© Springer-Verlag Berlin Heidelberg 2016
Zhou Xuedong (ed.)Dental Caries10.1007/978-3-662-47450-1_8
8. Dental Caries and Systemic Diseases
Department of Conservation Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China
Department of Preventive Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China
Dental cariesBacteremiaHead and neck cancerChildren growthCardiovascular diseaseImmune system diseaseKidney diseasesGastrointestinal diseasesDiabetes mellitusRespiratory infection
As stated by World Health Organization, oral health is fundamental to overall health and well-being and a determinant of quality of life . According to “Oral Health in America: A Report of the Surgeon General,” the mouth and face are mirrors of health and disease. A physical examination of the mouth and face can reveal signs of general health status. Imaging of the oral and craniofacial structures (x-ray, MRI, SPECT) may provide early signs of skeletal changes such as those occurring with osteoporosis and musculoskeletal disorders and salivary, congenital, neoplastic, and developmental disorders. For example, the research group of Dr. David Wong from UCLA has initiated a series of concerted efforts to spearhead the scientific and translational frontiers of salivary diagnostics. The potential use of saliva, a totally noninvasive biofluid without the limitations and difficulties of obtaining blood and urine, for oral and systemic disease detection, disease progression, and therapeutic monitoring is a highly desirable goal [2, 3]. In other words, oral health refers to the health of our mouth and, ultimately, supports and reflects the health of the entire body . In a sense, oral disease is not just a minor ailment of the soft and hard tissues of the mouth, and it may be a disease of the body that happens to begin in the mouth. If left unchecked, oral disease can contribute to other more harmful diseases that can seriously affect the quality of life .
As Hani T. Fadel from University of Gothenburg wrote in his doctoral thesis, “the link between oral and general health has been suggested since early times, almost as early as history itself. The concept of local or systemic diseases secondary to a localized chronic infection (e.g., in the oral cavity) is usually called focal infection. Its origin can probably be traced back to the time of Hippocrates” [6, 7]. Recently, a report titled “Links between oral health and general health – the case for action” from Dental Health Services Victoria summarized that oral health and general health are related in four major ways:
Poor oral health is significantly associated with major chronic diseases.
Poor oral health causes disability.
Oral health issues and major diseases share common risk factors.
General health problems may cause or worsen oral health conditions.
Dental caries and periodontal disease are the two biggest threats to oral health and are by far the most common oral infection diseases in the United States and Australia . It has been well proven that the oral cavity contains some of the most varied and vast flora in the entire human body, not only including those linked to dental caries and periodontal disease but also including systemic diseases that affect general health. In addition to bacterial organisms, oral microorganisms can include fungal, protozoal, and viral species. It is well accepted that our body is negatively affected by infection of any kind, no matter where it is located. Moreover, the more serious the infection and the longer it is present, the greater its potential for affecting systemic health. Infection can also seriously stress the immune system and diminish its ability to deal with other infections and diseases. Its effect on the immune system is directly related to the extent, type, and duration of the infection . Over 100 years ago the theory of focal sepsis, although lacking empirical scientific evidence, hypothesized that chronic infections in the mouth caused systemic diseases . The concept has been neglected for several decades and still is a subject of controversy . Since many teeth were extracted without evidence of infection, thereby providing no relief of symptoms, the theory was discredited and largely ignored for many years . Interestingly, increasing evidence over the past 30 years suggests that, due to dental bacteremia, the oral cavity can indeed serve as a reservoir for systemic dissemination of pathogenic bacteria and their toxins, leading to infections and inflammation in distant body sites, especially in immunocompromised hosts such as patients suffering from malignancies, diabetes, or rheumatoid arthritis or having corticosteroid or other immunosuppressive treatment .
Most studies stated above concerning the relationship between oral infection and systemic diseases are related to periodontal disease . And according to Thomas McGuire, the most important of oral diseases in regard to their impact on general health are:
Infected root canals
Cavitations (infected extraction sites)
Other diseases of the oral cavity, such as oral cancer 
“Dental caries” cannot be directly found in this list. Thomas McGuire explained the reasons as the following: certainly, dental caries can have an effect on a person’s overall health. For example, it can interfere with the mastication process and thereby affect digestion. It can cause tooth loss, again affecting digestion. The main difference is that, unlike periodontal disease, dental caries is not an infection that has access to the systemic body. Clearly, it can contribute to systemic health problems, but its effects on overall health are significantly less than the effects of periodontal disease .
As mentioned before, dental caries is one of the most common causes of pulpitis and periapical diseases by penetrating through the enamel and dentin to reach the pulp. Untreated decay can become so advanced that the tooth must be removed (extraction). Most studies supported that dental caries was the main cause for tooth loss, but a few studies revealed that a greater proportion of tooth extractions were due to periodontal disease, especially in patients over 40 years old. Overall, 70 % of tooth loss is due to tooth decay, 20 % due to periodontal diseases, and 10 % due to other causes [14, 15]. It was reported that caries accounted for a higher proportion of extractions than periodontitis at all ages over 20 years in 1968 and only up to 45 years of age in 1988 . According to another study, although there is an increase in orthodontic extractions or a decline in extractions for caries in under-21-year-olds, when extractions from the population as a whole are considered, caries and its sequelae remain the principal reason for loss of all tooth types apart from lower incisors which were extracted mainly for periodontal reasons . In 2012, a quantitative study evaluated the prevalence and factors related to tooth loss due to dental caries among workers in industrial estates in central Thailand. There were 457 adult (283 males; 174 females) between 19 and 53 years participants. The results showed that 62.2 % participants had tooth loss due to caries . The latest study also proved that dental caries and its complications were the leading reasons for extraction. Their study included a total of 2,620 teeth extracted from 1,382 patients. The highest rate (36.9 %) of extraction occurred for those of 41–60 years of age. Tooth loss due to caries was 51 %; periodontal disease was 14.4 %; and supernumerary and tooth impaction were 13.9 %. Although 86 % of teeth extracted for periodontal disease were in patients over 40 years of age, caries was still the main reason for extraction even in elderly patients, but to a less degree than in younger ones .
Our goal of this chapter is to discuss the relationship between dental caries and general health; we will summarize the limited recent advances in this topic. Since the effect of dental caries on the overall quality of health and well-being has not been well studied, in order to enrich the content of this chapter, studies associating systemic diseases with periapical diseases, tooth loss, root canal treatment, and other conditions caused by dental caries directly are also included .
This chapter explores what the dental caries can reveal about general health, describes the role the mouth plays as a portal of entry for infection, and concludes with studies that are associating oral infections with serious systemic diseases and conditions. Following this introduction and overview, the remainder of the chapter is organized as follows: first defining dental caries and bacteremia, head and neck cancer, and children growth; then briefly describing dental caries and atherosclerosis, cardiovascular disease, and heart attack; next discussing dental caries and immune system disease and kidney diseases; and last describing dental caries and gastrointestinal diseases, diabetes mellitus, and respiratory infections.
8.1 Dental Caries and Bacteremia
Bacteremia is an invasion of the bloodstream by bacteria. The blood is normally a sterile environment . So the detection of bacteria in the blood (most commonly accomplished by blood cultures) is always abnormal. This may occur through a wound or infection or through a surgical procedure or injection when other foreign bodies are entering the arteries or veins. Bacteremia may cause no symptoms and resolve without treatment, or it may produce several consequences like fever and other symptoms of infection. In some cases, the immune response to the bacteria can cause sepsis and septic shock, a potentially life-threatening condition which has a relatively high mortality rate. Bacteria can also use the blood to spread to other parts of the body (which is called hematogenous spread), causing infections away from the original site of infection.
The oral cavity is intensely colonized by bacteria. Recent advances in bacterial identification methods, particularly culture-independent approaches such as 16S rRNA gene sequencing, have shown that the oral cavity is inhabited by more than six billion bacteria representing in excess of 700 species belonging to at least nine different phyla . Bacteremia occurs with various frequencies following dental procedures and has been well documented. As early as 1990, Heimdahl et al. detected the patients with bacteremia after dental extraction, third-molar surgery, dental scaling, endodontic treatment, and bilateral tonsillectomy by means of lysis filtration of blood samples with subsequent aerobic and anaerobic incubation. Their results showed that bacteremia was observed in 100 % of patients after dental extraction, 55 % of patients after third-molar surgery, 70 % of patients after dental scaling, 20 % of patients after endodontic treatment, and 55 % of patients after bilateral tonsillectomy. And anaerobic microorganisms were isolated more frequently than aerobic microorganisms . Transient bacteremia is produced not only as a result of dental manipulation. Even daily life activities such as eating, chewing gum, brushing the teeth, or using toothpicks also induce bacteremia detectable by means of blood cultures in a variable percentage of subjects .
Three mechanisms or pathways linking oral infections to secondary systemic effects have been proposed for several years . Li et al. summarized the mechanisms as the following: metastatic spread of infection from the oral cavity as a result of transient bacteremia, metastatic injury from the effects of circulating oral microbial toxins, and metastatic inflammation caused by immunological injury induced by oral microorganisms .
Till now, there is no direct evidence to prove the connection between the dental caries and bacteremia, but we can find some clues from published papers. Debelian et al. used phenotypic and genetic methods to trace microorganisms released into the bloodstream during and after endodontic treatment back to the root canal. Microbiological samples were taken from the root canals of 26 patients with asymptomatic apical periodontitis of single-rooted teeth. The blood of the patients was drawn during and 10 min after endodontic therapy. The results found that microorganisms from the root canal and blood presented identical phenotype and genetic characteristics within the patients examined,which demonstrated that endodontic treatment can be the cause of anaerobic bacteremia and fungemia. Interestingly, some cariogenic bacteria were also isolated from the blood, such as Streptococcus sanguinis . Streptococcus mutans and Streptococcus sanguinis are most consistently been associated with the initiation of dental caries. The results not only illustrated that dental caries is the most common cause of pulpitis and periapical diseases but also showed a clue that cariogenic bacteria may be related to bacteremia.
These bacteria are normally harmless as long as they are kept in check by the body’s natural barriers and the immune system. In the oral cavity there are several barriers to bacterial penetration from dental plaque into the tissue: a physical barrier composed of the surface epithelium; defensins, which are host-derived peptide antibiotics, in the oral mucosal epithelium; an electrical barrier that reflects the Eh difference between the host cell and the microbial layer; an immunological barrier of antibody-forming cells; and the reticuloendothelial system (phagocyte barrier) . However, once the equilibrium is disturbed by an overt breach in the physical system (e.g., trauma) or immunological barriers (e.g., through neutropenia, AIDS), organisms can propagate and cause both acute and chronic infections with increased frequency and severity [25, 26]. In addition, medical treatment (e.g., immunosuppressant therapy) may bring a person in contact with new types of bacteria that are more invasive than those already residing in that person’s body, further increasing the likelihood of bacterial infection.
8.2 Dental Caries and Head and Neck Cancer
8.2.1 Dental Caries and Head and Neck Cancer Treatment
Head and neck cancer accounts for more than 550,000 cases annually worldwide. The incidence rate in males exceeds 20 per 100,000 in regions of France, Hong Kong, the Indian subcontinent, central and eastern Europe, Spain, Italy, and Brazil and among African Americans in the Unites States. Mouth and tongue cancers are more common in the Indian subcontinent . Surgical resection, radiotherapy, and chemotherapy, either used singly or in combination, are the three most common modalities used in head and neck cancer treatment. Despite their effects in eradicating the tumor, they also negatively impact the normal head and neck structures surrounding the tumor. Surgical resection removes abnormal tissue, while radio- and chemotherapy frequently cause direct damage to the oral soft and hard tissue, and indirect damage may also arise from systemic toxicity.
Firstly, we will discuss the radiotherapy because radiation caries is a common disease in clinic. We all know that saliva in the oral cavity protects hard tissues against acid attacks and demineralization. Salivary glands are very susceptible to radiation, and any disturbances in their function are detrimental to the hard tissues in the oral cavity. Radiation caries is mainly an indirect effect of irradiation-induced changes in salivary gland tissue that result in hyposalivation . Hyposalivation leads to accelerated dental caries through changes in salivary composition, a shift in oral flora toward cariogenic bacteria, and dietary changes . It is reported that the initial caries usually occur around the third week of treatment . Mohammadi et al.  reviewed 27 cases with head and neck cancers undergoing radiotherapy. Of these cases, class V dental caries of posterior teeth were evaluated in three intervals: before treatment, 3 weeks after the initiation of the treatment, and at the end of the treatment. The baseline is that there were no class V decays prior to radiotherapy. Their results found that mean percentages of class V caries 3 weeks after radiotherapy and at the end of radiotherapy were 28.42 % ± 14.41 and 67.05 % ± 19.02, respectively. These findings are in accordance with the results of other studies [28, 32]. Since the severity of xerostomia is related to the radiation dose, dose rate, and amount of salivary tissue irradiated, the authors also pointed out that further studies should evaluate the effects of new techniques such as intensity-modulated radiotherapy on occurrence of dental caries, in which a higher dose is beamed at the tumor site without increased received dose of the surrounding tissues .
Secondly, we talk about which one of the three modalities, either used singly or in combination, is the most common cause of dental caries after therapy. In order to determine the prevalence of dental caries in cancer survivors, Catherine et al. conducted a systematic literature search with assistance from a research librarian in the databases MEDLINE/PubMed and Embase for articles . Finally, 64 published papers between 1990 and 2008 were reviewed. Dental caries was assessed by the present (Y/N), DMFT/dmft, and DMFS/dmfs indexes if available. Their results showed that the weighted overall prevalence of dental caries was 28.1 % and was determined from 19 studies. The weighted prevalence of dental caries in patients who received only chemotherapy was 37.3 %. The weighted prevalences of dental caries in patients who were post-radiotherapy and those who were post-chemotherapy and post-radiotherapy were 24 and 21.4 %, respectively. The authors attributed the discrepancy to the distinct differences in the dental management of patients prior to radiotherapy versus those being prepared for chemotherapy. Another explanation for the unanticipated caries prevalence may be because 12 of the 19 studies included were carried out on children undergoing hematologic malignancies who were treated largely by curative chemotherapy. They could have higher caries activity because of the need to frequently consume highly cariogenic dietary supplements for weight maintenance or are taking sucrose-rich medications. In addition, their oral hygiene may be ignored. In contrast to the caries prevalence, the DMFT index is expectedly highest in patients who were post-radiation therapy compared to patients who were post-chemotherapy and healthy controls .
8.2.2 Dental Caries and Head and Neck Squamous Cell Carcinoma
Recently, an interesting paper published online in JAMA Otolaryngology – Head and Neck Surgery showed that the bacteria that caused tooth decay are linked to an immune response, which may be protective against cancer . The researchers from the University at Buffalo, NY, set out to determine if there is a significant link between dental cavities and head and neck squamous cell carcinoma (HNSCC). The study involved 399 patients newly diagnosed with HNSCC and 221 participants without the cancer who were all selected from the Department of Dentistry and Maxillofacial Prosthetics at Roswell Park Cancer Industry between 1999 and 2007. The dental history of all patients, particularly their history of dental cavities, was analyzed by measuring the number of decayed, missing, and filled teeth. Of the 399 patients with HNSCC, 146 (36.6 %) had oral cavity squamous cell carcinoma (SCC). Oropharyngeal SCC occurred in 151 (37.8 %) patients, while 102 (25.6 %) had laryngeal SCC. The results of the study overall showed that those who had high cavity numbers were less likely to have HNSCC, compared with participants who had low cavity numbers. The authors explained that “Caries is a dental plaque-related disease. Lactic acid bacteria cause demineralization (caries) only when they are in dental plaque in immediate contact with the tooth surface. The presence of these otherwise beneficial bacteria in saliva or on mucosal surfaces may protect the host against chronic inflammatory diseases and HNSCC. We could think of dental caries as a form of ‘collateral damage’ and develop strategies to reduce its risk while preserving the beneficial effects of the lactic acid bacteria” .
8.2.3 Tooth Loss and Head and Neck Cancer Risk
As previously mentioned, caries is one of the most common reasons of tooth loss; we will include the relationship between tooth loss and tumors in this chapter. Actually, multiple epidemiologic studies regarding the potential association of tooth loss with head and neck cancer risk have been published nowadays [35–38]. But considering the modest sample size and different study designs, the evidence still remains controversial. Therefore, a quantitative and systematic summary of the evidence using rigorous methods is necessary. We know that meta-analysis is the use of statistical methods to combine results of individual studies. This allows us to make the best use of all the information we have gathered in our systematic review, and by statistically combining the results of similar studies, we can improve the precision of our estimates of treatment effect and assess whether treatment effects are similar in similar situations. Recently, some Chinese researchers from Guangxi Medical University conducted a meta-analysis involving 5,204 patients and 5,518 controls to assess the inconsistent results from published studies on the association of tooth loss with head and neck cancer risk . Their overall estimates provided evidence that tooth loss was significantly associated with increased risk of head and neck cancer. In addition, the moderate [6–15] tooth loss and the severe (>15) tooth loss experienced a significantly increased risk of head and neck cancer by 18 and 54 %, respectively. Furthermore, the moderate [6–15] tooth loss was associated with a 45 % increase in the risk of larynx cancer. The authors also summarized that several plausible mechanisms may explain why a significant increased association of tooth loss with head and neck cancer was observed in their analysis.
Whether tooth loss is an independent risk factor of head and neck cancer is an interesting question. But the answers have not reached consistent conclusions yet. Guha et al. observed that missing 6–15 teeth increased the odds ratio of esophageal squamous cell carcinoma by more than twofold in both Latin America and central Europe. However, when missing teeth were more than 15 in number, no increase risk was observed . On the other hand, Wang et al. found that moderate and severe tooth loss did not change such an association, suggesting that tooth loss is probably an independent risk factor of head and neck cancer .
8.2.4 Cariogenic Bacteria and Oral Cancer
Alcohol is one of the main risk factors for oral cancer. Alcohol itself is not carcinogenic, but it is oxidized to carcinogenic acetaldehyde in saliva by the ADH enzyme of some oral microbes of the normal oral microflora. Oral streptococci, especially S. mutans, are the primary pathogens causing dental caries, and Neisseria strains are related to the early stage of caries. About a decade before, some Neisseria strains are found to be able to produce significant amounts of acetaldehyde, probably via their high alcohol dehydrogenase (ADH) activity . Neisseria strains are considered to be part of the normal oral flora, but they are found only in low numbers in the oral cavity. Later, in 2007, oral streptococci were proved to contribute significantly to the normal individual variation of salivary acetaldehyde levels after alcohol drinking and thereby also to the risk of oral cancer . We believe that the effect of cariogenic bacteria on oral cancer provides some evidence between caries and cancer from another side.
8.3 Dental Caries and Children Growth
There’s no doubt that dental caries constitutes the single most common chronic disease of childhood: as many as 60 % of school children have experienced dental caries, and the data can reach as high as 90 % in some countries according to the report of World Health Organization (WHO) . Among 5- to 17-year-olds, dental decay is five times as common as asthma and seven times as common as hay fever . Current evidences show that dental caries is a multifactorial disease and complexly modulated by genetic, behavioral, social, and environmental factors . A recent descriptive cross-sectional study assessed dental caries experience among 12-year-old school children from low socioeconomic status background attending public primary schools in Zimbabwe. The results showed that there was a high prevalence of dental caries in both urban (59.5 %) and rural (40.8 %) children . While most people in rural areas in Zimbabwe cannot afford and perceive these sugary products as non-beneficial, affording them is often considered as a symbol of higher socioeconomic status. Another retrospective cohort study gave support to the idea that children who lived in urban areas showed 75 % greater probability of presenting caries when compared to those children residing in rural areas . This disparity between urban and rural children has been partially attributed to increased access and consumption of high sugar-containing foods and beverages in urban areas . Based on the recent studies, socioeconomic status has been shown to be a major risk for caries incidence. Children living in poverty represent a large population of high-risk individuals who have undiagnosed and untreated diseases coupled with limited access to care. Nearly twice the proportion of US children with family incomes less than the federal poverty level (FPL) show decay of the primary or permanent dentition (55 %), compared to those whose family incomes are greater than 200 % of the FPL (31 %). Low-educated and low-income families that pay less attention to the dental hygiene of their children may be one of the reasons .
Apart from structurally weakening teeth, dental caries can lead to infection, pain, abscesses, chewing problems, poor nutritional status, and gastrointestinal disorders. Moreover, serious caries can damage a child’s sense of self-esteem, which in turn may affect his or her school performance, ability to learn, and potential to thrive . Specifically, in young children, there is a relationship between dental caries and childhood obesity [51, 52]. Dental caries can also contribute to poor nutritional status and affect the growth of adult teeth . In addition, children with extensive dental caries may need to undergo treatment under general anesthesia in hospital. This is a significant side effect of childhood caries that is widely acknowledged by the experts. It is essential to remember that dental caries is one of only very few common childhood diseases which cause large numbers of the child population to undergo general anesthesia.
The relationship between dental caries and child’s body weight was firstly noticed by Miller 30 years ago . Caries of the primary teeth or “early childhood caries” (ECC) is one of the most prevalent health problems in infants and toddlers . A recent study found a positive correlation between severe early childhood caries (S-ECC) and body mass index (BMI) of 3- and 6-year-old children, which means the mean BMI of S-ECC children is significantly more than the caries-free children . We know that if caries involve the pulp, the eating of some foods will cause pain; therefore, toothache and infection alter eating and sleeping habits, dietary intake, and metabolic processes . For example, some of the patients may thereby avoid certain nutritious foods and select high-calorie, high-fat food, which is recognized as risk factors for obesity. On the other hand, some patients cannot pulverize the foods well and may have an adverse effect on the internal absorption of nutrients. But if such bad oral condition has been changed, the children’s growth will be better. In 2009, Malek et al. conducted a longitudinal clinical trial study to examine whether the removal of carious teeth affected children’s growth relative to that of a standard population. Five- and six-year-old children who attended for extraction of carious teeth under general anesthesia took apart in this study. The children’s dental caries levels, weight, and height were measured prior to extraction using standard criteria and a single trained examiner, and they were then remeasured 6 months later. The participants had a mean dmft of 7.18 (SD 3.27) at baseline, and at follow-up children showed a statistically significant gain in BMI SDS and a small gain in height SDS . In their another longitudinal birth cohort, Kay et al. found that children who had caries at 61 months had slower increases in weight and height than those without decay at the same age . These observations were consistent with a recent study which examined the association between untreated dental caries in primary and permanent teeth with age-adjusted height and weight among 6–12-year-old children in Bangladesh .
However, the relationship between dental caries and child’s growth is inconclusive so far. A research from the department of cardiology, endodontology, and pedodontology in Academic Centre for Dentistry Amsterdam (ACTA) has been published in Clin Oral Investig in 2011. The study has two objectives: first, to assess the relation between dental caries and body proportions cross-sectionally in a Suriname caries child population and, second, to investigate whether dental treatment had a significant influence on body growth of these children in a randomized controlled trial using different treatment strategies. Three hundred eighty 6-year-old children with untreated dental decay participated in the study. Participants were evaluated after 6 months and 1, 2, and 3 years. However, negative correlations were observed between anthropometric measures and the number of untreated carious surfaces and caries experience of the children. Next, no significant differences in growth pattern between the treatment groups were observed. Thus, the authors suggested that caries activity is a negative predictor for body growth in children, and dental intervention does not show significant improvement within 3 years . Later, Merrilyn et al. undertook an updated systematic review of the relationship between body mass index and dental caries in children and adolescents. The authors searched MEDLINE, ISI, Cochrane, Scopus, Global Health, and CINAHL databases and conducted lateral searches from reference lists for papers published from 2004 to 2011, inclusive. Finally, a total 48 studies were included. Three main patterns of relationships were found between dental caries and BMI: 23 of the 48 studies found no association between BMI and dental caries, 17 found a positive relationship between BMI and dental caries, and 9 found an inverse relationship. The reasons that authors analyzed may be method of dental examination, sample differences, dental caries prevalence, and BMI distribution. And they also recommend that future research investigate the nature of the association between body mass index and dental caries in samples that include a full range of body mass index scores and explore how factors such as socioeconomic status mediate the association between body mass index and dental caries .
8.4 Dental Caries and Atherosclerosis, Cardiovascular Disease, and Heart Attack
Atherosclerosis (also known as arteriosclerotic vascular disease or ASVD) is a specific form of arteriosclerosis in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol and triglyceride. Cardiovascular disease (CVD) is the broad term used to categorize any abnormal condition characterized by dysfunction of the heart and blood vessel system, principally referring to cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease. Evidence suggests a number of traditional risk factors for atherosclerosis and CVD: age, gender, high blood pressure, high serum cholesterol levels, tobacco smoking, excessive alcohol consumption, sugar consumption , family history, obesity, lack of physical activity, psychosocial factors, diabetes mellitus, and air pollution . However, these factors cannot explain all the deaths from CVD. For example, about 40 % of coronary heart disease (CHD) deaths occur in people with cholesterol levels that are lower than the population average . Therefore, medical researchers’ attention has focused in recent years on identifying additional risk factors that are nontraditional but may play major roles in explaining some of the variability in atherosclerosis and CVD risk.
During the last three decades, there has been an increasing interest in the impact of oral health on atherosclerosis and subsequent cardiovascular disease (CVD). Just as Meurman et al. wrote in their paper which was published in Crit Rev Oral Biol Med: “chronic infections caused by a variety of micro-organisms are thought to be involved in the etiopathogenesis of CVD by releasing cytokines and other pro-inflammatory mediators that may initiate a cascade of biochemical reactions and cause endothelial damage and facilitate cholesterol plaque attachment. Yet, due to the multi-factorial nature of dental infection and CVD, confirming a causal association is difficult, and the published results are conflicting. The main deficit in the majority of these studies has been the inadequate control of numerous confounding factors, leading to an overestimation and the imprecise measurement of the predictor or over adjustment of the confounding variables, resulting in underestimation of the risks” .
8.4.1 Dental Caries and Atherosclerosis and Cardiovascular Disease
Many studies have looked at poor dental care as a risk factor for cardiovascular disease (CVD). The results have been inconsistent, but most studies support a modest association between them . Mattila et al. may be one of the first researchers to indicate a relationship between orofacial infections and cardiovascular disease. In 1989, they published an article in British Medical Journal (BMJ) and reported that there was an unexpected correlation between dental disease and systemic disease. After adjusting for age, exercise, diet, smoking, weight, blood cholesterol level, alcohol use, and health care, people who had caries and periodontal disease had a significantly higher incidence of acute myocardial infarction . Another prospective cohort study, published in 1993, found that patients with periodontal disease had a 25 % increase in CVD, and men younger than 50 years had a significantly higher risk. However, no association between extent of active dental decay and risk of coronary heart disease was observed. Since tooth loss in people under 60 is usually caused by dental caries, the authors said they cannot rule out the possibility that the increased risk of coronary heart disease among young men with no teeth may have been related to previous dental decay . These important discoveries resulted from the study is not the only reason that makes it noteworthy. Actually, the 9,760 subjects included in this work make it the largest sample size of its kind at that time. Since then, investigating the relationship between dental disease and CVD has become a priority.
Later, in 2001, a prospective cohort study in Stockholm, Sweden, followed 1,393 individuals for 27 years and concluded that oral health was a risk factor for death due to CVD, especially in combination with smoking, another risk factor. In this investigation, a significant correlation between caries and death due to CVD when adjusted for age and gender was demonstrated, indicating that this possible etiological pathway should be further investigated in the future. And the number of tooth surfaces with caries and presence of plaque were significantly increased for smokers compared to nonsmokers .
Maharaj and Vayej studied 44 black patients with severe rheumatic heart disease before they had cardiac surgery in 2012. Abnormalities were detected in the panoramic radiographs of 84.1 % of patients. The most frequent lesion was caries, present in 56.8 % of patients, followed by missing teeth in 54.5 %, and impacted teeth in 25 % of patients. Retained roots were present in 22.7 % and periapical pathology was detected in 18.1 % of patients .
It is clear that minimal carious lesions, caries with and without involvement of the pulpal cavity, and chronic apical periodontitis (CAP) represent different stages of the same inflammatory process. A recent study shows for the first time that dental caries, pulpal caries, and chronic apical periodontitis are associated positively, while restorations are associated inversely, with aortic atherosclerotic burden . The authors’ result showing that not only CAP but also caries with pulpal decay or no visible pulpal decay was associated with a greater atherosclerotic burden was somewhat surprising. We know that early stage of caries is an inflammatory process localized in the oral cavity that does not affect the pulpal cavity or the bone, indicating that a lesser extent of association of the early stage of caries with the atherosclerotic burden was expected than with the other two serious stages. One obvious explanation for this finding may be the covariance of these factors, as pulpal caries and CAP occur primarily in patients with extensive tooth decay. The initial carious lesion and caries not yet affecting the pulpal cavity exist for a longer period compared with the pulpal decay, which can precede pulpal decay by a number of years. An explanation other than the disease lasting many years is that even forms of caries not yet involving the pulp are not merely local inflammatory lesions but rather disease affecting the entire body. The authors suggested that prospective studies are required to confirm these observations and answer the question of possible causality .
8.4.2 Root Caries and Cardiac Dysrhythmia and Gerodontology
Cardiac dysrhythmias, especially atrial fibrillation, are known to cause ischemic heart disease. Many studies suggested that inflammation plays a prominent role in the onset of atrial fibrillation . With respect to the result of logistic regression analysis, cariogenic bacteria have a specific impact on the pathogenesis of cardiac diseases, especially dysrhythmias . In 2005, researchers from University of Copenhagen designed a cross-sectional study to examine whether caries is associated with cardiac arrhythmias in community-dwelling people aged 80 and older. The primary finding of the multivariate logistic regression analysis was that persons with three or more active root caries lesions had more than twice the odds of cardiac arrhythmias than persons without active root caries. The findings indicated that there may be a link between active root caries and cardiac arrhythmias in the oldest old . In order to explain the link, we should turn to the immune response because several studies have reported that an increase in dental caries is associated with a heightened immune response. In addition, dental caries affects the production of IgG and induces acute-phase proteins. The inflammatory-mediated cytokines and acute-phase proteins are practical markers of increased risk of cardiovascular disease, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) . Bacterial species lying within the root surfaces supporting structures induce systemic inflammation and immune response, thereby increasing levels of serum CRP and serum IgG. In 2011, Kaneko et al. conducted a longitudinal study to elucidate the relationship between root caries and the onset of dysrhythmias on electrocardiographs in community-dwelling persons aged 75 and older. Serum CRP level was used as a variable to link root caries with dysrhythmias directly. They found that a high mean CRP serum level group had a significantly higher number of sites with root caries than a low CRP group. Moreover, number of sites with root caries events was significantly associated with cardiac dysrhythmia among nonsmokers. These results confirmed that root caries is related to the incidence of dysrhythmias in nonsmokers .
8.4.3 Streptococcus mutans and Atherosclerosis
We know that Streptococcus mutans (S. mutans) is a major cariogenic pathogen that is a normal inhabitant of the oral cavity in most individuals. S. mutans has also been isolated from the blood of patients with infective endocarditis (IE), which strongly suggests a close relationship of the pathogen with IE [76, 77]. Ullman et al. pointed out that their experience agrees with the literature and indicates that S. mutans is primarily a pathogen in elderly patients with heart disease and may be associated with IHSS . In 2006, Nakano from Osaka University Graduate School of Dentistry and coworkers published the first study to analyze the presence of streptococcal species in diseased heart valve and atheromatous plaque specimens, as well as in dental plaque samples from the same subjects by a PCR method. Unexpectedly, S. mutans was detected at high frequencies and quantities in both heart valve tissues and atheromatous plaque samples in their study. Their conclusion indicated that S. mutans is a possible causative agent of cardiovascular disease . In addition, when using DNA fingerprinting to compare S. mutans isolated from dental plaque and an infected heart valve from a patient who underwent heart surgery, Nomura and colleagues demonstrated that the oral isolates differed from those found in the heart valve . Three years later, Nakano et al. published another paper titled “Detection of oral bacteria in cardiovascular specimens” in Oral Microbiology and Immunology. This time, they found that S. mutans was the most frequently detected species in the cardiovascular specimens, followed by Aggregatibacter actinomycetemcomitans. Furthermore, the positive rate of S. mutans in cardiovascular specimens from patients whose dental plaque specimens were also positive for S. mutans was 78 %, which was significantly higher than any other tested species when the same analysis was performed . Collectively, these findings lend credence to the idea that there are subpopulations of S. mutans carried in humans that, while not necessarily associated with caries, may have an enhanced capacity to interact, and possibly invade, the cells of the cardiovascular system . S. mutans is classified into four serotypes (c/e/f/k) based on the chemical composition of its cell surface serotype-specific rhamnose–glucose polymers (RGPs), which form a backbone of rhamnose polymers with side chains of glucose polymers. Serotype c is reported to be the most prevalent in oral isolates at approximately 70–80 %, followed by e, f, and k. Serotypes e and f have been found to invade endothelial cells . Serotype k, with a defect of the glucose side chain in RGPs, was found to show low cariogenicity but high virulence in blood as compared to the other serotypes, due to alterations of several cell surface structures . When it comes to the possible reasons of the link between S. mutans and cardiovascular system diseases, it may be summarized as the following:
One crucial step for the development of atheromatous plaque lesions is formation of foam cells, which are macrophages that accumulate from excess cholesterol, and S. mutans strain GS-5 has been shown to enhance their formation .
The infection with S. mutans expressing collagen-binding protein (CBP) is a potential risk factor for hemorrhagic stroke . Lately, two types of cell surface collagen-binding proteins, Cnm and Cbm, have been studied to see if they play a role in S. mutans attachment and invasion of human umbilical vein endothelial cells (HUVEC). The results found that most of the Cbm-positive strains showed higher levels of binding to type I collagen as well as higher rates of adhesion and invasion with HUVEC as compared to the Cnm-positive strains. Furthermore, the gene encoding Cbm was detected significantly more frequently in heart valve specimens from IE patients than from non-IE patients .
8.4.4 Tooth Loss and Cardiovascular Disease and Stroke
While some studies have shown that decay is not a direct risk factor, it can and does cause tooth loss, which has been demonstrated to be a greater risk for cardiovascular disease [89, 90]. Recent evidence showed a direct link between oral health and CVD and that the number of teeth can be used to assess increased risk of CVD in adults. They drew the conclusion from a fairly large (n = 7,647), prospective study with a long follow-up period (1976–2002) that presents for the first time a dose-dependent relationship between number of teeth and both all-cause and CVD mortality. The authors found that a person with fewer than 10 of their own teeth remaining is seven times more likely to die of coronary disease than someone with more than 25 of their own teeth .
As pointed out by Watt et al., although there is increasing epidemiological evidence linking poor oral health with the development of chronic diseases and mortality, these associations are still doubtful due to imprecise measurement of important risk factors of systemic disease. Indeed, most previous studies exploring the link between tooth loss and systemic disease have been conducted in selected samples and have failed to control adequately for socioeconomic, behavioral, and general health status . Thus, their recent prospective cohort study of a national sample of Scottish adults published in PLOS ONE caught our attention. The sample consisted of 12,871 participants and they were followed for 8.0 (SD: 3.3) years. During 103,173 person-years, there were 1,480 cases of all-cause mortality, 498 of CVD, and 515 of cancer. After adjusting for demographic, socioeconomic, behavioral, and health status, edentate subjects had significantly higher risk of all-cause and CVD mortality compared to subjects with natural teeth only. Their findings confirm previous studies which have shown a small but significant association between tooth loss and all-cause and CVD deaths after controlling for a range of potential confounding factors .
However, there were different opinions from other studies, such as the study using the data from the Glasgow Alumni Cohort to investigate whether oral health in young adulthood is independently associated with cause‐specific mortality after accounting for childhood socioeconomic background and other risk factors in young adulthood. Over 12,000 subjects (30 years or younger at baseline) were traced during up to 57 years of follow‐up, and 1,432 deaths occurred among subjects with complete data, including 509 deaths from CVD and 549 from cancer. When the number of missing teeth was treated as a categorical variable, there was evidence that students with nine or more missing teeth at baseline had an increased risk of CVD compared with those with fewer than five missing teeth. When the number of missing teeth was transformed using fractional polynomials, there seemed to be a nonlinear relation between missing teeth and CVD mortality .
Stroke remains the third leading cause of death (after heart disease and cancer) in most developed countries. Cerebrovascular ischemic strokes are the commonest kind of stroke and occur as a result of an obstruction, usually a clot, within a blood vessel supplying blood to the brain. Heitmann and Gamborg examined if the number of remaining teeth was associated with the development of cardiovascular morbidity and mortality over 5–12 years. The prospective observational study among1474 men and 1458 women born 1922, 1932, 1942 or 1952 from The Danish MONICA follow up study (monitoring trends in and determinants of cardiovascular disease) in 1987–88 and 1993–94. Their results showed that tooth loss was strongly associated with incidence of stroke and, to a lesser extent, incidence of cardiovascular disease and coronary heart disease, during averagely 7.5 years of follow-up . Choe et al. conducted a prospective cohort study of stroke in Korea on hypertension, diabetes, smoking, and tooth loss to characterize their independent effects and interactions. They confirm that tooth loss is independently associated with increased risk of stroke, and hypertension does interact antagonistically, particularly for hemorrhagic stroke . A recent study found that stroke patients in their 50s and 60s had significantly fewer remaining teeth than did patients hospitalized for other conditions in the corresponding age groups. Moreover, the number of remaining teeth was significantly lower among stroke patients in their 50s than data reported for that age group in the Survey of Dental Diseases, suggesting the possibility that stroke patients may have lost teeth at a younger age. The authors also pointed out that the association between stroke and tooth loss can be explained by common risk factors associated with lifestyle such as hypertension, diabetes, smoking, and alcohol intake. It is quite difficult to rule out all common risk factors as confounding variables; therefore, the exact mechanisms of the relationship between stroke and tooth loss are difficult to identify . Interestingly, periapical lesions, normally resulting from an infected root canal (caused by caries), are also a factor in stroke risk. This is another example of how dental caries can play a role, however indirectly, in heart disease .
8.4.5 Pulpal Periapical Diseases and Coronary Heart Diseases
Endodontic inflammation occurs after bacteria or their byproducts enter a tooth’s pulp chamber. Apical periodontitis is an acute or chronic inflammatory lesion around the apex of a tooth root which is caused by bacterial invasion of the pulp of the tooth. Despite numerous differences between chronic inflammatory disease of periodontal and endodontic origins, Caplan et al. summarized their similarities, primarily that: (1) both conditions share a common microbiota that often is associated with Gram-negative anaerobic bacteria, and (2) elevated systemic cytokine levels have been observed in conjunction with both disease processes [97