Association of chronic periodontitis in a broad spectrum of cardiometabolic syndrome: A minireview

Abstract

The prevalence of cardiometabolic syndrome (CMS) and increasing mortality rate play a significant role in the global increase of cardiovascular disease (CVD) in developing countries. A group of metabolic syndromes that are risk factors for CVDs are referred to as the CMS. Although the exact mechanism(s) behind the development of the CMS are not known, but multi-organ insulin resistance, a prevalent characteristic of the syndrome, is probably one of them. The two most prevalent dental diseases i.e. periodontitis (PD) and dental caries have been related to several systemic diseases and disorders, such as CMS. Age, alcohol consumption, being obese, possessing diabetes, as well as smoking are risk factors for periodontal diseases, while both CVD and periodontal diseases are linked to systemic inflammation. It has a multifactorial aetiology and is associated with many systemic diseases. When bacteria and their products attack the periodontal tissues, the tissue raises an immune-inflammatory response against the pathogens. This acute phase response is a result of the pathogen’s systemic attack and contributes to the overall inflammatory burden of the system. CVD and PD are both diseases associated with systemic inflammation and may be related as they share many common risk factors. Hence, the correlation between these conditions might also have an impact on how dentistry and medicine are practised, thus helping to build a working relationship between the dentist and the physician.

Key Words: Cardiometabolic syndrome; Chronic periodontitis; Periodontal diseases; Coronary artery disease; Clinical attachment loss

Core Tip: Cardiometabolic syndrome (CMS) plays a pivotal role in global increase in the incidence of cardiovascular disease (CVD) in the developing countries. The multi-organ insulin resistance appears to key driver of both metabolic syndrome and CVDs. The two most prevalent dental diseases i.e., periodontitis (PD) and dental caries have been related to several systemic diseases and disorders, such as CMS. Age, alcohol consumption, being obese, possessing diabetes, as well as smoking are risk factors for periodontal diseases and CVD alike. Periodontal diseases are intricately linked to systemic inflammation and are associated with many systemic diseases. When bacteria and their products attack the periodontal tissues, the tissue raises an immune-inflammatory response against the pathogens. This acute phase response is a result of the pathogen’s systemic attack and adds to the overall inflammatory burden of the system. CVD and PD are both diseases associated with systemic inflammation and may be related as they share many common risk factors. Hence, the correlation between these conditions might also have an impact on how dentistry and medicine are practised, thus helping to build a working relationship between the dentist and the physician.

INTRODUCTION

A collection of metabolic disorders known as the cardiometabolic syndrome (CMS) is a risk factor for cardiovascular diseases (CVDs). People with the CMS have a greatly elevated risk of myocardial infarction, coronary artery disease (CAD), and stroke than people without the condition[1]. There isn't a single, widely agreed-upon description of the CMS, and at least five different groups have put up their own set of diagnostic criteria[2]. The World Health Organization and National Cholesterol Education Program Adult Treatment Panel III provided the clinical criteria that are most frequently used for diagnosing the CMS, respectively[3,4]. Given that diabetes and hypertension are the two main CVD risk factors which kill 18 million people worldwide, interest in these disorders is easily justified[5]. The CMS is characterized by all populations by obesity in the abdominal region (large waist circumference and/or high body mass index), insulin resistance, and glucose metabolism.

Tens of millions of preventable deaths are expected because of the epidemic prevalence of CMS in the modern world and its detrimental effects on the immune system, cardiovascular system, cancer diagnosis, respiratory system, renal system, cerebrovascular system, as well as oral health[6].

INCIDENCE OF CMS AND ITS RISK FACTORS

Sedentary lifestyle, fewer physical activities, and a more positive energy balance are the results of changing socio-economic conditions, which have been exacerbated by calorie-dense, unhealthy diets, improved disposable income, increased urbanization, and increased dependence on public and private transportation[4,7]. The growth in cardiovascular-related diseases and mortality in emerging countries is thought to be caused by this phenomenon, which has recently been given the names "lifestyle syndrome" or "New World syndrome"[7]. The discovery that CMS is a disease entity that affects people of all ages is even more concerning. Due to increased food intake and decreased activity, child and adolescent obesity rates are on the rise in many nations of the world, increasing the risk of CMS in paediatric patients. Despite the paucity of information on youth, one survey indicated that 4.2% of adolescents had CMS[8].

CHRONIC PERIODONTITIS

Oral health is critical to an individual’s overall well-being. Oral diseases are one of the most common diseases affecting individuals globally, and they have shown to have an impact on an individual’s health. Chronic periodontitis (PD) is one of the most prevalent periodontal disease, with a progressive rate of 15%-20%[9,10]. The teeth's supporting and investing structures are affected by the multifactorial chronic inflammatory disease known as PD[11]. Chronic PD, sometimes referred to as "adult periodontitis" or "chronic adult periodontitis". It involves teeth via gradual attachment loss as well as bone loss. The following characterization lists the main etiologic and clinical traits among the diseases: (1) Development of microbial plaque; (2) Periodontal tissues inflammation; and (3) Loss of alveolar bone and attachment[11].

This is a progressive process that affects many people over a long period of time and can be stopped if caught early and treated. However, disease development may become more aggressive in the presence of systemic or environmental variables, like diabetes, smoking, or stress, that might alter the host response to plaque formation[12]. However, though chronic PD is typically seen in adults, it may also affect young children and adolescents due to the formation of persistent plaque and calculus[13]. The incidence and severity increase with ageing, typically affecting both genders equally. Chronic PD is an age associated, not an age-related, disease. To put it another way, the duration of chronic plaque formation in the periodontal tissues, rather than an individual's age, is what drives a rise in the prevalence of disease[14].

Epidemiological research has provided strong proof for a significant correlation between chronic PD and coronary heart disease (CHD). A systematic review in 2013 found six cohort and case-control studies on CHD, and these epidemiological studies, showed individuals with more severe or clinically diagnosed PD had a higher risk of having their first coronary event compared to those with less severe PD or without PD[15]. According to a report from two cohort studies, there is a correlation between chronic PD and increased cardiovascular mortality (from coronary and cerebrovascular heart disease) (Table 1)[16-32]. Increased arterial calcification scores, stiffness of the arterial walls (such as pulse wave velocity), flow-mediated dilatation, and a noticeably thicker carotid intima media are indicators of significant endothelial dysfunction in PD patients, according to epidemiological studies. Low levels of positive atheromatous plaque remodelling and high levels of antibodies against periodontal pathogens have been linked in one imaging research (ATHEROREMOIVUS study)[16].

Table 1 Epidemiological evidence for the association between chronic periodontitis and cardio-vascular disease.

Ref.	Year	Main findings
Gonçalves et al[17]	2010	Patients with chronic PD have PBMC in their peripheral blood that had been activated with LPS. These LPS were used to measure the amounts of TNF-α, IL-6, IL-10, and IL-8 that are released. The findings of their investigation showed that when compared to PBMC from persons without PD, Escherichia coli LPS-stimulated PBMC from subjects with PD presented a distinct pattern of cytokine release
Genco et al[18]	2010	Patients with CVD who exhibit the signs and symptoms of gingivitis or have sudden tooth loss should have a periodontal assessment. Additionally, a dentist and a doctor should work closely together to maximize periodontal care and CVD risk reduction when PD is initially detected in a patient with CVD
Kebschull et al[19]	2010	Periodontal infections may be independently linked to both preclinical and symptomatic atherosclerotic vascular disease, according to evidence from epidemiologic research. They concluded that although there is significant variation in responses, periodontal therapy generally has positive effects on subclinical atherosclerosis indicators
Kaptoge et al[20]	2010	CRP levels were consistently associated with a risk of developing CAD and ischemic stroke. However, it is unknown how CRP relates to such a wide spectrum of illnesses. Relationships with ischemic vascular disease were largely influenced by traditional risk factors and additional inflammation-related indicators
Bălan[21]	2010	Determined that there is a direct causal link between periodontal diseases and CVDs. He concluded that the high prevalence of both conditions and some common risk factors could account for their relationship
Dhotre et al[22]	2011	Stated that a highly significant increase in total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels with a concomitant decline in high-density lipoprotein-cholesterol was observed in PD patients. The increased oxidative stress and altered lipid profile in PD patients could contribute to the development of CVD
Matsuo et al[23]	2011	The prevalence of latent pulmonary veins conduction was observed to be the same in individuals with paroxysmal AF, persistent AF, and long-lasting AF. In vitro, animal, and clinical studies do support the interaction and biological mechanism, intervention trials to date were not sufficient to make further inferences; and there was consistent and strong epidemiologic evidence that PD imparts an increased risk for future CVD
Tonetti and Van Dyke[24]	2013	Undertook a study to look into the epidemiological evidence for a link between incident ACVD, e.g. peripheral artery disease, cerebrovascular disease, coronary heart disease, and PD. They concluded that patients without PD had a lower risk of acquiring ACVD. Not all demographic groupings may be affected by this. The relationship between PD and the frequency of subsequent cardiovascular events is not supported by enough data
Dietrich et al[16]	2013	Researched to give a summary of studies on the connection between CVD and periodontal disease and its function as a potential danger for the onset of cardiac disease. According to a study of epidemiological data, they discovered that there was evidence of a link between periodontal diseases and CVD. A possible connection joining oral bacteria and atherosclerosis is also highlighted by the in vitro investigations. To determine how these therapies can have a favourable impact on CVDs, there is an urgent need for accurate case controls and effective interventional trials
Ahmed and Tanwir[25]	2015	Stated that the risk for myocardial infarction was significantly increased among subjects with PD with a crude OR of 1.49 (95%CI: 1.21–1.83). When edentulous participants (patients: 12; controls: 4) were excluded from the analysis of periodontal status, the corresponding prevalence was 41% vs 33% and the OR for myocardial infarction risk was 1.46 (95%CI: 1.19–1.80). Following statistical adjustments for confounders (diabetes mellitus, smoking habits, years of education, and marital status) and including edentulous participants, there was still a positive association between PD and the risk of myocardial infarction with an OR of 1.28 (95%CI: 1.03–1.60)
Rydén et al[26]	2016	Stated that periodontal inflammatory response could exacerbate vascular inflammation via secreted cytokines that ultimately modulate atherosclerosis and CVD. The inflammatory cytokine IL-6 and TNF-α, and CRP levels in serum increased are associated with CVD and periodontal diseases. Periodontal intervention had a positive impact on the established risk factors for CVD to reduce inflammatory responses. Periodontal intervention studies have strengthened the evidence for an association between periodontal disease and CVD, and have also indicated a causal link
Chen et al[27]	2017	Undertook a study investigating the association between PAOD and periodontal diseases. They concluded that the data is consistent with a connection between periodontal diseases and PAOD. Additional research on the temporal relationship between periodontal diseases and PAOD as well as randomized controlled intervention trials looking at the causative role of periodontal diseases in PAOD is required
Kaschwich et al[28]	2019	HbA1c and smoking history were found to be reliable indicators of adults in the United States with a specificity of 67.6% and sensitivity of 70.0% for moderate-to-severe PD
Montero et al[29]	2019	A study was conducted to establish and evaluate a predictive model for adult Americans with moderate-to-severe PD. Data from the National Health and Nutrition Examination Survey cycle of 2011–2012 were used in the study. The results of their investigation showed that, as per the Centers for Disease Control/American Academy of Periodontology categorization, there were 371% and 13.2% of people with moderate and severe PD, respectively. HbA1c and smoking history were found to be reliable indicators of adults in the United States with a specificity of 67.6% and sensitivity of 70.0% for moderate-to-severe PD
Kang et al[30]	2019	Performed a study to ascertain whether periodontal diseases and other CVD risk factors or prevalence had an independent association. Their investigation made use of the Korea National Health and Nutrition Examination Survey's representative details. They discovered that as PD severity increases, the percentage of participants with high FRS and/or prevalent CVD increases. The FRS according to the severity of PD rose in people without prevalent CVD, and they concluded that PD was linked to CVD in the Korean population. Therefore, people with PD in particular young adults with severe PD-may need to have their risk for CVD constantly evaluated
Voinescu et al[31]	2019	Performed a systematic review to update the degree of evidence that connects periodontal disease and CVD. Despite significant methodological heterogeneity and the lack of randomized research, they discovered a strong link between CVD and periodontal pathology in 17 of the examined studies. Although the underlying mechanism was still not conclusively established, they concluded that there is a connection between periodontal and CVD
Sadiqa and Cheema[32]	2020	Conducted a review of the literature and discovered a brief description of the aetiology, pathophysiology, importance of the relationship, and common mediators of CVDs and PD. Epidemiological research confirmed that persistent PD plays a causal role in CVDs. Atherosclerosis has been associated with periodontal flora and the toxic substances it produces. The aetiology of heart and vascular diseases was significantly influenced by common immune-inflammatory mediators

ACVD: Atherosclerotic cardiovascular disease; AF: Atrial fibrillation; CVD: Cardio-vascular disease; CRP: C-reactive protein; FRS: Framingham Risk Score; HbA1c: Glycated hemoglobin; IL: Interleukin; LPS: Lipopolysaccharide; OR: Odds ratio; PAOD: Peripheral artery occlusive disease; PBMC: Peripheral blood mononuclear cell; PD: Periodontitis; TNF-α: Tumour necrosis factor alpha.

EPIDEMIOLOGY OF THE PERIODONTAL DISEASES

The presence of the disease, its extent (the total number of teeth or sites affected), and its severity (pocket depth or attachment loss) are all included in the epidemiology of periodontal diseases.

Risk factors and risk indicators are important variables studied in the epidemiology of periodontal diseases. The risk factors include poor oral hygiene, systemic diseases (such as diabetes, and CVDs), local irritants, oral pathogens, etc. The risk indicators that are associated with periodontal disease but not etiologically involved include age, race, gender, or socio-economic status. Various criteria were used to determine the prevalence of chronic PD, which include morphological changes and clinical findings. The morphological changes include pocket probing depth and clinical attachment loss (CAL). In the clinical findings, gingival bleeding and the presence of calculus were used.

Based on CAL, periodontal diseases are categorized as mild, moderate, or severe. Apical 2 mm to cementoenamel junction, alveolar bone attachment loss is mild type, while up to 4-5 mm attachment loss is considered moderate, and more than 5 mm attachment loss is considered severe PD. Early detection of risk factors targeted at patients who have shown mild attachment loss to prevent further progression of PD is helpful.

The periodontal diseases are prevalent throughout the world. It is believed that PD is a disease that causes inflammation in the tissues that support teeth. Specific microorganisms resulting in periodontal tissue destruction and alveolar bone loss are the causative agents that lead to pocket formation and attachment loss. This concept paved the way for understanding PD as an infectious disease that is the main causative agent of adult tooth loss. Scientific evidence was scarce to prove the correlation between microorganisms and periodontal diseases until the mid-twentieth century. On clinical impression, it is stated that periodontal diseases occur as a consequence of local factors.

Epidemiological studies were limited until the mid-1950s. However, in 1955, an epidemiological study stated that periodontal diseases were the main cause of tooth loss. This study further establishes that gingivitis leads to destructive periodontal diseases. In the advancing age, gingivitis progresses to chronic destructive periodontal disease and leads to tooth mobility. The results also indicate that PD is widespread in adults above 35 years. It was postulated that even a few years of bad oral hygiene might lead to destructive periodontal diseases.

An experimental study on gingivitis was conducted in 1965 to determine how oral hygiene affects the progression of gingivitis. The participants in the study showed the danger of neglecting oral hygiene, resulting in the accumulation of plaque and the development of gingivitis at different rates. These results develop a hypothesis of cause-and-effect associations that plaque is responsible for periodontal diseases.

This hypothesis was proved wrong by studying a population with plaque accumulation for a long time, but not resulting in periodontal diseases and tooth loss. This diversity led to a study focusing on the high-risk group and individual models to identify believable risk factors for periodontal diseases. The most common risk factors identified include diabetes and smoking, which were widely accepted as risk elements for the advancement towards PD.

PERIODONTAL HEALTH AND CVDS- DISTRIBUTION OF RISK FACTORS

Smoking

One of the major preventable causes of human disease is smoking. Smokers not only develop a variety of pathological conditions but also have a significantly increased hazard of all-cause mortality. A firm and direct causal relationship between the prevalence and the severity of periodontal diseases and smoking exposure has already been strongly established. Even though oral bacterial infections are the primary cause of PD, on the other hand, smoking is possibly the most important behavioral risk element for the development and progression of the disease. The commonest risk factor associated with CAD is smoking, and it continues to be the major preventable cause of mortality globally. Cigarette smoke is a composition of chemical substances which are either free in the gas phase or enclosed in aerosol particles. It has been estimated to have over 7000 chemical substances, including at least 72 carcinogens[33]. CVDs are common comorbidities in obstructive sleep apnea patients[34]. It has been linked to a higher risk of heart attack, CHD, arterial hypertension, stroke, and heart failure[35].

It is still unclear exactly what components of cigarette smoke cause inflammation on a local and systemic level. As an active component of tobacco smoke, the bacterial endotoxins found in tobacco can withstand combustion[36]. Thus, it could be one of the many pathogenic substances that contribute to the inflammatory response activated by cigarette smoke.

Diabetes mellitus

The evidence not only indicates that diabetes increases the severity of chronic gingivitis and PD, but it is also a major risk factor[37]. Diabetes is a condition that increases microbially initiated periodontal degeneration. Gingivitis and PD are two essential oral signs in the diabetic individuals. Individuals with unidentified or inadequately managed type 1 and type 2 diabetes are more susceptible to periodontal diseases. Numerous studies have indicated a correlation between diabetes and a higher vulnerability to oral health conditions, including PD.

Many studies also reported that in diabetic patients, there are abnormalities in neutrophil adhesion, phagocytosis, chemotaxis, and bacterial death that compromise the host's ability to fight against microbial infections. This reduced neutrophil chemotaxis is linked with increased periodontal disease severity. The consequence of periodontal bacterial infection in diabetics results in impaired function of polymorphonuclear leucocytes. This is due to the lipopolysaccharides, which alter oxidative burst potential to reduce mortality. Low opsonic antibody production in the pocket may be caused by the high prostaglandin E2 Levels in the gingival crevicular fluid of diabetic patients. In diabetics, the connective tissue metabolism can delay wound healing and ultimately increase the periodontal disease severity. PD in diabetics possesses an abnormal monocyte phenotype that may make the disease more susceptible to severe cases[37].

Contrarily, chronic PD might be a potential risk factor for poor glycemic control in patients suffering from diabetes and might increase the prospect for diabetic complications. Similar to obesity, chronic PD might also initiate and propagate the insulin resistance by increasing the activation of the systemic immune response as a whole, which is induced by cytokines, for example, prostaglandins (prostaglandin E2), interleukins (ILs), and the tumour necrosis factor alpha (TNF-α)[38,39]. All mediators are equally important in the inflammation of periodontal tissues and show effects on lipid as well as glucose metabolism, especially after an acute infectious hazard and trauma[40-42]. It has been found that TNF-α is an insulin antagonist and interferes with lipid metabolism[43,44]. The prevalence of CVD, such as CAD and congestive heart failure is higher in patients having diabetes and they are at the greatest risk of death[45,46]. The inflammatory responses are correlated with the variations in a broad array of pro-inflammatory cytokines and plasma proteins. The concentration of a wide range of plasma proteins, referred to as acute-phase proteins, can increase or decrease in response to inflammation as part of the systemic reaction known as the acute-phase response[47]. These pro-inflammatory cytokines are produced at every stage of the inflammatory process and are the main stimulants of acute-phase proteins and other chronic inflammation markers that are frequently found in rheumatoid arthritis, osteoarthritis, diabetes mellitus, periodontal diseases, and other conditions[48,49].

Hypertension

One of the most prevalent of all CVDs is hypertension which has values greater than 140 mmHg for the blood pressure in its systolic level and/or greater than 90 mmHg for blood pressure in its diastolic level[50]. Hypertension is strongly associated with the incidence of adverse cardiovascular events, for example, myocardial infarction, peripheral artery disease, heart failure, stroke, sudden death, and end-stage renal disease[51,52]. Consistent observational data indicate that severe PD is correlated with a higher risk for future CVDs, irrespective of conventional risk factors, including obesity and smoking[53,54]. The interplay between bacterial load and host immune response is the most persuasive biological condition linking chronic PD to a number of chronic systemic diseases like obstructive sleep apnoea, diabetes mellitus, Alzheimer’s disease and CVDs[53,55]. A number of research studies seem to support an association between hypertension and chronic PD[56-59]. Since, hypertension is a complex and multifactorial disease hence no single clear mechanism will entirely explain the blood pressure rise[60]. The development of hypertension is implicated in endothelial dysfunction (as shown by changes in the endothelin and nitric oxide), inflammation and oxidative stress.

HOST FACTORS

Diminished immune response to bacterial infection results in periodontal diseases

Active neutrophils mediate tissue destruction in localized aggressive PD. Periodontal diseases are linked to IL-1 gene polymorphism; therefore, the presence of pathogens linked to specific IL-1 genotypes is associated with an increased risk of periodontal disease in smokers.

It has been observed that IL-1 genotype and smoking are responsible for up to 80% of periodontal disease in a population studied by Kornman et al[61].

According to research done by Guzman et al[62], there is a relationship between diabetic patients' IL-1 genotype and periodontal diseases. However, another study carried out by Meisel et al[63] showed that there is no effect of IL-1 genotype in non-smokers for acquiring periodontal disease. However, there are no sufficient studies carried out to know the possible or conclusive link to the correlation between chronic PD risk and the IL-1 genotype. Periodontal diseases might be the outcome of complicated interactions between environmental and genetic factors, as suggested by the potential link between IL-1 genotype, smoking, and diabetes.

Alcohol

Similar to smoking, alcohol consumption might be associated with chronic PD irrespective of oral hygiene level, contrary to other studies indicating that periodontal diseases are the result of self-negligence due to excessive alcohol consumption[64-66]. Many a times, the information on the effect of alcohol use that may not necessarily reach alcoholism levels is generally overlooked. Alcohol can affect periodontal tissues through many pathways. There is evidence that alcohol consumption adversely affects the host defense mechanism through complement deficiency, defective neutrophil function and higher incidence of infections[67,68]. Alcoholics frequently exhibit increased gingival inflammation, reddish-blue discoloration, and bleeding on probing. Alcohol intake generally disrupts protein metabolism and tissue healing. Alcoholics frequently have a history of combined vitamin B-complex and protein deficiencies. According to in vitro research, ethanol inhibits the formation of new bone and also stimulates bone resorption[69]. Lastly, alcohol may directly affect the periodontal tissues[70]. In our own study, the percentage of the case group was considerably greater than the control group and showed a marked variation between the two groups[71]. Increased consumption of alcohol was correlated with a higher risk of CVDs mortality, obstructive sleep apnoea, and osteopenia[72]. The risk of these diseases is increased because alcohol intake lowers genioglossal muscle tone, predisposing patients to upper respiratory collapse and generally increasing the upper airway resistance[73,74]. High alcohol consumption also contributes to dietary energy intake and hence is a risk factor for CVD[75].

Recommendations

Patients with chronic PD and a diagnosis of CVD should be informed that they may be at higher risk for subsequent CVD complications, and therefore, they should regularly adhere to the recommended dental therapeutic, maintenance and preventive regimes.

Patients collect a careful history to assess for CVD risk factors, such as diabetes, obesity, smoking, hypertension, hyperlipidemia and hyperglycemia. Patients suggest that the patient consult his/her physician if any of these risk factors are not appropriately controlled.

Oral health education should be provided to all patients with PD, and a tailored oral hygiene regime, including twice-daily brushing, interdental cleaning and, in some cases, the use of adjunctive chemical plaque control, may be appropriate.

CONCLUSION

The comorbidity of CVD & PD is supported by several studies, although the strength of their conclusions is constrained by flaws in study design, unreliable measurement, and small sample sizes. Depending on population variables and case criteria for PD, relative risk estimates vary between researchers. Given the common inflammatory nature and underlying pathologies, the present review suggests a robust, possible existing association between chronic PD and CVDs (Figure 1).

Figure 1 Pathophysiological correlation between periodontal disease and cardiovascular diseases. CAD: Coronary artery disease; DM: Diabetes mellitus; MI: Myocardial infarction; OSA: Obstructive sleep apnea.