidence linking chronic infection, inflammation, oxidative stress, and immune dysfunction to CVD with the biofilm as a predisposing factor.33,34 The connection between oral bacteria and cardiac disease is not a recent development in the literature. Oral bacteria, specifically Streptococcus mutans (cariogenic) and Porphyromonas gingivalis (periodontitis), induce platelet aggregation, leading to thrombus formation.35

One or more periodontal pathogens as reported in the literature are found in 42% of atheromas in patients with severe periodontal disease.36 It has been reported that P gingivalis actively can adhere to and invade fetal bovine heart endothelial cells and aortic endothelial cells.37 Additionally, a 14-year study found periodontal disease patients had a 25% higher risk to develop CVD than their healthy counterparts.38 Men younger than 50 years with periodontal disease demonstrate 72% more risk to develop CVD. Additionally, periodontal disease increased risk for both fatal and nonfatal strokes twofold.39 Despite the strong evidence of an association between periodontal disease and CVD, it is unknown if it is a direct or causal relationship.

Periodontal disease releases bacteria that may enter the circulation, invading the heart and vascular tissue, causing harmful effects. People with higher levels of bacteria in their mouths tend to have thicker carotid arteries, an indicator of CVD.40 Bacteria near diseased gingiva appears to induce clumping of blood platelets, which can then cause the clotting and blockages that can lead to heart attacks or strokes. The body’s response to periodontal infection includes production of inflammatory mediators, which travel through the circulatory system and may cause harmful effects on the heart and blood vessels. Inflammatory mediators such as lipoprotein and triglycerides are significantly higher in patients with periodontitis than in control groups.41 Increased levels of C-reactive protein, a biomarker for inflammation, is associated with periodontitis.42 Periodontal disease’s emergence as a potential risk factor for CVD is leading to a convergence in oral and medical care. Proper management of oral health may very well be key to prevention of cardiac disease or worsening of existing heart conditions.


Atherosclerosis and Periodontal Disease as Inflammatory Processes

The major component of the pathology of cardiovascular disease, particularly atherosclerosis, involves an inflammatory response to the multiple components of the adaptive immune system.43 Links between atherosclerosis and periodontal disease can be predicted based on the bacterial initiated inflammatory mechanisms associated with periodontal disease both locally and systemically. This has an influence on the initiation and propagation of atherosclerotic lesions, which may be initiated by local or systemic inflammation.

Inflammation produces cytokines and chemotactic agents causing endothelial changes, which include upregulation of adhesion molecules.44 These endothelial changes promote interactions with leukocytes (monocytes) promoting leukocyte migration into the interior layer of the arteries. Lipid streaks result. Additionally, upregulation of the endothelium releases chemotactic cytokines (monocyte chemotactic protein-1 [MCP-1]), which further attract cells that can transport bacteria into the lesion. Resident dendritic cells (DCs) and monocytes attracted by cytokines become foam cells following ingestion of LDLs releasing inflammatory cytokines and matrix metalloproteinases (MMPs) further enhancing the localized inflammatory response.45 Thus, initiation and propagation of early atherosclerotic lesions may be enhanced by periodontal disease when periodontal bacteria or their effects on the host immune response such as T-cell responses contribute to endothelial dysfunction. Additionally, attraction of monocytes and enhanced lipid uptake by the cells leads to plaque formation in the vessel wall (Figure 28.1). Excess inflammation mediated by those inflammatory cells can cause plaque cap instability leading to rupture resulting in myocardial infarction or a stroke.46

Periodontal disease is generated by microorganisms that can enter the general circulation causing a bacteremia. Some species have been identified as high-risk pathogens. High-risk pathogens are currently understood as Aa, Pg, Tf, Td, and Fn. These high-risk pathogens can adversely influence the atherosclerosis pathogenesis triad in three distinct ways. High-risk periodontal pathogens affect serum lipoprotein concentration, endothelial permeability, and lipoprotein binding in the intima. Also, strong evidence supports periodontal bacteria affect vascular elasticity, lipid concentration, vascular biomarkers, HDL efflux, and endothelial function. Therefore, the dental community has a substantial opportunity to assist in mitigating the number one cause of morbidity and mortality, namely cardiovascular disease, by effective management of periodontal disease due to those high-risk pathogens.47,48


Diagnosing Periodontal Disease

Periodontal disease is not strictly a bacterial issue. We now know that yeast and viruses play a role in periodontal disease progression and are part of the complex biofilm. It is the biofilm that initiates a personalized immunoinflammatory process that is host dependent on genetics and environmental influence. It is this unique host response that ultimately determines the individual’s sensitivity and reaction to the initiating insult.49 Chronic stress (an environmental factor) has been shown to increase the severity of the pathological progression of periodontal disease, and lifestyle modification may improve oral health status but also its systemic connections.50 As with inflammation systemically, patients’ response will vary from patient to patient to the same insult. Periodontally, some patients will exhibit high degrees of inflammation with minimal insult from the biofilm present, whereas other patients will present with high levels of biofilm but exhibit minimal or no gingival inflammation. Recognizing the etiology and the inflammatory nature of periodontal disease opens new opportunities for diagnosis, treatment, and
long-term management of the disease. Managing the disease can prevent tooth loss and improve cardiovascular and other systemic involvement.






Figure 28.1 Artery cutaway of various disease stages with related biomarkers. Initiation and propagation of endothelial inflammation leading to plaque formation may be initiated by periodontal inflammation and other risk factors. (Courtesy of the Cleveland Heart Lab. In: Penn MS, Klemes AB. Multimarker approach for identifying and documenting mitigation of cardiovascular risk. Future Cardiol. 2013;9(4):497-506.)

Traditionally, periodontal disease has been diagnosed by increases in pocket depth, bleeding gums, and bone loss around the teeth leading to clinical attachment loss. Today, we are using the same information to determine if the disease is and has been present; however, we are using the presence of gingival bleeding (bleeding on probing) to determine if the disease is active or stable. The presence of a periodontal pocket (4 mm or greater) alone does not indicate active disease, especially when bleeding is not identified on probing. As with radiographic evidence of bone loss associated with the teeth, this may indicate prior disease that is currently not active. When bleeding on probing has been identified, it confirms the presence of inflammation. Recognize that identifying inflammation requires a histological diagnosis and bleeding on probing is a result of that inflammation. All dental practitioners must recognize that bleeding on probing and gingival inflammation can also be initiated by other systemic issues as well such as caries, failing restorative dentistry, some herbals taken in supplement form, and others.

For the purposes of this chapter we are referring to inflammation of the gum complex that is biofilm mediated and host modulated. When periodontal disease is biofilm related, treatment traditionally consisted of mechanical debridement of the supra and subgingival tooth surfaces (scaling and root planning) to remove the oral biofilm (plaque) and any hard deposits (calculus) present. Following a healing period, traditionally of 6 weeks, we expect a favorable host response evidenced by the elimination of bleeding on probing. Observing zero bleeding on probing becomes a surrogate endpoint and a sign that the periodontal disease and its associated inflammation has been arrested.

In addition to the bacteria in the biofilm, numerous studies have demonstrated periodontitis severity in adults is closely linked with increases in local inflammatory mediators due to genetic mutations of genes regulating the production of inflammatory cytokines. One commonly recognized cytokine is interleukin-1(IL-1). A mutation of the IL-1 gene can cause overexpression of IL-1, making it a key player in the inflammatory process and a prime candidate for a genetic association with periodontal disease.51,52,53,103 Thirty (30) percent of the population can be identified with IL-1 polymorphisms.54 Presence of the IL-1 genotype does not confer an expected periodontal disease diagnosis; however, the gene mutation has been implicated as a contributory factor to the host immunoinflammatory response determining the severity of adult periodontitis.55

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Feb 27, 2020 | Posted by in CARDIOLOGY | Comments Off on Periodontal Disease, Inflammation, and Cardiovascular Disease
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