Degree in Dentistry Final Degree Project To what extent does Periodontal therapy may help against patients suffering from Cardiac disease and Periodontitis: A Systematic Review

Abstract

Objectives:

The objective of the present study is to investigate the relation between cardiovascular disease and Periodontitis and to find out if Periodontitis is a Risk factor for cardiovascular disease (CVD). In addition, the aim is to find out if Periodontal therapy can improve therefore the cardiac health of patients with cardiovascular illnesses such as Myocardial Infarction (MI) or coronary artery disease (CAD).

Materials & Methods:

For the systematic review, the recommendations of the PRISMA method were applied and the electronic research of the databases Web of Science and PubMed were used including the keywords.

Results:

Herby 4 Randomized Clinical trials which completely fullfeed the inclusion criteria were applied and the indications & assessment of Periodontal therapy on adults suffering from cardiovascular diseases and Periodontal diseases were compared for each Value (CRP, IL- 6, HDL. LDL, PD) in a follow up of 3- 6 months.

Conclusion:

Periodontitis is an independent risk factor of cardiovascular disease and the usage of Periodontal treatment could benefit by promoting endothelial function.

In addition, Periodontal treatment can be used as Primary & secondary Prevention against Patients suffering from CAD or MI.

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Resumen

Objetivos:

El objetivo del estudio es investigar la relación entre la enfermedad cardiovascular y la periodontitis y averiguar si la periodontitis es un factor de riesgo de enfermedad cardiovascular (ECV). Además, el objetivo es averiguar si la terapia periodontal puede mejorar la salud cardíaca de los pacientes con enfermedades cardiovasculares como el infarto de miocardio (IM) o la enfermedad de las arterias coronarias (EAC).

Materiales y métodos:

Para la revisión sistemática se aplicaron las recomendaciones del método PRISMA y se utilizó la búsqueda electrónica en las bases de datos Web of Science y PubMed incluyendo las palabras clave.

Resultados:

Se han empleado 4 ensayos clínicos aleatorizados que cumplieron completamente con los criterios de inclusión y se compararon las indicaciones y la evaluación de la terapia periodontal en adultos que padecían enfermedades cardiovasculares y enfermedades periodontales para cada valor (CRP, IL-6, HDL. LDL, PD) en un seguimiento de 3 a 6 meses.

Conclusión:

La periodontitis es un factor de riesgo independiente de las enfermedades cardiovasculares y el uso del tratamiento periodontal podría beneficiarse al promover la función endotelial. Además, el tratamiento periodontal se puede utilizar como prevención primaria y secundaria contra pacientes que sufren de CAD o MI

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Keywords

Periodontitis, Biofilm, Chronic Periodontitis, Heart, Cardiac, Periodontal Therapy

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1

1. Introduction

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Around 7 million individuals die each year as a result of cardiovascular diseases (CVD). The causes of cardiovascular illnesses are characterized by several variables. Hereby many risk factors of Cardiac Diseases are already known like Physical inactivity, Tobacco intake, Hypertension, cholesterol and poor Nutrition.

However, there are more Risk factors which might influence the cardiac state and must get into considerations (1). For example, increased systemic inflammation markers, as assessed by high levels of C-reactive protein (CRP) and interleukin- 6 (IL-6), have also been associated to an increased risk of cardiovascular disease and Periodontitis (2). Therefore, scientists have investigated these systemic inflammation markers and compared them to other Diseases to find out if there might be an interrelation between an existing cardiac disease and another localized or generalized disease. Hereby a lot of attention was received to the link between Periodontal and Cardiovascular disease, because they both share the same risk factors (i.e., smoking, age, diabetes, etc.). and show similar etiologies (2). According to the systemic inflammation markers, more markers like the Heat shock protein and the serum Lipid level were investigated and discovered to contribute to the worsening of the Cardiac health. At the same time, these markers were also found in high quantities in patients suffering from Periodontitis (1). A recent meta-analysis has identified substantial connections between periodontal disorders and CVD, indicating that periodontal inflammation might be a CVD risk factor. Beside the inflammation markers, also certain Oral Bacteria which are normally found in Periodontitis cases, are contributing to the worsening of the Cardiac health (2). Therefore, scientists were wondering if Periodontal Therapy might solve Cardiac Diseases which are related to Periodontitis.

The aim of the present study is to investigate the relationship between cardiovascular disease and Periodontitis and to find out if Periodontal therapy can improve the cardiac health of patients with cardiovascular illnesses such as Myocardial Infarction (MI) or coronary artery disease (CAD).

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3 1.1 Periodontitis

"Periodontitis" derives from the Greek term "periodontium," (peri) which means

"surrounding¨, (odont) the tooth." The gum (gingiva), the bone, the anchoring fibers, and the anchoring structure on the surface of the root are all part of the periodontium, which holds the tooth in the jawbone (cementum). The periodontium covers the whole root of a healthy tooth (3). In the case of Periodontitis, the bacteria accumulate in the gum pockets around the tooth and causes tissue degradation between the tooth surface and the gingiva. It is a common Oral inflammatory condition that worsens with age (4) and exists in various types. Each type shows different degrees of severity and progression period.

1.1.1 Types of Periodontitis

According the Periodontitis, there are multiple types of Periodontitis with different characteristics.

Aggressive periodontitis: This type of gum disease affects people who are otherwise healthy. The rapid loss of gum attachment, persistent bone degeneration, and familial aggregation are all symptoms for aggressive Periodontitis (5). The Progression of this inflammation occurs faster than in chronic Periodontitis.

Necrotizing periodontitis: This kind of periodontal disease is particularly common in those who have systemic illnesses including HIV, immunosuppression, or malnutrition. The periodontal ligament, alveolar bone, and gingival tissues all experience necrosis (5).

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Chronic periodontitis: It is the most prevalent type of Periodontitis found in the population. In this type of Periodontitis, the inflammation around the tooth causes a gum recession. Herby the gingiva around the tooth starts retracting apically (towards the root of the tooth). As a consequence of this retraction the tooth appears to look longer and loses a high amount of attachment to its surrounding tissues. In the worst case, the tooth will get too loose and must get extracted. Our current study will focus on this type of Periodontitis in relation to the Cardiac Diseases (5).

1.2 Cardiovascular diseases

There are many kinds of cardiovascular heart diseases with different etiologies.

Evidences show that the Oral bacteria, due to a Periodontitis Infection, can reach through the bloodstream to the arterial walls and cause blockage. Therefore, the cause of certain cardiac disease like Arteriosclerosis, MI or CAD might be due to the cause of Periodontitis (1). In this study we want to focus on the most common heart diseases: coronary artery disease and Myocardial Infarction which are associated to Periodontitis

Myocardial Infarction

A myocardial infarction (often referred to as a heart attack) is a life-threatening disorder caused by a shortage of blood supply to the heart muscle. Blood flow problems can be caused by a variety of things, but the most common reason is a blockage in one or more of the heart's arteries. The affected cardiac muscle will begin to die if there is no blood supply. A heart attack can result in irreversible cardiac damage and death if blood flow is not restored soon (6).

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5 Arteriosclerosis

Atherosclerosis , sometimes called hardening of the arteries, can slowly narrow the arteries throughout the body (7). The formation of fatty plaques, cholesterol, and other compounds in and on the artery, walls cause atherosclerosis, which is a particular kind of arteriosclerosis caused by the deposition of fatty plaques, cholesterol, and other things in and on the artery walls. It can be caused by smoking, a poor diet, or a variety of hereditary factors. Coronary artery disease (CAD) and stroke are caused by it (8).

Coronary Artery Disease

Coronary Heart Disease is caused when the arterial walls of the coronary arteries get blocked by fatty plaque(atherosclerosis). Therefore, as a consequence the blood cannot flow through the arteries and cannot supply the heart. Finally, this can lead to a heart attack (8)(7).

1.3 Epidemiologic Evidence of the relationship between Periodontitis and Cardiovascular disease

3,9 million European citizens in Europe are dying each year due to cardiovascular diseases. In addition, the senior population is growing rapidly. Because this demographic group is growing in size and because more older people are dentate than in the past, Periodontitis is becoming more common in this patient group (9).

Therefore, in the last 10 years, scientists started researching more precisely on the link between PD and CVD. During these years, many recent studies have found out, that there is strong evidence from epidemiological research between PD & CVD (10). A comprehensive analysis found six case–control and cohort studies that showed people with clinically confirmed periodontitis or more severe periodontitis have a higher risk of a first coronary incident than patients without periodontitis or less severe periodontitis (10). Herby high levels of antibodies against periodontal bacteria were found. In addition, atheromatous plaque

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(Atherosclerosis) was found in the coronary arteries. According to demographic characteristics and periodontitis case criteria, relative risk estimates differ between research. Another study found a link between periodontitis and and increased risk of cardiovascular death, due to coronary heart disease (10).

Research suggests that inflammation would play an important role in the pathogenesis of both diseases. In addition, the elevation of systemic markers is considered among the risk factors for CVD (1). In this study we will investigate specifically the CRP, IL-6, Serum Lipid Level & Heat Shock Protein Markers.

Furthermore, interventional studies have shown that periodontal therapy might help to lower systemic inflammation. Through the therapy, it is possible to lower the number of periodontal bacteria which might be responsible for the plaque formation on the endothelial walls of the Heart (3). Additionally, periodontal therapy may enhance endothelial function while also lowering cytokines linked to atherosclerosis (2). A randomized clinical trial has shown that through the use of Diode Laser Therapy, the gingival pocket depths got significantly reduced and therefore also contributes to the lowering of the total count of periodontal bacteria during a 3-month observation period (11). Depending of the severity and progression of the Periodontitis, different Periodontal Therapies are available. In this study we will investigate specifically the CRP, IL-6, Serum Lipid Level.

1.4 Systemic Mediators of Inflammation

C- reactive protein (CRP)

Increases in systemic inflammatory markers have been linked to periodontal inflammation. The liver produces CRP as a plasma protein in reaction to inflammation. It is considered that its primary purpose is to activate the complement system. As a result of acute inflammation, plasma levels of CRP in humans rise rapidly, up to 1000-fold.

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It may also be used to diagnose acute myocardial infarction and cerebrovascular accidents, and it can be a marker for coronary heart disease (1). The reason for this quick rise is that hepatocytes activated by different cytokines, particularly IL- 6, boost these proteins. CRP elevation is thought to be a risk factor for atherosclerosis problems. (1).

IL-6

IL-6 is a fundamental stimulator of the acute phase response that is secreted by macrophages, monocytes, T cells, and fibroblasts. IL-6 increases synthesis and release of acute phase proteins, such as CRP, β-fibrinogen, amyloid A, C3 complement component and ceruloplasmin. Healthy people were monitored for 6 years in research on IL-6, and throughout that time, IL-6 levels were greater in patients who had a Myocardial Infarction (MI) compared to those who did not have a MI. This suggests that IL-6 levels in healthy people are an expected risk factor for future MIs (1).

Serum Lipid Level

Because of alterations in lipid metabolism, hyperlipidemia is defined as a rise in total blood cholesterol and triglyceride levels. Triglycerides are created when one fatty acid is esterified with three hydroxyl groups, and they make up the bulk of body fat. Cholesterol, on the other hand, is a steroid present mostly in animal tissues and is involved in the pathophysiology of artery atheroma. Low density lipoprotein (LDL) transports cholesterol from the liver to other tissues and is made up of both fat and protein. HDL is a protein-and-fat-rich lipoprotein that aids in the excretion of cholesterol from the liver to the gall bladder (1). Hyperlipidemia is thought to be a risk factor for CVD. LDL, which is commonly combined with animal fats, causes atherogenesis by causing lipid oxidation and lipid product buildup on artery walls. Increased blood lipid levels are a risk factor for cardiovascular disease and atherosclerosis on their own. Daily fat intake is restricted to avoid atherosclerotic CVD, and pharmacological assessments are taken to maintain a low blood level of LDL. Patients with low LDL cholesterol have a lower risk of cardiovascular disease.

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A study looked at the association between blood lipid levels and periodontal health (1). Periodontitis has been observed to raise plasma cholesterol levels by 8%. Because it has no direct impact on circulating

Lipoproteins and shields LDL from oxidation, HDL is an antiatherogenic lipoprotein. Periodontitis has been linked to an increase in atherosclerosis due to a reduction in HDL's antiatherogenic action. HDL levels in people with periodontitis were shown to be low in one investigation, but they restored to normal after periodontal treatment. Individuals with deep periodontal pockets had increased LDL levels too. Researchers conclude that Periodontal bacteria and their products are thought to enter the bloodstream and trigger the immune system, affecting serum lipid and proinflammatory cytokine levels (1).

Heat Shock Protein

Infection and disease are extremely stressful on the human cells. When a cell is under stress, it naturally increases the production of stress proteins, including heat shock proteins such as HSP60 (11)(1). The heat shock response is a homeostatic mechanism that protects a cell from damage by upregulating the expression of genes that code for HSP60. The upregulation of HSP60 production allows for the maintenance of other cellular processes occurring in the cell, especially during stressful times. They can also serve as virulence factors against certain bacteria species. Hsp60 is excreted by cells when they are subjected to trauma or oxidative stress. Endothelial dysfunction and atherogenesis are caused by a cross interaction between bacterial heat shock protein in endothelial cells (GroEL) and human heat shock protein 60 (HSP60) (11). Immune responses against HSPs caused by Mycobacterium TB, Chlamydia pneumoniae, Helicobacter pylori, and Escherichia coli have been linked to CVD. However, Bacterial Heat shock proteins have been identified as a periodontal pathogen (1).

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1.5 Oral Bacteria linked to cardiovascular diseases

Periodontal bacteria are anaerobic and facultative gram-negative bacteria, such as Porphyromonas gingivalis (P. gingivalis), Prevotella intermedia (P.

intermedia), and Aggregatibacter actinomycetemcomitans. They can grow in deep gingival pockets (A. actinomycetemcomitans) (1). Various toxic chemicals generated by particular subgingival plaque bacteria, as well as bacterial plaque and its metabolites, cause damage to periodontal tissues (11). This can lead to a worsening of the Periodontium due to the direct bacterial process (for example, bacterial enzyme activity). Bacterial DNA from Tannerella forsythia, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia was discovered in atherosclerotic plaques. Finally,

“Vascular endothelial activation" can be used to explain the fundamental process of inflammatory-induced atherosclerotic plaque development.

Lipopolysaccharides, bacterial outer membrane vesicles, fimbriae, and other bacterial antigenic features can enter the bloodstream through an ulcerated periodontal pocket epithelium (11). Then they behave as antigens, affecting the host's local and systemic response. This causes endothelial cell receptors to be upregulated, followed by monocyte vascular wall adherence. Monocytes travel into the subendothelial region, where they absorb LDL cholesterol and transform into foam cells. Lipids accumulate in the vessel wall after apoptosis and are covered by a matrix, which is followed by a smooth muscle cell proliferation driven by invasive periodontal infections. Plaque rapture and exposure of prothrombotic components resulting in subsequent thrombus formation, eventually leading to blood artery blockage. As a consequence, people with cardiovascular disorders require therapy for oral cavity diseases as well as active promotion of periodontal disease prevention (11).

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10 1.6 Periodontal Therapy

There are many different surgical and non- surgical ways of treatment to control the periodontal state of a patient. Each periodontal treatment has the aim to clean the pockets around teeth and prevent damage to surrounding bone. In addition, the aim is also to lower the periodontal bacteria in the oral mouth (11). Through the lowering of the periodontal bacteria, we might achieve an Improvement of the cardiac health by preventing the periodontal bacteria to enter the bloodstream and cause plaque formation (11). Depending on the degree of severity of Periodontist there are various periodontal treatment options available.

Gum Graft Procedure

In the case of a gum recession, the tooths gets exposed. Therefore, the root of the tooth is more visible and more susceptible to bacteria. A Gum graft surgery is a surgical therapy that would cover the exposed root, preventing further recession and bone loss (12).

Mechanical Debridement

Another Option would be the use of mechanical debridement of the tooth. Hereby the tooth surface gets mechanically cleaned from deposits, biofilm, and toxins.

Using machine and manual instruments is the most basic nonsurgical therapy for periodontitis (11).

Root Scaling

In the case of Root Scaling, the dentist will scrap the tooth surfaces sub gingivally using manual curettes. Through this method even hard tartar can be removed. In addition, it also reduces the inflammation but does not totally remove it. In deep pockets, furcation zones, and root depressions, its usefulness is restricted (11)(12).

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11 Diode Laser

Bacteria and poisons may be effectively removed using diode lasers. A diode laser can expedite wound healing, facilitate collagen production, accelerate angiogenesis, and enable hemostasis, in addition to antibacterial and detoxifying actions. They also have the benefit of requiring less anesthetic and causing less postoperative discomfort as compared to hand instruments. (11) (12).

Periodontal Pocket Procedures

The dentist folds back the gum tissue and eliminates disease-causing bacteria before putting the tissue into place during a periodontal pocket operation. In other situations, the injured bone's irregular surfaces are smoothed to restrict the locations where disease-causing germs can hide. This permits the gum tissue to reconnect to the healthy bone more effectively (12).

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2. Justification, Objectives

and Hypothesis

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13 2.1 Justification

Normally the body's natural defenses and good oral health care, such as daily brushing and flossing, keep bacteria under control. However, without proper oral hygiene, bacteria can reach levels that might lead to oral infections like Caries or Periodontitis for example. The Public must become aware of the importance of the oral hygiene and the impact of the oral health on the whole body. In addition, they must become more conscious of the Oral Health and understand the relation between Periodontitis and Heart Diseases. Therefore, periodic checkups at the dental clinics are essential. The article will provide Importance of Oral Health and clarify more how to treat patients suffering under CVD and are exposed to Periodontitis. Through the Periodontal Therapy, Life Expectancies of populations may increase and heart diseases could get more under control.

2.2 Hypothesis

Adults with Myocardial Infarction or CAD who suffer Periodontitis will have a considerable improvement in their cardiac health if they undertake periodontal therapy.

2.3 Objectives

The main objective of this systematic review is to analyze the relation between Periodontitis and Heart Diseases.

The specific objectives are:

- to evaluate if Periodontitis is an independent novel risk factor for incident of cardiovascular disease

- to evaluate if Periodontal Therapies can improve the cardiac health of an adult suffering under MI or CAD and chronic Periodontitis.

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3. Materials and Methods

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15 3.1 Protocol

This study was planned and prepared in accordance with the principles outlined by the PRISMA declaration for the production of systematic reviews and Meta- Analyses.

3.2 Search Strategy

The electronic search was conducted on 2 databases: PubMed & Medline (through the Universidad de Europea de Valencia (UEV) interface. Furthermore, an online search was conducted with the help of the search engine Google, aiming for reliable Journals about the Relation of Periodontitis and Heart Diseases. Herby the World Journal of Stomatology & Journal of Periodontology were used as sources. The gathering of reliable sources was performed from November 2021 to March 2022.

The following key words and Boolean operators used for the study were:

(Periodontitis) OR (Biofilm) OR (Chronic Periodontitis) AND (Heart) OR (Cardiac) And (Periodontal Therapy)

Data Base Search Filters Date

PubMed (Periodontitis) OR (Biofilm) AND (Cardiac) OR (Heart) AND (Periodontal Therapy)

Clinical Trial, Randomized Controlled Trial, Less than 5 years,

March 2022

Web of Science (Periodontitis) OR (Biofilm) AND (Cardiac) OR (Heart) AND (Periodontal Therapy)

Clinical Trial, Randomized Controlled Trial, Less than 5 years,

March 2022

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16 3.3 Selection Criteria

According to the Selection Criteria, the following inclusion criteria were determined using the PICO (Patients; Intervention; Comparison; Outcomes) method. (P) Patients: Adults suffering from Periodontitis & have a cardiovascular disease. (I) Intervention: Periodontal therapy (C) Comparator: Compared with Adults who also express same diseases but don’t undergo Periodontal Therapy (O) Outcomes: Assess changes of cardiac state of Intervention group after Periodontal Therapy.

To assure greater validity criteria, the final papers were chosen using the Critical Appraisal Skills Program (CASP) Randomized Controlled Trial Standard Checklist. In addition, animal studies & any duplicate studies were excluded in the research.

3.4 Inclusion & Exclusion Criteria

We have included studies if they fulfill the following criteria: English language, article which are 5 years old or less, Clinical Trials, Controlled clinical trials &

Randomized controlled trials

We have excluded studies: systematic reviews, Meta Analysis & Books/

Documents. In addition, animal studies & any duplicate studies were excluded in the research.

3.5 Study Selection Process

To select a reliable and eligible article, the articles were filtered by the eligibility criteria. Therefore, first the title of the article was screened. Afterwards the structure of the Article was checked. Hereby it was examined if the article has included an Abstract, Introduction, Materials, Results and Conclusion. In addition, duplicated studies were excluded in the research. Following that, studies that met the eligibility criteria were added after a full-text review.

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17 3.6 Data Extraction

Using a data extraction form, we independently extracted data. When available, the following data were gathered on a standard form for each of the identified studies that were included: Authors / year of publication, Type and aim of study, Presence of Cardiovascular disease, Intervention of Periodontal Therapy, age and sex of participants, assessment duration, sample size, periodontal and heart disease evaluation values after Periodontal Treatment were also collected.

3.7 Quality Assessment

According to the quality of the studies, the Critical Appraisal Skills Program (CASP) Randomized Controlled Trial Standard Checklist was used (Table 4).

Hereby the criteria are individually assessed for ever study and answered with YES, NO or CAN`T TELL.

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4. Results

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19 4.1 Selection of studies. Flowchart

During the Research a Total amount of 113 articles were collected, of which 63 came from Web of Science and 50 Articles from PubMed.

Afterwards before continuing with the Screening of the articles, were excluded 11 articles which were duplicated. In the screening process we used 103 articles and evaluated the title and abstract. 79 articles were excluded in this process, because most titles were not matching at all with the objectives of the present study. In addition, in some articles the abstract was incomplete and was therefore not reliable. The remaining articles were then sought for retrieval and assessed for eligibility. At this point all articles which expressed a significant amount of Bias or used a very small quantity of participants were sorted out. In Total 4 articles matched the inclusion criteria.

All Articles which were included at the end of the Selection process were Randomized controlled trials. The selection process is collected through the following Flow Chart 1. One study was hold in China, another study in Italy and the other three included studies are from Brazil. Although no new studies were found, a cross-search was conducted to locate research using other methods such as websites, organizations, and citation searches

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Flowchart 1: Identification of studies via databases and registers

Studies included in review (n =4)

Reports of included studies (n = 0)

Identification of studies via databases and registers

Screening

Records screened by title and abstract

(n =103)

Records excluded (n =79)

Reports sought for retrieval (n =24)

Reports not retrieved (n =20)

Reports assessed for eligibility

(n = 4) Reports excluded:

Reason 1 (n = 0) Reason 2 (n = 0) Reason 3 (n = 0)

IncludedIdentification

Records removed before screening:

Duplicate records removed (n =11)

Records marked as ineligible by automation tools (n = 0) Records removed for other reasons (n = 0)

Records identified from Databases:

PubMed (n =50) Web of Science (n= 63)

Total of Registers (n =113)

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4.2 Analysis of the characteristics of the studies reviewed

All 4 Randomized clinical trials (21, 15, 2, 13) are evaluating the impact of the Periodontal therapies on the cardiovascular state of the Participants. Herby the variables: CRP (C-reactive protein), LDL (low-density lipoproteins), HDL (High- soluble- density lipoproteins), IL-6 (Interleukin- 6) and PD (Probing Depth), are evaluated before and after the Periodontal treatment of the Participants. The Systematic review gathered in total an amount of 306 patients ranging from the age of 18- 71 years old. Each study is presenting Adults who are suffering from Periodontitis and Cardiovascular disease. All Participants are undergoing a Periodontal treatment to evaluate in how far the values of the CRP, LDL, HDL, PD and IL- 6 changed and could benefit the cardiac health (21, 15, 2, 13). In 2 randomized clinical trials, smokers and diabetic patients were also put as Participants (15, 2). The follow ups of the studies were ranging from 1 month until 6 months. In the study of Qian Bing et al., prehypertensive patients with Periodontitis were undergoing intensive Periodontal treatments with a follow up of 1,3,6 Months (21) In the study of Marco et al., patients with stable coronary disease and Periodontitis were undergoing non- surgical Periodontal Treatment with 3 months Follow up (15) In the study of Marlon et al., patients with stable coronary disease and Periodontitis were divided in 2 groups. One group (Test Group) received non-surgical Periodontal treatment whereas the other group (Control Group) received a session of plaque removal. The follow up were in 3 months (2). The Randomized clinical trial from Marcelo et., studied patients with a recent myocardial infarction and severe periodontal disease undergoing Periodontal treatment with a follow up measured at baseline and after 3 months (13). All studies performed Root scaling & planing and in 2 studies (2,15) the Treatment period was 14 days and in the other 2 studies it was 4 weeks (13, 21).

All general characteristics of the included Randomized controlled trials were put in Table 1. Furthermore, the Authors, Publication country, type of study, total participants, gender proportion, average age and topic of Investigation are listed.

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Table 1: Showing General characteristics of all included Randomized controlled trial

Autor / Date

Country Type of study Total Participant s / Group A

& Group B

Gender Proportio n (M: F)

Average Age

Investigation

Qian-Bing

et al.

(2017)

China Randomized

controlled trial

Total:107 Group A: 54 Group B: 53

56:51 39,5 Effect of Intensive

Periodontal Therapy on Blood Pressure and Endothelial

Microparticles in

Prehypertensive Patients with Periodontitis

Marco et al. (2018)

Brazil Randomized controlled trial

Total: 69 Group A: 38 Group B: 31

52:17 59 Evaluate the effects of periodontal treatment on endothelial function in patients with coronary artery disease

Marlon et al. (2019)

21:61 59 Evaluate effect of

periodontal treatment on cardiovascular risk biomarkers in patients with stable coronary artery disease

Marcelo et al. (2020)

34:14 53 Investigate the impact of periodontal treatment in patients with a recent myocardial infarction and

severe periodontal

disease

Table 2: Variables affecting the Cardiac state used in each study

Autor / Date Variables Evaluated

Qian-Bing et al. (2017) CRP, LDL, HDL, PD, IL- 6

Marco et al. (2018) CRP, LDL, HDL, PD

Marlon et al. (2019) CRP, LDL, HDL, PD, IL- 6 Marcelo et al. (2020) CRP, LDL, HDL, PD

(CRP, C- reactive protein; LDL, low density lipoprotein; HDL, High density lipoprotein; PD, Probing Depth; IL-6, Interleukin 6)

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Table 3: Periodontal Treatment & period used for each study

Author/date Treatment type Treatment Period Qian-Bing et al. (2017) Scaling and root planing Maximum 4 weeks

Marco et al. (2018) Scaling and root planing Maximum 14 days Marlon et al. (2019) Scaling and root planing Maximum 14 days Marcelo et al. (2020) Scaling and root planing Maximum 4 weeks

4.3 Risk of BIAS assessment

In the study of Qian Bing et al., the prehypertensive patient’s Blood pressure values could only be measured in office and not 24 hours ambulatory in home (21) Therefore, the Blood pressure value cannot be of complete validation and was therefore taken out of the systematic review due to high risk of Bias.

Additionally, there were concerns about bias in 2 studies (15, 2) which included Smokers and diabetic patients in their study. These two categories of patients are also recognized as risk factors for cardiovascular diseases and may affect the systemic markers of inflammation (CRP & IL-6) evaluated in the study.

Additionally, the sample size of 2 studies (15, 13) were not high and an increase of the sample size could alter the observed finding and is therefore likely for bias.

In the study of Marco et al., the participants of the Treatment group were also measured in FMD (Flow mediated vasodilation) but due to the reason that they were undergoing cardiovascular treatment apart from the study, the FMD cannot be of complete validation and was also taken out of the systematic review (15).

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Table 4 is a checklist for Randomized Controlled Trials, involving prompt questions to help evaluate the research studies according their quality.

Table 4. CASP checklist for Randomized Controlled Trials.

Qian- Bing et al.

(2017)

Marco et al.

(2018)

Marlon et al.

(2019)

Marcelo et al.

(2020)

Did the study address a clearly focused research question?

Was the assignment of participants to interventions randomized?

Were all the participants who entered the study accounted for at its conclusion?

a. Were the participants “blind” to intervention they were given?

b. Were the investigators blind to the intervention they were giving to participants?

c. Were the people assessing/analyzing outcome/s “blinded”?

Were the study groups similar at the start of the RCT?

Apart from the experimental intervention, did each study group receive the same level of care (that is, were they treated equally?

Were the effects of intervention reported comprehensively?

Was precision of the estimate of the intervention or treatment effect reported?

Do benefits of the experimental intervention outweigh the harms and costs?

Can the results be applied to your local population/in your contest?

Would the experimental intervention provide greater value to the people in your care than any of the existing interventions?

YES CAN’T TELL NO

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25 4.4 Results of the individual studies

In the Table 5, the results of each study are listed before the Intervention of Periodontal Therapy at Baseline. Hereby the variables evaluated are CRP, LDL, HDL, Il-6 and PD, because they all can be used as Inflammation markers and may have correlation to the Cardio vascular diseases and Periodontitis. Each study represents a Treatment group and a Control group.

Table 5: Results of studies at Baseline

Study Group CRP

(mg/l)

LDL (mmol/l)

HDL (mmol/l)

IL- 6 (pg/ml)

>4mm PD (in %)

Qian-Bing et al.

(2017)

Control Group (n= 54)

3,37mg/l average

1,58 mmol/l average

3,39 pg/ml average

47 %

> 4mm PD

Treatment Group (n=53)

3,20mg/l average

1,58 mmol/l average

3,26 pg/ml average

49 %

> 4mm PD

Marco et al. (2018) Control Group (n= 38)

51 %

< 3mg/l

5,1 mmol/l average

2,16 mmol/l average

---

3,07 mm average

Treatment Group (n= 31)

48,4 %

< 3mg/l

5,4 mmol/l average

2,2 mmol/l average

---

3,22 mm average

Marlon et al.

(2019)

4,82mg/l average

5,2 mmol/l average

2,16 mmol/l average

8,73 pg/ml average

3,11mm average

5,75mg/l average

5,0 mmol/l average

2,1 mmol/l average

6,20 pg/ml average

3,33 mm average

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26 Marcelo et al.

(2020)

0,52mg/l average

10,6 mmol/l average

2,3 mmol/l average

2,3

pg/ml ---

0,34mg/l average

8,3 mmol/l average

2,5 mmol/l average

3,5 pg/ml

75 %

> 4mm PD

(Normal values: CRP 0,1- 3.0; HDL 1,03- 1,89; LDL 0- 3,37; PD <4mm; IL 5-15)

In the Table 6, the results after the Periodontal therapy and a follow up of 3 months are listed for each variable

Table 6: Results of studies after 3 months

Study Group CRP

(mg/l)

LDL (mmol/l)

HDL (mmol/l)

IL- 6 (pg/ml)

>4mm PD (in %)

Qian-Bing et al. (2017)

3,49 mg/l

average --- ---

3,44 pg/ml average

15 %

> 4mm PD

Treatment Group (n=53)

2,54 mg/l

average --- ---

2,86 pg/ml average

18 %

> 4mm PD Marco et al.

(2018)

--- --- --- ---

3,16 mm average

--- --- --- ---

2,27 mm average

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27 Marlon et al.

(2019)

5,28mg/l average

5,16 mmol/l average

2,2 mmol/l average

11,87 pg/ml average

3,27mm average

3,26 mg/l average

5 mmol/l average

2,16 mmol/l average

4,11 pg/ml average

2,43 mm average

Marcelo et al. (2020)

--- ---

--- --- ---

---

--- ---

11 %

> 4mm PD (after 6 months)

--- (Green indicates decrease of value compared to Baseline)

--- (No color indicates no change of value after 3 Months compared to Baseline)

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28 4.5 Synthesis of Results

All 4 Randomized clinical trials evaluated the outcome of Periodontal treatment on adults with a cardiac disease. Both tables with each 4 studies were compared before and after 3months of Intervention. Hereby all significant changes of values in the Table 6 were marked in Green. Each study always represented a Treatment and a Control group.

2 studies evaluated participants who suffer from Periodontitis and Cardiac disease (13, 2). The other 2 studies concentrated only on participants who suffer from cardiovascular diseases like coronary artery disease and hypertensive patients (21, 15). The results showed a significant decrease of Periodontal pocket depth after 3 months of Periodontal treatment (21, 15, 2, 13) in Table 6. No matter whether the Periodontal treatment was invasive or non-surgical, they all contributed well to a decrease of the Periodontal pocket in the Treatment Group.

In addition, 2 studies evaluated the outcome of the CRP Value at the Baseline 3,2 mg/l & 5,75mg/l (Table 5) of the Trials and after 3 months (21,2) shown in Table 6. They found out that the CRP value decreased to 2,54mg/l & 3,26mg/l when compared from the Baseline and after 3 months (21, 2). In two studies, the inflammation maker IL- 6 was also taken into account and the values of the Treatment Groups here also decreased from 3,26pg/ml & 6,2pg/ml (Table 5) to 2,86pg/ml & 4,11pg/ml (21,2). On the other hand, one study showed that the only values which didn’t express any changes during the 3 months of trial were HDL and LDL (2) shown in Table 6.

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5. Discussion

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Our systematic review is analyzing the relationship between Periodontitis and Cardiovascular disease and the aim is to find out if the collected evidence is convincing enough to establish Periodontitis as an independent Risk factor for cardiovascular diseases and furthermore conclude if a Periodontal treatment could improve the Main Risk factors of a Cardiac disease and therefore improve the cardiac state of a Patient. The research done in our study only include most recent and reliable studies which all are Random clinical trials. All study achieved similar outcomes during their trials. According to the findings of all articles, they all have as a common result the decrease of the Periodontal depth which is due to the bacterial elimination inside the periodontal pockets around the teeth (21,15,13,2). Even in Participants which do not express characteristics of Periodontitis achieve a decrease of their Periodontal depth (2,15). Herby, Marco et al. discovered that a non-surgical periodontal therapy benefits more according the elimination of periodontal inflammation and recovering clinical attachment level, than a supragingival plaque removal (15). The diminution of the Periodontal depth would be the first main step to achieve to ensure that the Inflammation level in the bloodstream decreases. The periodontal bacteria should be prevented then to enter the bloodstream and the CRP levels of the Participants who suffer from Periodontitis and Cardiac Disease showed significant decrease of CRP levels after Periodontal treatment (21,2). The Follow up in all studies was a minimum of 3 months and the Treatment Group was compared to the control group (21,15,13,2) Marlon et al. confirmed, that the CRP level could be the most important Risk factor out of all the system mediators of inflammation such as IL- 6 or the serum lipid level, because it has a main role as a determining factor in the development of atherosclerosis (2). CRP is able to attenuate the bioavailability of nitric oxide in endothelial cells via impaired endothelial nitric oxide synthase (eNOS) mRNA expression and stability, decreasing protein expression and enhancing oxidative stress which accelerate Nitric oxide degradation (2). Herby it is important to mention, that nitric oxide is essential for overall health, because it allows blood, nutrients and oxygen to travel to every part of the body effectively and efficiently (2). In a randomized clinical trial, the prehypertensive Participants who participated, did not take any antihypertensive

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treatment and only got treated by intensive mechanical Periodontal treatment (21). Important to know that the Participants also expressed Periodontitis in the Treatment Group and Control Group. Therefore, they do all suffer from Periodontitis. The CRP is significantly gone down after 3 months of follow up in the Treatment Group 2,54mg/l compared to the Baseline 3,2mg/l. Herby it is also important to mention that these Participants did not undergo any antihypertensive medication nor any other cardiovascular treatment (21). Apart from the decrease of the CRP also the IL-6 got lowered from 3,26pg/ml to 2,86pg/ml.

Therefore, it can be suggested to prescribe Periodontal treatments during secondary preventions. Intensive periodontal therapies may be an effective non pharmacologic intervention to reserve the decline in endothelial function (21). In comparison to that, in the study of Marco et al., is showing all participants who express a chronic CVD like coronary artery disease but not Periodontitis. In this case, even though the Treatment Group do not suffer from Periodontitis, they all experienced an improvement in the Periodontal depth and also in CRP, IL-6 after non-surgical periodontal therapies. Nevertheless, it must be mentioned that all participants in this study also undergo cardiovascular treatment apart from the study (15). Therefore, the Periodontal therapy only showed small success in the improvement & stabilization of the Inflammation markers during the 3 months (15). Apart from that, another randomized clinical trial evaluated the same phenomenon as the previous study and the participants who suffer from coronary artery disease also don’t express Periodontitis (2). In addition, the majority of participants were non-smokers or former smokers, well controlled for LDL and total cholesterol and did not undergo cardiovascular treatment. Therefore, potential Bias can be excluded. Only non-surgical periodontal therapy was done on the treatment group and the values have improved CRP and IL-6 pretty well (2). On the contrary, the control group who did not get treated, even show a slightly increase of CRP & IL-6. This study shows that especially the great and significant decrease of IL- 6 from Baseline 6,2 pg/ml to 4,11 pg/ml (after 3 months) might proof a success of the Periodontal treatment (2). It is important to know that IL- 6 play an important role in the adaptive immune response.

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Therefore, a decrease of IL- 6 indicates a diminution of risk to achieve a future Myocardial Infarction. Periodontal therapy can show here a great affinity in cases of secondary prevention to CVD to avoid the recurrence of major cardiovascular events in CVD patients by the reduction of the systemic inflammation (2). These findings suggest that the Periodontal treatments can serve as a potential risk modifier in stable coronary artery diseases (2). In contrast to the stable coronary artery disease, the findings of Marcelo et al. are evaluating participants with a recent Myocardial infarction and Periodontitis. (13). In this case the Cardiac state is not as stable as compared to the previous studies. Herby the values have been achieved in the Periodontal depth of the treatment group which has improved around 64 % in the last 6 months of follow up after non-surgical Periodontal therapies. In addition, no adverse effects have been detected during the treatments (13). Herby an important advice of the study is to avoid surgical periodontal therapies on patients suffering from CVD, because there is a high risk of adverse effects. In the hours and days following periodontal therapy, it may cause an increase in inflammation and a decrease of endothelial function. These side effects have been linked to temporary bacteremia that can develop when a periodontitis patient's mouth is surgically treated. While these physiological reactions were not linked to overt clinical outcomes in healthy people, patients with cardiovascular illnesses may be more susceptible to these effects due to their own cardiovascular conditions (13). Except the adverse effect of surgical periodontal therapy on CVD patients, non-surgical periodontal therapy could offer a unique way to contribute to the improvement of cardiovascular outcomes in individuals with a recent MI because periodontal disease might promote or worsen cardiovascular disorders by its contribution to the inflammatory milieu (13). In addition, the study concentrated on doing several Periodontal therapy sessions through a staged approach instead of single session periodontal therapy (13). By executing a staged approach, the participants can receive a potential advantage by getting explained more frequently the preventive measures and there might be less acute trauma to the patient because on each session there will be treated one quadrant instead of all quadrants at the same day (13).

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Limitations of the studies and results

Although all 4 random clinical trials achieved positive results about the indication of Periodontal treatment in adults suffering from CVD and

Periodontitis or only suffer from CVD, it is also important to mention that there are limitations according the sample sizes in one trial, which showed a low number of participants in the study. An increase of the sample size could alter the value results (13).

In addition, the amount of reliable and up to date studies until the year 2022 is limited to 4 random clinical trials which mostly showed a follow up of until 3- 6 months. Herby A one-year follow-up would be preferable since improvements in endothelial function might still occur during this time.

Another limitation of all the studies is the interpretation of the important

inflammation marker CRP. Herby it is important to clarify that the CRP value is used as the golden standard measure, however it also has get criticized since it is a nonspecific measure of inflammation that may or may not be connected to the patient’s cardiovascular condition.

In addition, another limitation is the usage of Medications against

Cardiovascular diseases. to minimize Bias and alteration of the inflammation markers, the participants should avoid the usage of any CVD Medication, but on the other side this could get into conflict with the ethical values.

If further studies consistently identify periodontal disease as a risk factor for CHD and treatment trials indicate benefit, the consequences for public health are enormous, because periodontal disease is usually preventable and curable when not prevented. Furthermore, effective preventative dental care offers several other advantages, particularly in terms of quality of life.

Implications for future research

Based on this present research as a fundament, further research has to be done to clarify which type of Periodontal Treatment can be more effective to treat cardiovascular diseases.

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6. Conclusion

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Based on the results of the present study it can be confirmed that Periodontitis is a novel risk factor in Patients with Coronary artery disease or recent Myocardial infarction since the CRP & IL- 6 Level is always higher in the control group and significantly lower in the Treatment Group after Periodontal Therapy even though in some studies the Participants didn’t even have Periodontitis.

Furthermore, the usage of Periodontal therapies has shown great success in Adults with Cardiovascular diseases and with or without Periodontitis.

Therefore, Periodontal therapies might be used as primary or secondary Prevention treatment on patients suffering from Cardiac diseases because in patients with cardiovascular diseases the higher severity of periodontal disease, poor oral hygiene, and increased periodontitis activity may contribute to more systemic inflammation and therefore Adults with Myocardial Infarction or CAD might have a considerable improvement in their cardia health if they undertake Periodontal Therapy.

However, since the investigations and studies about this topic are new, further investigations should be done and it's crucial to investigate more in studies with an increased sample size and longer Follow ups. In addition, different types of Periodontal Therapy should be included in studies to compare which Treatment could be the most beneficial to improve the cardiac state.

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36 7. Acknowledgements:

I would like to thank Prof. Dr. Israel A. González Ramírez for his great help and advices during the process of the study .

Competing interests:

There was no competing interest during this study.

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8. Bibliography

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5. Mymed.com [Internet]. Penny Theodoulou [actualized 15 January 2022];

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9. Prasad D, Deepti G, Rohit M. The link between periodontal disease and cardiovascular disease: How far we have come in last two decades? 2010 Jul;14(3):148-54.

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16. Krutika Y, Jaideep M, V M Kurian. The Periodontal‐Cardiovascular alliance: Evaluation of miRNA‐146a in subgingival plaque samples of chronic periodontitis patients with and without coronary heart disease. J Investig Clin Dent. 2019; 10(4): e12442.

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1 Annex 1: Prisma Checklist for systematic reviews

Section and Topic

Item

# Checklist item

Location where item is reported TITLE

Title 1 Identify the report as a systematic review. Page 0

ABSTRACT

Abstract 2 See the PRISMA 2020 for Abstracts checklist. Page 0

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of existing knowledge. Page 2- 11

Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses. Page 13

METHODS

Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses. Page 16 Information

sources

6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.

Page 15

Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used. Page 16 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record

and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

Page 16

Data collection process

9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

Page 17

Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

Page 17

10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.

Page 17

Study risk of bias assessment

11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

Page 17

Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results. / Synthesis

methods

13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

/

13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

/

Degree in Dentistry Final Degree Project To what extent does Periodontal therapy may help against patients suffering from Cardiac disease and Periodontitis: A Systematic Review