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Review

Association between periodontal disease and its treatment,ow-mediated dilatation and carotid intima-media thickness: A

systematic review and meta-analysis

Marco Orlandi a , *

, Jeanie Suvan a, Aviva Petrie b, Nikolaos Donos a, Stefano Masi c,Aroon Hingorani d, John Dean eld c , 1, Francesco D ’ Aiuto a , 1

a Unit of Periodontology, UCL Eastman Dental Institute, 256 Gray ' s Inn Road, London WC1X 8LD, United Kingdomb Biostatistics Unit, UCL Eastman Dental Institute, 256 Gray ' s Inn Road, London, United Kingdomc Vascular Physiology Unit, Great Ormond Street Hospital, 34 Great Ormond Street, London, United Kingdomd Faculty of Population Health Sciences, Institute of Cardiovascular Science, UCL, 1 e 19 Torrington Place, London, United Kingdom

a r t i c l e i n f o

Article history:Received 6 April 2014Received in revised form27 May 2014Accepted 4 June 2014Available online 17 June 2014

Keywords:Cardiovascular diseasePeriodontitisCarotid intima-media thickness

Flow-mediated dilatationEndothelial function

a b s t r a c t

Objective: This meta-analysis sought to investigate the association between carotid intima-mediathickness (c-IMT), ow-mediated dilation (FMD) and periodontitis (PD) and to assess the effect of periodontal treatment on c-IMT and FMD.Methods: Electronic database searching, hand searching of bibliographic references of included papers,related reviews, and journals in relation to oral, cardiovascular and ultrasound imaging eld was carriedout. Random effects meta-analyses were performed to investigate the association of co-existence of increased c-IMT, impaired FMD and PD with potential changes in these variables following periodontalintervention.Results: 2009 citations and 101 full text articles were screened, with 35 meeting the review inclusioncriteria of which 22 suitable for quantitative analysis. Meta-analysis demonstrated that the diagnosis of

PD was associated with a mean increase in c-IMT of 0.08 mm (95% C.I. ¼ 0.07 e 0.09) and a mean dif-ference in FMD of 5.1% compared to controls (95% C.I. ¼ 2.08 e 8.11%). A meta-analysis of the effects of periodontal treatment on FMD showed a mean improvement of 6.64% between test and control (95%C.I. ¼ 2.83 e 10.44%).Conclusions: This review demonstrated an association between increased c-IMT, impaired FMD and PD.Data from intervention studies suggested a bene cial effect of periodontal treatment on FMD indicatingan improvement in endothelial function. The ndings support investigation of periodontitis treatment oncardiovascular outcomes.

© 2014 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.1. Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.2. Study inclusion/exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.3. Search and screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.4. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Data extraction and synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Descriptive results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding author. Tel.: þ 44 20 3456 1276; fax: þ 44 20 3456 1137.E-mail address: m.orlandi@ucl.ac.uk (M. Orlandi).

1 These authors equally contributed to the manuscript.

Contents lists available at ScienceDirect

Atherosclerosis

j ou rna l homepage : www.e l sev i e r. com/ loca t e / a the rosc le ros i s

http://dx.doi.org/10.1016/j.atherosclerosis.2014.06.002

0021-9150/©

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3.1.1. PD and c-IMT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1.2. PD and FMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.2. Bias assessment protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.3. Quantitative results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.3.1. Mean c-IMT value in individuals with or without PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.3.2. Mean FMD values in individuals with or without PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.3.3. Effect of periodontal therapy on EDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6. Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Abbreviation list . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

Periodontitis (PD) is a chronic oral in ammatory disease initi-ated by the accumulation of a bacterial bio lm on the tooth surfaceand perpetuated by a deregulated local and systemic immune-in ammatory response [1]. Along with dental caries they repre-sent the two major global oral health burdens of our society, withsome forms of PD being detectable in 20% e 50% of the generalpopulation [2] . Inparticular, PD shares a number of risk factors withother non-communicable diseases, including cardiovascular (CV)diseases.

Numerous epidemiological studies have investigated the natureof the association between PD and CV diseases, focusing primarilyon the role of common in ammatory pathways [3] linking the twodiseases, however whether the association is causal is still a matterof debate [4] .

Several studies have reported an association between PD and

increased carotid intima-media thickness (c-IMT), a non-invasivetechnique, which has been shown to correlate with the individualCV risk factor burden as well as the risk of future CV events,including coronary artery disease and stroke [5] . Similarly, severalstudies have reported associations between PD and endothelialdysfunction which occurs at the early stages of atherogenesis asassessed by ow-mediated dilatation (FMD) [6] .

We have undertaken a systematic review and meta-analysisbased on the following question: “ What is the association be-tween PD and vascular function as assessed by c-IMT and FMD andwhat is the impact of PD treatment on these variables in adultsuffering from PD? ”

2. Methods

2.1. Scope

The purpose of the review was to investigate, by means of ameta-analysis: i) whether current data support an association be-tween PD, increased c-IMT and impaired FMD, ii) whether peri-odontal treatment has any effect on these variables and iii) tosummarize the existing evidence of an association between PD (theexposure) and vascular alterations (the outcomes).

PD was de ned to include any measure of disease according toclinical, radiographic and microbiological assessment (includingpocket Probing depth, clinical attachment level, bleeding onprobing, plaque index, gingival index, X-ray and microbiological

results).

Surrogate markers of CV disease eligible for inclusion were: B-ultrasound measurements of c-IMT, expressed as Mean (SD) andFMD as Mean (SD) of the percentage of the brachial artery dilationfollowing the hyperemia induced by 5 min cuff occlusion. Thesample comprised individuals aged 17 years.

2.2. Study inclusion/exclusion criteria

Broad inclusion criteria were set to search for human observa-tional and experimental study designs (cross-sectional, case-control, population surveys, cohort studies, pilot studies,controlled trials and randomized controlled trials).

Comments, letters, editorials, casestudiesand series, newsitems,abstracts not followed by publication and consumer health materialwere excluded, as were studies performed in animals, duplicatedreports, studies providing associations between different markers of CV disease or particular pathogens involved in PD and CV disease,

studies de ning endothelial function with different methodologythan FMD and those providing the IMT in other vascular beds.

2.3. Search and screening

The search strategy was developed using medical subjectheadings (MeSH terms) as well as free text terms and wascustomized as appropriate before application to each database (seeexample in supplemental Table 1).

All publication years through 31st of January 2014 wereincluded. No language or year restrictionswere applied. In addition,bibliographic references of the identi ed papers and previous re-views were hand searched. Online hand searching of issues withinthe past 10 years of some periodontal, CV and imaging journals was

also performed ( supplemental Table 2 ).Two investigators (MO, JS) independently screened titles/ab-

stracts and full text articles were subsequently assessed from thefollowing databases:

F0A7 The Cochrane Oral Health Group 's Trials Register, (wholedatabase to current date)

F0A7 The Cochrane Central Register of Controlled Trials (CENTRAL,whole database at current issue)

F0A7 MEDLINE via OVID, (1946 to present)F0A7 EMBASE via OVID, (1980 to present)F0A7 SCI-EXPANDED via Web of Science, (1900 to present)F0A7 LILACS via VHL, (1982 to present)F0A7 System for Information on Grey Literature in Europe (Open

SIGLE, 1980e

2005)

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The present article was written according to the PRISMA(Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [7] .

2.4. Quality assessment

Cohort, case-control and cross-sectional studies were assessed

for quality using the validated Newcastlee

Ottawa Quality Assess-ment Scale [8] (Table 1 ).

2.5. Data extraction and synthesis

Data was extracted from all included studies independently andin duplicate (MO, JS). Disagreements were resolved through dis-cussion with a third person (FD).

Data were analyzed using descriptive (evidence tables insupplemental material ) and quantitative (meta-analysis) methods.Statistical analyses were performed using Stata v 11 (StataCorp.2007, TX: StataCorp LP.). Mean differences in both c-IMT and FMDwere used to perform meta-analyses of the difference in individualswith PD compared to controls in observational and intervention

studies. If data were not available in the publications, the missinginformation was obtained directly from the authors. Heterogeneitywas assessed using the c 2-based Q-statistic method and consid-ered signi cant if p < 0.05 and quanti ed with the I-squared sta-tistic [9] . The pooled estimates of the mean differences werecalculated using random effects models to take into account po-tential inter-study heterogeneity and to adopt a more conservativeapproach. The pooled effect was considered signi cant if p < 0.05.Small study bias was examined using a funnel plot and Egger 's test.Sensitivity analyses were performed to understand the in uence of individual studies, by omitting one study each time in a series of meta-analyses to identify in uential studies.

3. Results

2066 hits were obtained from electronic searches and 2 paperswere located from online and hand searching of mentioned jour-nals of interest. Following removal of 59 duplicates, 2009 poten-tially suitable titles and abstracts were screened. After excluding

1906 non-relevant citations, 101 publications were selected andretrieved for full-text review ( Fig. 1).

Among these full text articles and abstracts, 66 were excluded.This resulted in a total of 35 publications eligible to be included inthe systematic review. Of these, 22 papers were included in themeta-analyses. 6 publications did not contain the full informationnecessary for the meta-analyses [10 e 15] , however it was possibleto obtain the required data from the authors. All 35 studies reportedevidence on an association between investigated CV diseasemarkers and PD.

3.1. Descriptive results

3.1.1. PD and c-IMT 26 publications included measures of c-IMT of which 25 were

observational studies ( Supplemental Table 3 ) and 1 interventiontrial ( Supplemental Table 4 ). There was considerable variation interms of de nition of PD, observed population, study sample size,age range, carotid segments studied and de nition of c-IMTamongthe studies. 16 publications were included for further analysis as 10did not provide estimates that were comparable to the other

studies. The de nition of the carotid segments was the majorsource of heterogeneity. Only one uncontrolled longitudinal studyevaluated the impact of periodontal treatment on c-IMT in in-dividuals with mild or moderate PD. After a follow up of 6 and 12months this study showed a reduction of c-IMT compared to theBaseline measurements [16] .

3.1.2. PD and FMDThe relationship between PD and FMD was investigated in 10

articles of which 3 were observational ( Supplemental Table 5 ), and7 intervention studies ( Supplemental Table 6 ). 2 randomizedcontrolled trials were excluded for the meta-analysis as endothelialfunction was assessed using acetylcholine [17,18] and one inter-vention pilot trial had no control group [19] .

Table 1Quality assessment observational studies (Newcastle e Ottawa Scale).

Selection Comparability Exposure Overall

Case-control c-IMT Leivadaros 2005 *** ** *** ********(8/9)Soder 2005 **** *** *******(7/9)Soder 2007 **** *** *******(7/9)Cairo 2008 *** ** *** ********(8/9)Lopez J 2012 *** *** *****(6/9)Zahnd 2012 *** ** *** ******(6/9)Puhar 2012 *** *** ******(6/9)Cross-sectional c-IMT Beck 2001 *** ** *** ********(8/9)Franeck 2006 *** *** ******(6/9)Li X 2009 *** *** ******(6/9)Ylostalo 2010 *** * *** *******(7/9)LI P 2011 *** *** ******(6/9)Vieira 2011 *** * *** *******(7/9)Franek 2012 *** ** *** ********(8/9)Pinho 2013 *** **Hayashida 2013 *** *** ********(8/9)Case-control-FMDAmar 2003 ** ** *** ********(8/9)Ruiz 2013 *** *** ******(6/9)Cross-sectional-FMDLi 2011 *** *** ******(6/9)

Fig. 1. Flow chart of the study selection procedure.

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3.2. Bias assessment protection

According to the Newcastle e Ottawa Quality Assessment Scale,the majority of the studies were categorized as low or medium riskof bias ( Table 1 ). There was a discrepancy in the periodontal di-agnoses, de nition of controls and not a uniform adjustment forpotential confounders. In case-control studies, individuals includedin control groups were recruited from hospital rather than from thecommunity, introducing a possible selection bias. All cross-sectional studies were considered comparable in quality and thesame was for controlled trials.

3.3. Quantitative results

3.3.1. Mean c-IMT value in individuals with or without PD7 out of 10 case-control studies comparing differences in c-IMT

between individuals with and without PD were included in ameta-analysis [13,15,20 e 24] . 3 publications were excluded; 2papers reported data on the same population analyzed in previ-ous publications [25,26] and 1 study resulted biased in the se-lection of controls [27] . 9 out of 15 cross-sectional studies

[10 e 12,14,28 e 32] were suitable for a meta-analysis. 6 studieswere excluded for the following reasons: 1 performed analysis onthe same sub-sample of another included study [33] , 3 related c-IMT to antibody levels of periodontal pathogens [34 e 36] , 2calculated c-IMT values across quintiles or tertiles of periodontalde nitions [37,38] . Li P. et al. [29] assessed c-IMT in two differentsamples, individuals with or without metabolic syndrome andwith or without PD. We therefore considered the data as 2separate studies. In some of the included studies, individuals weredivided in different groups according to PD severity. In this case,the severe PD group was chosen for the analysis. The mean dif-ference in c-IMT values in the individual studies ranged from -0.04 mm to 0.19 mm. Adopting a random-effects model ( Fig. 2), ameta-analysis (2021 cases, 3431 controls) indicated a higher c-IMT in individuals with PD (0.08 mm 95% CI [0.07, 0.09], p < 0.0001) compared to controls. A chi-squared test for hetero-geneity and the I-squared index did not show statistically signif-icant heterogeneity ( p ¼ 0.922 and I 2 ¼ 0%). Funnel-plot analysis(Fig. 3A) did not show evidence of bias using the Egger test of symmetry ( p ¼ 0.876) and sensitivity analysis did not suggest thepresence of in uential studies.

3.3.2. Mean FMD values in individuals with or without PDDifferences in FMD (%) between individual with or without

PD, reported by 3 observational studies [29,39,40] and baselinedata from 3 controlled trials [41 e 43] , were included in the meta-analysis. Li P. et al. assessed FMD in two different samples, in-dividuals with or without metabolic syndrome and with or

without PD [29] . We therefore considered the data as 2 separatestudies. Individual studies mean difference in percentage of endothelial dependent dilatation (EDD) ranged from 1.59% to12.48%.

In individuals (155 subjects) with PD, FMD was lower on averageby 5.1% (95% CI 2.08, 8.11], p < 0.001) compared to controls (136subjects) ( Fig. 4). A chi-squared test for heterogeneity and the I-squared index indicated that there was statistically signi cantheterogeneity ( p ¼ 0.000 and I 2 ¼ 80.1%).

Funnel-plot analysis ( Fig. 3B) suggested asymmetry that couldbe evidence of publication bias, although the Egger test ( p ¼ 0.43)did notsupport this, possibly because of lowpower due to the smallnumber of studies. The funnel plot asymmetry may be attributed tothe high heterogeneity among the studies. A sensitivity analysis did

indicate that there were not any in uential studies.

3.3.3. Effect of periodontal therapy on EDDIt was possible to analyze the summary difference in mean

FMD (%) between test and control after periodontal treatment in3 of 6 controlled trials [41e 43] (147 individuals) ( Fig. 5). Meanimprovement in FMD after periodontal intervention ranged fromto 3.7 e 9.3%. The overall summary estimate of the mean increasein FMD based on a random-effects model was 6.64% (95% CI [2.83to 10.44], p < 0.0001). A chi-squared test for heterogeneity andthe I-squared index showed statistically signi cant heterogeneity( p ¼ 0.011 and I 2 ¼ 78%). The Egger test didn 't show a small studyeffect ( p ¼ 0.956) and sensitivity analysis identi ed two in u-ential studies potentially related to the small number of includedtrials.

4. Discussion

Our ndings indicate that PD is associated with greater c-IMTand impaired FMD and that periodontal treatment improvesendothelial function. Despite the number of reports on the topic,this is the rst systematic review and meta-analysis linking PD tospeci c CV surrogate outcomes in the general population. Theseassociations emphasize the importance of oral health as a commonunder-recognized factor increasing CV risk in individuals.

Our analysis relates to c-IMT measurements from 5452 (2021cases, 3431 controls) individuals and demonstrates that those withPD have, on average, a greater c-IMT (0.08 mm) compared withcontrols. Despite the small magnitude of this difference, currentevidence suggests that in the general population the mean esti-mates of c-IMT progression range from 0.001 to 0.030 mm per year[44] . Individuals with PD therefore exhibit greater burden of sub-clinical atherosclerosis compared to controls. Evidence suggeststhat per every 0.1 mm difference in c-IMT, the relative risk of futuremyocardial infarction increases of 1.15 times (95% CI, 1.12 e 1.17) andfor stroke increases of 1.18 times (95% CI, 1.16 e 1.21) [45] . A numberof traditional CV risk factors however are linked to c-IMT pro-gression: age, gender, systolic blood pressure, high-density lipo-

protein cholesterol, smoking, diabetes, hypertension treatment,and total cholesterol. Clearly PD shares most of these risk factorswith atherosclerosis and therefore it is dif cult to discern the po-tential impact of PD alone on the progression of c-IMT. The lack of auniform adjustment for all these confounders in the studiesincluded in our meta-analysis could have also reduced the accuracyof our results.

Despite the low level of statistical heterogeneity detected in ouranalyses (I-squared 0%) the robustness of our ndings could beaffected by differences in the research protocols (i.e. clinical het-erogeneity). The diagnosis of PD and c-IMT assessment criteriavaried considerably throughout the studies included. PD wasassessed using different criteria ranging from validated clinicalmeasures such as clinical attachment level and pockets probing

depth to self-de ned criteria showing the lack of a uniform de -nition of PD [46] . It should be also considered that there is not auniform de nition of severe periodontitis included in the manu-scripts reviewed as well as based on a variety of clinical periodontalparameters with different threshold levels. This could also add ontothe variability of the results presented because the populationcombined could not be relevant to study samples of differentperiodontal severity and extent. In addition, we could not groupindividuals with PD according to disease severity (mild, moderateand severe) as in the majority of the studies such differentiationwas not performed. We therefore followed a conservative approachby comparing healthy versus severe PD individuals. This could haveresulted in an underestimation of the reported associations. As theprevalence of PD is relatively high in the general population, the

identi cation of PD subgroups at increased CV risk would help in

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reducing possible costs associated with large scale screening pro-grams and further research is needed.

We identi ed multiple sources of clinical heterogeneity for c-

IMT. A recent consensus paper [47] recommends measurement of c-IMT in plaque-free areas and we did not nd explicit statementsabout this methodological aspect in any of the studies. The recentpublication of guidelines for c-IMT measurement is likely toimprove consistency of the technique in future studies.

We identi ed only one longitudinal study evaluating the impactof periodontal treatment on c-IMT in people with mild/moderatePD. 6 and 12 months following periodontal treatment, a statisticallysigni cant reduction in c-IMT compared to baseline measurementswas reported [16] . These ndings could support a potential causalassociation between PD and subclinical atherosclerosis but theabsence of a control group, inclusion of CV disease-free individualsand the lack of multiple measurements of the carotid thickness,

make causal inferences dif cult. Findings will need to be con rmedin larger, controlled trials including a high CV risk population (e.g.greater c-IMT).

The relationship between FMDof the brachial arteryand PD wasalso an objective of the present review. FMD is related to thepathogenesis of atheroma and provides information regarding theearly stage of its evolution. Endothelial function and speci callyFMD can also predict future CV disease outcomes. A recent meta-analysis reported that for every point decrease in FMD, future CV disease risk increases of 10% [48] .

The meta-analysis gathered data from baseline measurementsof 3 controlled trials [41 e 43] and 3 observational studies [29,39,40]showing a mean difference of 5.1% in FMD in individuals with PDcompared to controls and a mean increase of 6.64% followingperiodontal treatment. We included only 3 controlled trials asstudy design and the methodology in assessing FMD differed

Fig. 3. Association between periodontitis, c-IMT (3-A) and FMD (3-B). Funnel plots of observational studies.

Fig. 2. Association between Periodontitis and Carotid Intima-Media Thickness (c-IMT) Difference of c-IMT means between individuals with periodontitis versus controls inobservational studies. Horizontal lines representing 95% CI; lower diamond represents the overall effect size, random effects models. sscase sample size cases, sscontrols sample sizecontrols.

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considerably among trials examined. Indeed FMD average baselinevalues ranged from 4.1% to 8.4%. Additional sources of variationwere identi ed including underlying health status, different eth-nicities and length of follow-up ranging from 6 weeks to 3 months.Lastly, assessment of endothelial function with FMDis notfree frommethodological, physiological and technical factors that can in u-ence the validity, reproducibility and interpretation of results inclinical research [49] . As con rmation of our cautious interpreta-tion of the evidence, a statistically signi cant high level of het-erogeneity was observed (80.1% for case-control and 78% forintervention trials).

Nevertheless evidence supporting the bene cial role of peri-odontal treatment in improving endothelial function derives from 3RCT [17,18,50] ; two of which were conducted assessing endothelialfunction with a more invasive technique (response of brachialblood ow to acetylcholine injection) and both showed a statisti-cally signi cant improvement after periodontal therapy [17,18] . Thethird one is the only RCT reporting on measure of endothelialfunction with FMD in people with severe PD [50] . Our groupconcluded that 6 months after intensive periodontal therapy(associated with a substantial improvement in the gingival condi-tion) individuals had a 2.0% rise of FMD (95% CI 1.2 to 2.8; p < 0.001)

Fig. 4. Association between Periodontitis and Flow Mediated Dilatation (FMD) Difference of the FMD means between individuals with periodontitis versus controls in observationalstudies. Horizontal lines representing 95% CI; diamond represents the overall effect size, random effects models. sscase sample size cases, sscontrols sample size controls.

Fig. 5. Association between Periodontal Treatment and Flow Mediated Dilatation (FMD) Difference of the FMD means before and after periodontal treatment in controlled clinical

trials. Horizontal lines representing 95% CI; diamond represents the overall effect size, random effects models. sscase sample size cases, sscontrols sample size controls.

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on average compared to controls. Our interpretation of these re-sults and the meta-analysis collectively supports a causal associa-tion between PD and endothelial dysfunction. Several pathwayshave been proposed to support a potential involvement of peri-odontitis in the development and progression of atherosclerosis.Firstly a direct role of oral bacteria has been hypothesized followingpathogen 's DNA being detected in atheromas [51] . Periodontalbacteria could directly invade endothelial cells and promote avascular in ammatory state [52] . In addition bacterial end-products could trigger an innate [53] or auto-immune response(HSPs auto-antigens) [54] . Secondly, patients suffering from peri-odontitis exhibit higher systemic in ammation than controls [55] .Locally produced in ammatory by-products damped into the sys-temic circulation coupled with a systemic low-grade hepatic acutephase response to periodontitis could result in a state endothelialdysfunction and further promote the atherosclerotic in ammatoryprocess [56] . Lastly, cases with periodontitis tend to show a pro-atherogenic lipid pro le including alterations of lipoprotein func-tion [57] . A recent systematic review and meta-analysis [58]con rmed that periodontal therapy improves individuals ' in am-matory and lipidic pro le, especially in those with other co-morbidities (i.e. diabetes and cardiovascular diseases). Neverthe-less the impact of periodontal therapy on the individual cardio-metabolic pro le is still a matter of debate and should warrantfurther investigation.

5. Conclusion

In conclusion this review suggests that PD is associated withgreater subclinical atherosclerosis as assessed by increased c-IMT,an independent predictor of CV events in high-risk populations.There is evidence of an impaired FMD, which is restored by peri-odontal treatment in individuals suffering from by PD. Robustprospective studies are needed to improve our understanding of the mechanisms underlying these associations. It is encouraged theuse of standardized protocols to measure both c-IMT and FMD aswell as of universally-accepted case de nitions of PD as to facilitatefurther research.

6. Contributors

MO and JS screened the titles and abstracts, assessed trials forinclusion and trial quality, and extracted data. AP performed sta-tistical analyses. MO wrote the draft manuscript. All authorscontributed to writing, reviewing, or revising the paper.

Funding

The study did not receive speci c funding.

Competing interests

All authors declare no con ict of interest, no support from anyorganization for the submitted work; Francesco D 'Aiuto holds aClinical Senior Lectureship Award supported by the UK ClinicalResearch Collaboration. Marco Orlandi holds a UCL Impact Awardpartially supported with a fellowship grant by Johnson and JohnsonConsumer Services EAME Limited. All authors work at UCL, whichreceived a proportion of funding from the Department of Health 'sNational Institute of Health Research (NIHR) Biomedical ResearchCentres funding scheme. Authors declare no relationship with in-dustry; no other relationships or activities that could appear to

have in uenced the submitted work.

Acknowledgments

We are sincerely grateful to Prof Offenbacher (University of North Carolina, Chapel Hill, NC), Prof. Loos (Academic Center forDentistry Amsterdam, Amsterdam, The Netherlands.), Prof. Pussi-nen (University of Helsinki, Finland) and Prof. Franek (CentralClinical Hospital MSWiA, Warsaw, Poland), Dr Pinho (UniversityFernando Pessoa, Porto, Portugal), Prof. Saito (Nagasaki UniversityGraduate School of Biomedical Sciences, Japan) and Dr Puhar(University of Zagreb, Croatia) for generously sharing their datawith us.

Abbreviation list

c-IMT carotid intima media thicknessCV cardiovascularCI con dence intervalEDD endothelial dependent dilatationFMD ow mediated dilatationPD periodontal diseaseRCT randomized controlled trialsSD standard deviationVRFs vascular risk factors

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.atherosclerosis.2014.06.002 .

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