Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality worldwide. It is proved with evidence gathered by several observational and clinical trials that bacteremia-induced destruction of supporting structures of the tooth such as periodontium and alveolar bone results in the initiation and progression of periodontitis. Periodontitis is related to CVD s and a risk factor for CVDs which is proved by various observational and clinical trials. It is also found that patients with CVD commonly suffer from chronic periodontitis.
Periodontitis is a chronic oral inflammatory disease which is initiated by the accumulation of a bacterial biofilm on the tooth surface and it is perpetuated by a local and systemic immune-inflammatory response (Pihlstrom BL, Michalowicz BS, Johnson NW). Various forms of periodontitis are seen in most of the adult population. The disease is characterized by chronic and progressive bacterial infection of the gums leading to loss of soft tissue attachment to the teeth followed by alveolar bone destruction.
However, many confounding factors such as social status, smoking, ageing, hypercholesterolemia, diabetes mellitus, obesity, menstrual cycle, etc., may also affect the relationship between CVD and periodontitis. Periodontitis is responsible for a low-grade systemic bacteremia and inflammation causing atherosclerosis which starts off several biochemical reactions which causes atherosclerotic plaque formation and endothelial injury. Another mechanism by which periodontitis affects cyclic vomiting syndrome is due to the toxins released by various Gram-negative bacteria involved in periodontitis which invades superficial and deeper gingival tissues, which affect endothelial function.
The vascular endothelium is the largest paracrine organ in our body. It releases vasoactive agents and thromboregulatory substances. Reduced endothelial function has been frequently observed in patients with atherosclerosis and in healthy controls who are at high risk of developing atherosclerosis. Endothelial dysfunction is considered a common precursor to and occurs before cardiovascular events. Therefore, endothelial dysfunction is the first step in atherosclerosis growth that leads to CVD.
Oral diseases are an enormous health burden to the society. Periodontitis has many risk factors including CVDs. One such risk factor is endothelial dysfunction. Endothelial dysfunction is characterized by upset of the regulation of the balance between vasodilation and vasoconstriction, inhibition and promotion of vascular smooth muscle proliferation, and prevention and stimulation of platelet aggregation, thrombogenesis, and fibrolysis by the endothelium. Chronic periodontitis results in altered vascular response, increased pro-inflammatory cytokine production, and vascular endothelial dysfunction-inducing adhesion molecules. Disturbed vascular endothelial function can be restored by periodontal therapy.
Patients with periodontitis are ideal models for determining how endothelium-dependent vasodilation is affected by inflammation and it is seen that patients with periodontitis have impaired endothelial function. The mechanism by which periodontal disease disrupts vascular homeostasis remains unclear. As no systematic review has specifically evaluated the effect of endothelial dysfunction on endothelial dysfunction, a systematic review was conducted to compare various clinical trials in this field. The purpose of this review was to evaluate the effects of periodontal therapy on endothelial function.
This systematic review is conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines and the Joanna Briggs Institute critical appraisal checklist for systematic review.
Study inclusion/exclusion criteria
Randomized-controlled trials (RCTs) on the subject were included in this review. Studies wherein periodontal therapy was done and endothelial dysfunction was checked and included.
Types of studies
- Active interventions surgical or nonsurgical periodontal therapy was done
- Control: No treatment or oral hygiene instructions were given.
Types of outcome measures
Endothelial dysfunction was assessed through
- Change in flow-mediated dilatation (FMD)
- Change in flow independent dilatation (FID)
- Change in forearm blood flow (FBF)
- Change in Pulse amplitude tonometry (PAT).
Literature search and screening strategy
The population, intervention, comparison, and outcome strategy for the systematic review with the population having a full-text manuscript in English describing in vivo analysis of the effect of periodontal therapy on endothelial dysfunction. The intervention was Studies that use supra/and subgingival scaling and root debridement, periodontal flap surgery. The comparison was done before and after intervention and the outcome of endothelial function was assessed.
The search strategy was developed using medical subject headings (MeSH terms) as well as free text terms.
All publication years up to February 29, 2019, were included. No language or year restrictions were applied.
An initial electronic search of six databases including Cochrane Library, Embase, Ebscohost, Google Scholar, and Medline using the search terms (alone or in combination) endothelial dysfunction, periodontal therapy, flow-mediated dilatation, flow independent dilatation, periodontitis were carried out. All relevant titles, abstracts were identified and retrieved by the first two authors. Potentially relevant reports identified from the reference lists of relevant studies, review articles and chapters were hand searched. The University websites were accessed to obtain relevant unpublished dissertations.
As the primary step 3006 articles were identified during a literature search from different sources. At the second level, since multiple databases were searched, a total of 1022 abstracts were identified as duplicates and were excluded which brought down the number of articles screened to 2055. Further, 928 abstracts were excluded as they were clinical case reports or literature reviews. A total of 1033 records were further screened. In the next level, 93 articles were excluded to obtain 105 full-text articles.
At this level, a total of twelve records were considered potentially eligible and sought for further assessment and full-length articles were retrieved. These full-length articles were independently reviewed by three authors with expertise in the content area so as to establish whether the studies met inclusion criteria. Eventually, 12 records were selected to be included in this review and sought for qualitative synthesis in this systematic review. Disagreements among reviewers were resolved by discussion.
Each manuscript was analyzed for methodological quality according to a prepared checklist containing 15 main items as recommended by the JBI (Joanna Briggs Institute) critical appraisal checklist for systematic reviews. Details of the search steps and the reasons for exclusion from the review were documented and are presented in [Diagram 1].
Risk of bias assessment
The risk of bias in eligible studies was assessed using the Cochrane Collaboration's Tool for randomized clinical trial. The risk of bias was assessed and recorded in Table 2.
A total of 12 clinical trial studies were included in this conducted from 2004 to 2018, 3 were single-blinded RCTs while 1 was a double-blinded randomized control trial [Table 1]. To consider for confounding factors matching was done for age, sex, smoking status, and body mass index (BMI), half of the studies were found to have done matching in all these criteria, however, the studies included in this review did not do matching between cases and controls on endothelial function levels as cases had a cases had a lower endothelial function level compared to controls at the baseline. Sample size estimation was not mentioned in any of the studies, two studies were seen to have undertaken convenient sampling and others have mentioned to have done random sampling. The analysis of these studies revealed that studies ranged from 2 months to 6 months to analyze periodontal therapy on endothelial dysfunction. A total number of 813 subjects enrolled in all these selected studies. A higher number of studies was reported from Italy and Japan.
The maximum sample size was 120. Four studies had almost equal representation of males and females. Baseline examinations done in these studies which included periodontal indicators such as plaque index, gingival index, bleeding on probing, and clinical attachment loss are some of the common periodontal parameters while the endothelial parameters were FMD, FID, FBF, and pulse amplitude tonometry. Periodontal status taken for the study included chronic periodontitis. There was a range of male-to-female ratios listed. The mean age ranged from 64.8 ± 9.7 to 40 ± 5 years and the highest BMI was 27. Inclusion/exclusion criteria were listed out by each of the included studies. Among the 12 studies, two studies of the subjects were with a history of CVD and under medication and in another two studies, the participants were known hypertensive and under medications for the same.
The common interventions given for the intervention group in all of the studies were supra or subgingival scaling and root planing with some studies providing antibiotic medications such as amoxicillin and minocycline as an adjuvant for periodontal therapy. The effect of nonsurgical periodontal therapy on endothelial dysfunction was assessed. Controls were left with either no treatment or oral hygiene instructions. Primary and secondary outcomes were listed in most of the studies with the endothelial function being the primary outcome in most of the studies and various laboratory analyses such as total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, C reactive protein, and interleukins were secondary outcome measures in most of the studies. FMD values before intervention was minimum of 8.4 ± 4.0 in and after intervention maximum was 17.7 ± 5.7. FID values before intervention was minimum of 13.3 ± 6.3 and after intervention maximum of 24.9 ± 7.3. One study used PAT to measure ED which decreased from 2.41 ± 0.71 to 2.22 ± 0.62. Two studies used FBF to measure ED which showed a change of 5.2 ± 1.3 to 5.4 ± 1.4 in one while the other showed a change of 4.5 ± 1.4 to 4.6 ± 1.5. Analysis of the outcome variable measures revealed an effect size of 0.05-1.63 for FMD, 0.28–1.5 for FID, 0.26 for PAT, and 0.06–0.14 for FBF. All included studies reported a high level of evidence (LOE) of 1c by the Joanna Briggs Institute (JBI) critical appraisal checklist for systematic reviews PICO criteria has been mentioned for effect of periodontal therapy in endothelial dysfuction [Table 3].
Risk of bias assessment
Risk of bias assessment for randomized-control trial showed that most of the studies were having an “Unclear” to “low risk of bias.” “Unclear risk of bias” was seen in “allocation concealment” and “other sources of bias.” “Random sequence generation” and “Selective reporting” demonstrated a “low risk of bias”. Sample size estimation was not mentioned in any of the included studies, this accounted for bias under other bias column. Due to the high level of bias, meta-analysis was not undertaken as the quantitative accuracy of meta-analysis cannot be accurate [Table 2].
The study reviewed whether periodontal therapy causes a change in endothelial function. Several studies have shown that there is a positive association between periodontal infection and coronary heart disease. The effect of inflammation caused by periodontal infection which causes atherosclerosis is thought to be the cause of it. Periodontitis is a disease which causes destruction of periodontal ligament and alveolar bone and is most commonly seen as a chronic disease. Periodontitis has also been found to be a risk factor for peripheral vascular diseases.
Endothelial dysfunction is seen in most patients with periodontal diseases even though clinical signs of atherosclerosis may not be found in them.Endothelial dysfunction is also seen as a precursor for atherosclerosis. Endothelial dysfunction is a significant marker in predicting CVDs due to the inability of arteries to fully dilate. Endothelial dysfunction is of significance in predicting stroke and heart attacks due to the inability of the arteries to dilate fully. Multiple conditions, including diabetes or metabolic syndrome, hypertension, smoking, and physical inactivity can cause endothelial dysfunction. Not only does the healthy endothelium arbitrate endothelial-based vasodilation, but it also actively suppresses thrombosis, vascular inflammation, and hypertrophy.
Flow-mediated dilatation is the most common tool used to measure endothelial dysfunction. The diameter of the brachial artery is measured by high-resolution ultrasound and the blood flow is increased by cuff inflation and deflation. Thus we get endothelial independent dilatation/flow-mediated dilatation. Another method is using nitroglycerine which is an endothelium-independent dilatation to calculate flow-independent dilatation/endothelial-dependent dilatation. The measurement of the dilatation is done at 3 points of time that is at baseline, during reactive hyperemia and after administration of sublingual nitroglycerine. A standard dose of 400 μ of nitroglycerine is given. The cuff is inflated for 5 min before scanning of the artery diameter is done.
Most of the studies which we selected by FehmiMercanoglu, Arnon Blum, Gerald Seinost, John R. Elter, Stefania Piconi, Maurizio S. Tonetti, Yukihito Higashi showed improvement in endothelial function, while a study by Xiao Li showed a neutral effect on endothelial dysfunction. Two studies by Yukihito Higashi measured endothelial dysfunction by forearm blood flow (FBF) which also showed improvement in blood flow after periodontal treatment in healthy and hypertensive patients. A study by Marco Aurélio studied coronary disease patients and it did not show better vasodilatation in short-term follow-up. The study by Maurizio S. Tonetti showed improvement in long-term follow-up but showed inflammation and dysfunction in the short-term. A study by JH Ramırez showed no improvement in endothelial function. The study by María C. Rubio studied patients under Angiotensin inhibitor and showed improvement in endothelial dysfunction after intensive periodontal care.
A meta-analysis was done by Wijnad et al. in 2013 and another by Marco Orlandi in 2014 while the first one was checking for the effect of periodontal treatment on the atherosclerotic profile of which endothelial function was only a part of it and the latter checked both periodontal disease and its treatments effect on flow-mediated dilatation and carotid intima-media thickness. We in our study have exclusively checked for the effect of periodontal treatment and its effect on endothelial function, unlike the other studies.
A systematic review was done by Abhijit N. Gurav et al. in 2014 which checked for periodontitis in vascular endothelial dysfunction. In this systematic review, 10 studies were taken into consideration out of which only 9 could be included in the study as 1 of the study was found to measure Cell Adhesion Molecule rather than endothelial dysfunction. In our study, we have taken studies which check endothelial function with FMD/FID or similar measurement methods like PAT index or FBF (forearm blood flow).
This study has evaluated the study design of each study, checked for matching and the sampling type, we have also specifically checked if the periodontal disease status at the baseline is mentioned for each study. The study also analyses the characteristics of cases and controls including their male: female ratio, mean age, and BMI. The analysis has been done on the intervention given and any medication the patient is on or has been given as part of the study to check for its effects. Primary and secondary outcomes are enlisted for each including lab analysis done. The measurements for endothelial function at baseline and after intervention were analyzed both for cases and controls. A detailed study like this was conducted on the effect of periodontal therapy on endothelial function for the first time to the best of our knowledge.
When analyzing the selected studies, only one study by JH Ramırez was double-blinded rest of the studies were single-blinded or did not mention blinding. This can lead to bias at different stages of these studies. The maximum duration of all the studies was 6 months and one of the studies ranged only to 2 months and 2 weeks which could have affected the results. A major drawback of these randomized control trials was that none of the studies mentioned the sample size estimation, so we do not have a clear idea of how the sample size was determined for the studies. Studies by John R. Elte and Stefania Piconi have mentioned to have done convenient sampling, i.e., they have selected the patients who came to the department and probably assigned them to the respective case and control groups. Mean age and BMI are similar in cases and controls in most of the studies which shows they have been matched in most of the studies. Inclusion and exclusion criteria were mentioned in all the studies while some studies have given medication to the participants and studies have taken hypertension or CVD patients for the study these all can have a confounding effect on the question of whether periodontal therapy affects endothelial dysfunction. Flow-mediated dilatation normal range is from 7% to 10%. One of the major drawbacks or rather limitations of most of the studies analyzed was that the FMD or FID was not matched in cases and controls for example in the study by FehmiMercanoglu the baseline FMD and FID in cases were 8.4 ± 4.0, 13.3 ± 6.3, respectively, while those in controls were 19.4 ± 8.1, 29.5 ± 10.0 which was remarkably higher than the cases, so while the cases showed an improvement in endothelial function to17.7 ± 5.7, 24.9 ± 7.3 the controls did not show any significant difference but it cannot be said to have been due to the effect of the periodontal therapy as the endothelial function in controls at baseline were already higher. This discrepancy was found in most of the studies which can have a huge impact on the results and the conclusion which we come to after analyzing the results.
While analyzing the effect size we compared the cases before and after the intervention. FMD was compared in 6 of the studies with 1.63 as the highest and 0.05 as the lowest, out of which only 3 studies showed an effect size of >0.5 below which can be attributed to having a neutral change in FMD values, but the major drawbacks of these 3 studies were found to be that the controls already had baseline FMD values significantly higher than the baseline value of cases. Hence, it cannot be concluded that the improvement in endothelial function is due to the intervention given as it was better in controls at the baseline itself. Another measuring tool was FAD and 5 studies showed the data to calculate effect size which ranged from 1.5 to −0.28. Only one study showed an effect size of above 1 which had the same drawback that the baseline FID was at 13.3% in cases, while for controls, it was at 29.5% a value significantly higher than in the cases, this showed that no matching was done between both the groups and a random sample allocation is not seen to have been done. Two studies by Yukihito Higashi measured endothelial dysfunction using forearm blood flow (FBF) which showed an effect size of less than 0.5 which can be attributed to having a neutral effect on endothelial dysfunction after periodontal therapy. These 2 studies by the same author showed a similar value for FBF in both cases and controls and has also compared CVD patients and hypertensive patients under medication for the same. Another study that used a different measuring tool was Xiao Li which used PAT which had an effect size of −0.3 showing a neutral effect in this study. A study by Stefania Piconi did not show the data obtained but said that an improvement in endothelial function and the study by Maurizio S. Tonetti which was published in the New England journal of medicine which has an impact factor of 70 showed the values in a line graph which showed a significant improvement in both FMD and FID when compared over a period of 6 months.
This systematic review showed that periodontal therapy has an effect on endothelial dysfunction at an evidence level of 1c. This study focused on periodontal therapy and its effect on endothelial dysfunction precisely and compared the levels of endothelial function before and after intervention. This review revealed that more multi-centric randomized control trials are required in this area of research with proper randomization and adequate sample size and proper matching done between cases and controls. Further also required with both cases and controls having identical endothelial dysfunction at the baselines for coming to a definite conclusion on whether there is a significant improvement in the endothelial function after periodontal therapy as mentioned by other similar studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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