Periodontal Disease Associated with Aortic Arch Atheroma in Patients with Stroke or Transient Ischemic Attack

Periodontal Disease Associated with Aortic Arch Atheroma in Patients with Stroke or Transient Ischemic Attack

ARTICLE IN PRESS Periodontal Disease Associated with Aortic Arch Atheroma in Patients with Stroke or Transient Ischemic Attack Souvik Sen, MD, MS, MP...

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ARTICLE IN PRESS

Periodontal Disease Associated with Aortic Arch Atheroma in Patients with Stroke or Transient Ischemic Attack Souvik Sen, MD, MS, MPH, FAHA,* Matthew Chung, MD,* Viktoriya Duda, Lauren Giamberardino, MHA,* Alan Hinderliter, MD,† and Steven Offenbacher, PhD, DDS‡

MPH,*

Background: Periodontal disease (PD) is associated with recurrent vascular event in stroke or transient ischemic attack (TIA). In this study, we investigated whether PD is independently associated with aortic arch atheroma (AA). We also explored the relationship PD has with AA plaque thickness and other characteristics associated with atheroembolic risk among patients with stroke or TIA. Finally, we confirmed the association between AA and recurrent vascular event in patients with stroke or TIA. Methods: In this prospective longitudinal hospitalbased cohort study, PD was assessed in patients with stroke and TIA. Patients with confirmed stroke and TIA (n = 106) were assessed by calibrated dental examiners to determine periodontal status and were followed over a median of 24 months for recurrent vascular events (stroke, myocardial infarction, and death). The extent of AA and other plaque characteristics was assessed by transesophageal echocardiography. Results: Within our patient cohort, 27 of the 106 participants had recurrent vascular events (including 16 with stroke or TIA) over the median of 24-month follow-up. Severe PD was associated with increased AA plaque thickness and calcification. The results suggest that PD may be a risk factor for AA. In this cohort, we confirm the association of severe AA with recurrent vascular events. Conclusions: In patients with stroke or TIA, severe PD is associated with increased AA plaque thickness, a risk factor for recurrent events. Further studies are needed to confirm this finding and to determine whether treatment of PD can reduce the rate of AA plaque progression and recurrent vascular events. Key Words: Ischemic stroke—TIA—atherosclerosis—thrombosis—aortic arch—coronary artery disease—periodontal disease. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

From the *University of South Carolina, Columbia, South Carolina; †Division of Cardiology, University of North Carolina, Chapel Hill, North Carolina; and ‡Department of Periodontology, University of North Carolina, Chapel Hill, North Carolina. Received March 6, 2017; revision received April 21, 2017; accepted April 29, 2017. Grant support: This study was supported by grants from the Mid-Atlantic Affiliate of the American Heart Association grant-inaid 0755464U and NIH grants M01RR00046, ULTR000083, and UL1RR025747. Address correspondence to Souvik Sen, MD, MS, MPH, FAHA, Department of Neurology, University of South Carolina School of Medicine, 8 Medical Park, Suite 420, Columbia, SC 29203. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.04.035

Introduction Stroke is the fifth leading cause of death, a leading cause of serious, long-term disability, and a growing source of health-care expenditure.1 With an aging population, the incidence of stroke is expected to increase in the future.2 To circumvent this public health issue, effort has largely been directed toward stroke prevention by addressing modifiable risk factors and early secondary prevention.2 Recommendations for modifiable risk factors for ischemic stroke and transient ischemic attacks (TIAs) have largely focused on addressing hypertension, dyslipidemia, diabetes, cigarette smoking, atrial fibrillation diet or nutrition, obesity, and physical inactivity.3 The mainstay of treatment of those with previous ischemic strokes or TIAs

Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■

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have included aggressive medical management toward secondary prevention with antihypertensive agents, antiplatelet drugs, anticoagulation therapy for history of atrial fibrillation, statins for lowering cholesterol levels, lifestyle modification (including dietary changes, smoking cessation, physical activity, and weight reduction), and carotid endarterectomy in those with severe ipsilateral carotid stenosis resulting from atherosclerosis.4 With increasing age, interplay of multiple risk factors, and genetic predisposition, atherosclerosis of small and large vessels can progress to complicated lesions with surface defects, hemorrhage, or thrombosis.5 Aortic arch atheroma (AA) is an atherosclerotic lesion located in the ascending and the arch segments of the thoracic aorta that can embolize distally to the cerebral blood vessels.6 AA plaques proximal to the origin of the left subclavian artery measuring greater than or equal to 4 mm in thickness have a high risk for embolization into cerebral blood vessels.7 These types of lesions, referred to as significant AA plaques, are the second most prevalent risk factors for embolic event after atrial fibrillation and are believed to be responsible for 16%-20% of all strokes and TIAs.8,9 These high-risk AA plaques are a risk factor for new and recurrent strokes.10,11 Alongside atrial fibrillation and carotid stenosis, AA plaque is clearly a risk for ischemic strokes; however, no evidence-based approach currently exists for treatment or prevention of significant AA.11,12 Periodontal disease (PD) is a microbial infection that destroys the attachment fibers and supporting bones that hold the teeth in the mouth. Periodontal microorganisms from the oral cavity enter the bloodstream during normal functions, such as mastication, and the magnitude of this transient bacteremia is proportional to the severity of the PD.13,14 Viable periodontal microorganisms have been found at distant sites including the vascular endothelium of the major arteries.15 These microorganisms are hypothesized to contribute to systemic inflammation,16 which can lead to insulin resistance,17 lowdensity lipoprotein (LDL) oxidation,18 LDL aggregation and foam cell formation in the endothelium through ApoB lysis,19 and inhibition of endothelial nitric oxide synthetase, contributing to endothelial dysfunction.20 PD is positively associated with cardiovascular disease (including stroke) and atherosclerosis.21,22 PD has previously been described to have association with atherosclerosis at the level of the carotid and coronary vasculature; however, PD has not been previously described with AA atherosclerosis. An association between PD and AA may represent a more proximal lesion that could underlie the association of PD with increased risk for ischemic strokes and TIA.5,6 This study thereby sought to investigate the association between PD as a potential modifiable risk factor for AA and recurrent vascular events of ischemic stroke or TIA, and whether AA lesions were potentially in the causal pathway between PD and incident stroke or TIA.

Methodology In this prospective longitudinal hospital-based cohort study, consecutive patients admitted with an ischemic stroke or TIA, in whom a transesophageal echocardiogram (TEE) was performed as part of their initial workup, were screened for eligibility. Additionally, eligibility was based on the following inclusion criteria: non-disabling stroke (modified Rankin Stroke ≤3) or TIA 90 days or less; evaluable for periodontal examination (≥5 teeth) and able to sustain a dental examination; able to give consent, follow outpatient protocol, and available by telephone; and 18 years or older. Exclusion criteria included stroke due to intracerebral hemorrhage, subarachnoid hemorrhage, dissection, veno-occlusive disease, drugs, or vasculitis; coma; severe neurological or musculoskeletal problem that renders that patient dependent; previous neurological impairment that would make detection of a subsequent event difficult; comorbid conditions limiting life expectancy to less than 12 months (e.g., end-stage cancer); computed tomography (CT) or magnetic resonance imaging (MRI) showing lesion other than stroke as the cause of the syndrome; and history of medical conditions requiring antibiotic prophylaxis before dental examination. Eligible patients consented to a protocol for periodontal assessment and phone follow-up approved by the institutional review board. All patients had CT or MRI scan of the brain to confirm the ischemic stroke and had their stroke risk factors assessed during their initial stroke workup. Complete blood count, fasting lipid profile, and homocysteine level were measured as part of their stroke risk assessment. During the baseline interview, patients were asked about their medical history of stroke risk factors. Body mass index was calculated from height and weight obtained during the baseline visit. Follow-up phone calls were conducted at 12-month intervals from study inclusion. Patients were followed for a median of 24 months from the index stroke or TIA for vascular events including stroke, myocardial infarction (MI), and death. During the follow-up phone calls, patients were asked about hospitalization occurring since the previous contact. Patients were asked about their health and the occurrence of recurrent MI, stroke, or TIA. For patients with outcome events, the clinical records were reviewed for confirmation. Date and cause of death were recorded for patients who died during the study.

Periodontal Examination Clinical measures of periodontal exposure included plaque index, gingival index, bleeding on probing, depth (PD), and cementoenamel junction measures relative to the gingival margin (CEJ) as measured on 6 sites for all teeth. Probing depth and CEJ were measured on 3 facial surfaces (distofacial, facial, and mesiofacial) and 3 lingual surfaces (distolingual, facial, and mesiolingual). Clinical attachment level was calculated from the sum of probing

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depth and CEJ scores. The gingival index was scored on 3 facial surfaces (distofacial, facial, mesiofacial) and 3 lingual surfaces. Areas were examined by placing the periodontal probe under the gingival margin at approximately 1-mm deep and sweeping the probe from the distal surface to the mesial surface in quadrants I and IV, and mesial to the distal surface in quadrants II and III. After each quadrant was swept, calls were made based on gingival inflammation and the presence or absence of bleeding according to criteria, which range from 0 to 3 (0 = normal gingiva; 1 = mild inflammation: slight change in color, slight edema; no bleeding on probing; 2 = moderate inflammation: redness, edema, and glazing; bleeding on probing; 3 = severe inflammation: marked redness and edema; ulceration; tendency for spontaneous bleeding). A full mouth plaque assessment was assessed using the UNC Modified Plaque Index (Greene and Vermillion). Plaque scores were visually assessed at 6 sites per tooth (distobuccal, buccal, mesiobuccal, distolingual, lingual, and mesiolingual surfaces). Plaque scores ranged on a scale of 0-3 (0 = no debris or stain present on the clinical crown; 1 = soft debris covering not more than one third of the clinical crown [cervical third], or presence of extrinsic stains without other debris regardless of surface area covered; 2 = soft debris covering more than one third, but not more than two third [middle third] of the clinical crown; 3 = soft debris covering more than two third of the clinical crown). Calibrated dental examiners, including periodontology-trained dentists, conducted these measurements.

TEE Assessment of AA AA was assessed using a comprehensive TEE as part of the initial stroke workup. Details of the imaging protocol and measurement of AA severity have previously been described.6 Briefly, with an HP Sonos 1000 system (Providian Medical Equipment LLC., Highland Heights, OH) equipped with a 5.0-MHz omniplane transesophageal probe, the ascending arch and descending segments of the thoracic aorta were visualized and recorded on videotape for subsequent quantification. AA was graded as mild-moderate (<4 mm in thickness) or severe (≥4 mm in thickness) by use of the criteria by Amarenco et al.10 Each individual subject was categorized as having mildmoderate or severe disease based on the thickness of the thickest lesion. An experienced observer, masked to clinical status, reviewed each TEE videotape and graded AA severity. AA plaques noted on TEE were also assessed for morphological features including calcification, mobility, and ulceration, all of which have been specifically linked to cerebral embolism.19,23

Demographics and Risk Factors Cerebrovascular risk factors were defined as follows: hypertension, previously diagnosed and treated with an antihypertensive medication; diabetes, previously

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diagnosed with or without treatment with a medication for glycemic control; hypercholesterolemia, previously diagnosed with or without treatment with cholesterollowering medications; cigarette smoker, smoking one or more cigarettes daily; alcohol user, alcoholic beverages consumed daily; peripheral vascular disease, symptoms of intermittent claudication or peripheral vascular disease with confirmation by ultrasonographic vascular study or previous peripheral arterial revascularization procedure; atrial fibrillation, history of atrial fibrillation or atrial fibrillation on admission electrocardiogram (ECG) and or on ECG monitoring; coronary artery disease, confirmed history of MI, angina, or coronary artery revascularization procedure; and stroke, persistent neurological deficit of sudden onset (non-convulsive) lasting 24 hours with CT or MRI confirmation and TIA. Patients suspected of complicated migraine or seizures or those presenting with vague neurological symptoms were excluded.

Laboratory Measurements From samples taken at enrollment, patients were assessed for high-sensitivity C-reactive protein (hs-CRP) using commercial enzyme-linked immunosorbent assay kits, and hs-CRP was determined with Fluorokine MultiAnalyte Profiling and the Luminex 200 analyzer (Bio-Rad, Hercules, CA). Reagents for assays were from R&D Systems (Minneapolis, MN). Patients receiving antibiotics for infection at the time of enrollment were excluded (n = 1). Other causes of inflammation or chronic inflammatory disease were ruled out by screening the Atherosclerosis Risk in Communities inflammation form, administered at enrollment.17

Statistical Analysis Statistical analysis was performed with SAS version 9.4 (SAS Institute, Cary, NC). Association of the presence of PD with grade and morphologic features of AA plaques as noted on the index TEE included measures of thickness, ulceration, mobility, composition, and calcification. Two-tailed t-tests compared mean ages and mean levels of serum cholesterol, LDL, high-density lipoprotein, triglycerides, and homocysteine of the 2 groups of patients with mild or severe AA thickness. Univariate analysis with the χ2 test investigated the association between each stroke risk factors except age. The Cox proportional hazards analysis was used to identify risk factors for composite vascular events after adjusting for significant confounders using methods discussed subsequently. Complete exposure (AA) and outcome (recurrent vascular event) were available in all 106 enrolled subjects. The covariates assessed for confounding also included those that were found to confound the association between AA and stroke in prior studies6 and included age, gender, race, hypertension, diabetes, hypercholesterolemia, body mass index, coronary artery disease, smoking, alcohol use, educational level,

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Table 1. Baseline clinical characteristics of those patients with stroke or TIA with low and high periodontal disease Clinical characteristics

Low periodontal disease (n = 66)

High periodontal disease (n = 40)

P value

Age* Male gender Non-Caucasian race Hypertension Diabetes Hypercholesterolemia Coronary artery disease Atrial fibrillation Body mass index* Ever smoker Education† Income† Total cholesterol (mg/dL)* LDL cholesterol (mg/dL)* HDL cholesterol (mg/dL)* Triglycerides (mg/dL)† hs-CRP (mg/L)†

56 ± 16 45% 23% 68% 15% 64% 9% 11% 28.6 ± 4.4 53% 16 (12, 16) $52,200 ($32,375-$80,000) 185 ± 48 107 ± 43 52 ± 17 118 (75-166) 2.5 (1.0-4.0)

61 ± 12 68% 38% 70% 25% 75% 15% 15% 29.6 ± 7.6 58% 12 (12, 16) $33,000 ($16,758-$50,000) 181 ± 47 106 ± 43 51 ± 19 120 (95-167) 3.2 (1.6-10.7)

.05 .03 .10 .85 .21 .22 .35 .50 .42 .65 .01 .01 .74 .90 .66 .73 .17

Abbreviations: HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; TIA, transient ischemic attack. Proportions are depicted as (%) and compared using χ2 test except where indicated. *Normally distributed continuous values are depicted as mean ± standard deviation and compared using t-test. †Continuous variables that are not normally distributed are depicted as median (interquartile range) and compared using Mann–Whitney U test.

and estimated annual income. Only the covariates that were noted to change the hazard ratio (HR) by 5% or more were considered to produce significant confounding (age and educational level) and were included in the estimation of adjusted HR (model 1 and model 2). In model 3, propensity scores were calculated for each study subject by applying the subject’s values to the logistic model.21 The propensity score reflected each subject’s conditional probability of being exposed (severe AA) given the presence of the confounding variables. The results in each of these models were expressed as adjusted HRs and corresponding 95% confidence interval (CI).

Results Of the 156 patients who were screened, 110 met the selection criteria and were consented to participate in the study; 106 patients completed a full periodontal examination 29 ± 13 days from the index stroke or TIA. A total of 50 patients were excluded for the following reasons: 37 had less than 5 teeth or no teeth, 5 were severely disabled or had life expectancy of less than 12 months, 3 were unable to give consent and their next of kin were not available, 4 had inadequate imaging of the AA on TEE, and 1 had a heart valve abnormality requiring antibiotic prophylaxis. Baseline characteristics of the study patients stratified into high PD (N = 40, 38%) and low PD (N = 66, 62%) groups are described in Table 1. The prevalence of high PD is consistent with recent findings

from the Centers for Disease Control and Prevention, that periodontitis, the more advanced form of PD, is prevalent in approximately half of the general population aged 30 or older residing in the United States.24 Patients with high PD were more likely to be older (P = .05), more likely to be males (P = .03), had fewer years of education (P = .01), and had lower annual household income (P = .01). Furthermore, there were no significant differences in prevalence of other stroke risk factors, lipid profile, or hs-CRP levels between the groups. The mean maximum AA plaque thickness was significantly greater in those with high PD (highest tertile, with the extent of attachment loss ≥ 1.3%) than in those who had low PD (P = .004) (Fig 1).15 High PD was associated with moderate grade AA plaque thickness (odds ratio, 10.5; 95% CI, 1.3-84) as well as severe grade AA plaque thickness (odds ratio, 16.9; 95% CI, 1.8-158). In addition to the grade of AA plaque thickness (P = .01), AA plaque calcification was (P = .046) associated with high PD (Table 2). Other AA plaque characteristics measured including AA plaque ulceration and mobility were not associated with high PD. Over the median of 24 months from enrollment, 27 of 106 participants exhibited recurrent vascular events including 16 with cerebrovascular events (9 strokes and 7 TIAs), 3 MIs, and 8 vascular deaths. Seven (41%) of the 17 patients with severe AA had vascular events including 3 with cerebrovascular events (2 strokes and 1 TIA), 2 MIs, and 2 vascular deaths. Among the 89 patients with mild-moderate AA, 20 (22%) had vascular events including

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Figure 1. Aortic arch atheroma (AA) plaque thickness as measured by the omniplane probe in patients with stroke or TIA and low and high periodontal disease (PD). Abbreviation: TIA, transient ischemic attack.

7 strokes, 6 TIA, 1 MI, and 6 vascular deaths over the same period of follow-up. There was a significant difference in cumulative event-free survival between the severe AA group (mean survival, 1.9 years; 95% CI, 1.4-2.5 years) and the mild-moderate AA group (mean survival, 2.4 year; 95% CI, 2.2-2.7 years). The 2 distributions were significantly different according to log-rank testing (P = .04) and are depicted in the Kaplan–Meier survival curve (Fig 2). The participants with severe AA (N = 19) were more likely to experience recurrent vascular events than those with mild or moderate disease (unadjusted HR, 2.3; 95% CI, 1.02-5.32; P = .04; Table 3). As previously mentioned, patients with stroke or TIA and high PD were older, more likely to be males, have fewer years of education, and have lower annual household income (Table 1). It appears that among these factors, age and educational level significantly confounded the association between AA and recurrent vascular event (model 1 and model 2, in Table 3). Table 2. Aortic arch atheroma (AA) plaque thickness in patients with low or high periodontal disease (PD)

Low PD (N = 66) Plaque thickness: Mild (0-.99 mm) Moderate (1-3.99 mm) Severe (≥4 mm) Plaque mobility Plaque ulceration Plaque calcification *Fisher’s exact test.

χ2 test except High PD as indicated (P value) (N = 40)

15 (23%) 1 (3%) 43 (65%) 30 (75%) 8 (12%) 9 (23%) 0 1 (35) 12 (18%) 10 (25%) 19 (29%) 20 (50%)

.01

.38* .55 .046

Multivariable Cox regression showed that severe AA was also associated with composite vascular events, after adjustment for propensity score based on these confounders (HR, 2.3; 95% CI, 1.0-5.49; P < .05; Table 3). There was also a significant difference in cumulative event-free survival between the low PD group and the high PD group. The 2 distributions for PD severity were significantly different according to log-rank testing (P = .006). High PD was a significant risk factor for recurrent vascular event (HR, 2.8; 95% CI, 1.3-6.0). This association was only partly attenuated by AA (adjusted HR, 2.7; 95% CI, 1.2-5.8).

Discussion In our study, we explored the association between PD and AA, in the context of contributing to possible recurrence of vascular events in patients with stroke or TIA. It was found that those with high PD (as verified by dental examiners) had significant association with both moderate and severe AA plaque measurements (measured systematically by transesophageal echocardiography) in these patients. Additionally, we describe an association between PD and AA plaque thickness as well as calcification. Prior studies have shown the association between PD and atherosclerosis in the carotid arteries25 and atrial fibrillation,26 both conditions linked to risk of ischemic stroke. One pioneering study focused on the relationship of PD with atherosclerosis and found that periodontitis, in conjunction with its associated relationship with cardiovascular events, may also play a role in the development of atheroma formation. More specifically, individuals with severe PD were 1.5 times more likely to have thick carotid arterial walls than those with less severe PD after adjustment for traditional risk factors.27

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Figure 2. Kaplan–Meier survival distribution for MI, stroke, or death in patients with mildmoderate (0-3.99 mm) or severe (≥4 mm) thickness of the aortic (AA) plaque. Abbreviation: MI, myocardial infarction.

To our knowledge, we are one of the first to report an association between PD and AA in a population with stroke or TIA. PD has been suggested to cause local and systemic inflammation, and growing evidence suggests that periodontal infection may be linked to atherosclerosis. Microorganisms are introduced into the bloodstream when manipulated from their dental pockets during activities of tooth brushing, chewing, and dental treatments.15 This serves as a nidus for the constellation of events that include inflammation-mediated procoagulant state, atherosclerosis mediated by direct microbial invasion of the blood vessel wall, and increased systemic inflammatory markers.28 The released systemic inflammatory markers such as CRP are involved in the promotion of atherogenesis and accumulation of oxidized LDL, which contribute to an increase in the risk of atherosclerosis and atherosclerosisinduced vascular events.22 We demonstrated that the presence of severe AA plaque is associated with composite vascular events including stroke, TIA, MI, and vascular death (HR, 2.3; CI, 1.02-5.32).

Table 3. Severe aortic arch atheroma: HR (95% confidence interval) for recurrent vascular events in patients with stroke or TIA Unadjusted crude Adjusted (model 1)* Adjusted (model 2)† Adjusted (model 3) ‡

2.3 (1.02-5.32) 2.1 (.90-4.98) 2.2 (1.00-5.23) 2.3 (1.00-5.49)

Abbreviations: HR, hazards ratio; TIA, transient ischemic attack. *Adjusted for age. †Adjusted for educational level. ‡Adjusted for age and educational level combined into a single propensity score.

The association seemed to be attenuated on adjustment for significant confounders namely age and educational level. In patients with prior ischemic stroke, the risk of recurrent stroke or other vascular events has consistently been reported to be 3- to 4-fold higher in patients with AA plaque greater than or equal to 4 mm compared with those with AA plaques less than 4 mm or no plaque in the AA. 17,29-32 In our study, patients with severe AA plaque were older, and age was found to be a significant confounder to the association between AA and recurrent vascular event. A prior community-based study has demonstrated that age may significantly confound the association between AA and cerebrovascular disease.33 The effect of age probably indicates the importance of the duration of exposure to risk factors contributing toward the production of AA plaque. Additionally, we found that educational level was a significant confounder to the association between AA and recurrent vascular event. Low educational attainment, a marker of socioeconomic status, demonstrated significant association with both measures of plaque severity after adjustment for age, race, hypertension, cholesterol, diabetes, coronary artery disease, smoking, body mass index, and income. Liu et al reported that socioeconomic status, measured into tertiles based on years of education, contributed as a significant stroke risk, most notably in lower socioeconomic status.34 Two meta-analyses have shown that patients with fewer years of education are at a greater risk of developing PD35 and stroke, regardless of traditional risk factors.36 Despite the confounding, the association between AA and recurrent vascular event remained significant after adjustment for both the confounders combined. The above findings may have a significant clinical implication. AA, a significant stroke risk factor, is present

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in 16%-20% of all patients with stroke or TIA. Despite the prevalence, currently there is no consensus on secondary prevention strategies in patients with stroke who have arch atheroma. One retrospective study suggests that the use of statins can reduce the risk of stroke or vascular events by as much as 60%.37 In addition to standard secondary prevention with aspirin and lowering of blood pressure and cholesterol, there may be benefit from combination antiplatelet therapy, anticoagulation, or even from AA endarterectomy.38 The AA Related Cerebral Hazard study,39 an international, randomized controlled trial comparing the efficacy of warfarin with that of aspirin plus clopidogrel in patients with arch atheroma and stroke or peripheral embolism, was inconclusive. A prior randomized study involving patients with severe periodontitis, intensive periodontal therapy led to an improvement in endothelial function, hinting that aspects of periodontitisassociated inflammation and vascular injury might be reversible.40,41 There are few randomized control trials that are designed to examine the potential benefits of periodontal therapy on reducing incident strokes. Results of a recently published population-based study in Taiwan suggest that maintenance of periodontal health by dental prophylaxis and PD treatment can help reduce the incidence of ischemic stroke.42,43 Clearly, further studies are needed to assess whether PD treatment can lead to improvement in AA plaque thickness, a high-risk condition for recurrent stroke or TIA. Consistent with a prior report,15 we found that high PD was significantly associated with recurrent vascular event (HR, 2.8; 95% CI, 1.3-6.0). The association was only partly attenuated on adjusting for significant AA, suggesting that AA may only be a partial explanation to the PD-recurrent vascular event association. To the knowledge of the authors, this is the first study that explores the association of PD with AA atheroma and their associated severity in thickness in patients with a stroke or TIA. This study has a few limitations. First, generalizability may be limited by the requirement that patients with stroke or TIA agree to have TEE and PD assessments, both of which are very patient intensive. We recently described a strong correlation between TEE and cardiovascular MRI (less patient intensive) assessment of AA plaque.44 Second, our assessment of PD was limited to our initial screening, as we did not assess direct impact of possible progression or regression of PD throughout our follow-up for recurrence of vascular events. Third, we did not measure medical therapy noncompliance, known to adversely affect outcomes in patients with stroke or TIA. Further studies are needed to confirm our findings that PD may be a risk factor for AA where medical therapy noncompliance is measured. PD is reduced by regular tooth brushing, flossing, scaling, and planing by a dentist. Nonetheless, these findings provide justification for future studies including large clinical trials to assess the potential effects of treatment of PD on the

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incidence of first and recurrent vascular events including stroke.45-47 In summary, we confirm the association between severe AA is associated with recurrent vascular events in patients with stroke or TIA. High periodontal disease is associated with an increased AA plaque thickness and calcification. The results suggest that PD may be a risk factor for AA. Further studies are needed to confirm this finding and to determine whether treatment of PD can reduce the rate of AA plaque progression and recurrent vascular events.

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