Author + information
- Received May 4, 2013
- Revision received July 25, 2013
- Accepted August 12, 2013
- Published online December 24, 2013.
- Sharath Subramanian, MD∗,
- Hamed Emami, MD∗,
- Esad Vucic, MD∗,
- Parmanand Singh, MD∗,
- Jayanthi Vijayakumar, MD∗,
- Kenneth M. Fifer, BA∗,
- Achilles Alon, PharmD†,
- Sudha S. Shankar, MD†,
- Michael Farkouh, MD, MSc‡,
- James H.F. Rudd, MD, PhD§,
- Zahi A. Fayad, PhD‖,
- Thomas E. Van Dyke, DDS, PhD¶ and
- Ahmed Tawakol, MD∗∗ ()
- ∗Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- †Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey
- ‡Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre of Excellence, the University of Toronto, Toronto, Ontario, Canada
- §Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom
- ‖Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- ¶Forsyth Institute, Cambridge, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Ahmed Tawakol, Cardiac MR PET CT Program, Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, 165 Cambridge Street, Suite 400, Boston, Massachusetts 02114.
Objectives The purpose of this study was to test whether high-dose statin treatment would result in a reduction in periodontal inflammation as assessed by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT).
Background Periodontal disease (PD) is an independent risk factor for atherosclerosis.
Methods Eighty-three adults with risk factors or with established atherosclerosis and who were not taking high-dose statins were randomized to atorvastatin 80 mg vs. 10 mg in a multicenter, double-blind trial to evaluate the impact of atorvastatin on arterial inflammation. Subjects were evaluated using FDG-PET/CT at baseline and at 4 and 12 weeks. Arterial and periodontal tracer activity was assessed while blinded to treatment allocation, clinical characteristics, and temporal sequence. Periodontal bone loss (an index of PD severity) was evaluated using contrast-enhanced CT images while blinded to clinical and imaging data.
Results Seventy-one subjects completed the study, and 59 provided periodontal images for analysis. At baseline, areas of severe PD had higher target-to-background ratio (TBR) compared with areas without severe PD (mean TBR: 3.83 [95% confidence interval (CI): 3.36 to 4.30] vs. 3.18 [95% CI: 2.91 to 3.44], p = 0.004). After 12 weeks, there was a significant reduction in periodontal inflammation in patients randomized to atorvastatin 80 mg vs. 10 mg (ΔTBR 80 mg vs. 10 mg group: mean −0.43 [95% CI: −0.83 to −0.02], p = 0.04). Between-group differences were greater in patients with higher periodontal inflammation at baseline (mean −0.74 [95% CI: −1.29 to −0.19], p = 0.01) and in patients with severe bone loss at baseline (−0.61 [95% CI: −1.16 to −0.054], p = 0.03). Furthermore, the changes in periodontal inflammation correlated with changes in carotid inflammation (R = 0.61, p < 0.001).
Conclusions High-dose atorvastatin reduces periodontal inflammation, suggesting a newly recognized effect of statins. Given the concomitant changes observed in periodontal and arterial inflammation, these data raise the possibility that a portion of that beneficial impact of statins on atherosclerosis relate to reductions in extra-arterial inflammation, for example, periodontitis. (Evaluate the Utility of 18FDG-PET as a Tool to Quantify Atherosclerotic Plaque; NCT00703261)
Periodontal disease (PD) affects more than 47% of adults in the United States (1), and the combined cost for periodontal and preventive dental services amount to over $14 billion in the United States alone (2). Moreover, PD is a common, independent risk factor for atherosclerotic disease (3,4). Multiple pathogenic mechanisms linking PD and cardiovascular disease have been proposed. Most prominently, local periodontal inflammation, through pro-inflammatory cytokine release, leads to increased systemic inflammation as measured by C-reactive protein (CRP), tumor necrosis factor-α, interleukin-6, and other biomarkers (5–7). Augmented circulating inflammatory mediators, in turn, promote inflammatory activity within atherosclerotic plaque (8,9). Interestingly, local treatment of PD has also been shown to reduce systemic inflammation in patients with a history of cardiovascular events (10). To date, however, no definitive evidence exists that treatment of PD decreases cardiovascular disease progression or cardiovascular events.
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging provides a noninvasive measure of inflammation, including inflammatory activity within atherosclerotic plaques. Several studies have demonstrated a strong correlation between carotid FDG uptake with histopathological measures of macrophage infiltration and inflammatory gene expression (11–15). The arterial FDG signal is reproducible (16), correlates with atherosclerotic inflammatory burden, and is modifiable by antiatherosclerotic therapies (17–20). We have previously demonstrated that periodontal inflammation correlates with carotid artery inflammation (21), and, most recently, others have shown that periodontal FDG uptake correlates with PD severity as measured by alveolar bone loss (22).
5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, so called “statins,” have clear benefits in atherosclerotic diseases (23). These drugs effectively decrease low-density lipoprotein cholesterol (LDL-C) levels and have other beneficial pleiotropic effects beyond lipid lowering, especially with respect to reducing systemic inflammation and also inflammatory activity within atherosclerotic plaques (17,24). Multiple retrospective epidemiologic studies have demonstrated that statin therapy is also associated with reduced severity of periodontitis (25–28). Most recently, a small prospective study suggested an additional benefit of combined statin and standard local periodontal treatment compared with standard local therapy alone (29). Nevertheless, the direct anti-inflammatory actions of statins in periodontal tissue have not been previously demonstrated. Accordingly, we used FDG-PET/computed tomography (CT) imaging to evaluate a potentially novel pleiotropic effect of statin treatment on periodontal tissue. We specifically tested the hypothesis that atorvastatin treatment would lower PD activity, mirroring its action on atherosclerotic plaque activity (20), and thereby providing a link between both disease states.
This double-blind, randomized, active-comparator study (NCT00703261) was conducted at 10 U.S. centers in order to study the impact of high-dose statin therapy on arterial inflammation. The protocol was reviewed and approved by each center's institutional review board, and all participants provided written informed consent prior to any study procedures. In the current study, we performed a separate, blinded analysis of FDG uptake in the periodontium to assess the impact of statin treatment on periodontal tissue inflammation. Permission was received from the Partners Healthcare Institutional Review Board to evaluate PD indexes on the anonymized imaging data.
A total of 163 subjects were initially screened, and 83 subjects (median age 59 years, range: 37 to 78 years, 78% men) were randomized in this study. Men and women 30 to 80 years of age were included if they had documentation or history of any 1 of the following: 1) carotid artery disease; 2) coronary artery disease; 3) cerebrovascular disease; 4) peripheral arterial disease (ankle-brachial index ≥0.5 and ≤0.9); 5) type 2 diabetes mellitus; or 6) body mass index 30 to 40 kg/m2 (inclusive) and waist circumference >102 cm in men and >88 cm in women. Patients were excluded if they had a history of: 1) type 1 diabetes mellitus; 2) any significant cardiovascular event or intervention within 12 weeks of screening; 3) significant heart failure (e.g., New York Heart Association functional class III or IV, defibrillators); 4) active or chronic hepatobiliary disease; or 5) a chronic systemic inflammatory condition (such as rheumatoid arthritis or psoriasis) or chronic infection. Additionally, eligible subjects were required to have LDL-C ≥60 mg/dl, to have a triglyceride level <350 mg/dl, and to be statin naïve or taking no more than low-dose statins (defined as: atorvastatin ≤10 mg, simvastatin ≤20 mg, rosuvastatin ≤5 mg, pravastatin ≤40 mg, or fluvastatin ≤40 mg).
After the initial clinical screening, patients underwent baseline imaging using FDG-PET/CT. Because the parent study was designed to evaluate the effect of statin treatment on arterial inflammation, subjects without evidence of any arterial inflammation at baseline were excluded from randomization (i.e., target-to-background ratio [TBR] ≥1.6 present in either aorta, right or left carotid), which resulted in the exclusion of approximately 10% of the initially screened population. Eligible patients were randomized (after prior statin therapy was discontinued) in a double-blinded manner to a 10-mg atorvastatin tablet (Lipitor, Pfizer, New York, New York) plus an 80-mg atorvastatin matching placebo daily or an 80-mg atorvastatin tablet plus a 10-mg atorvastatin matching placebo daily for 12 weeks. Following randomization, FDG-PET/CT images were obtained again after 4 and 12 weeks. Seventy-one subjects completed the 12-week drug treatment period. In 12 subjects, coverage of the mouth was not included within the PET/CT field of view; hence, the final analysis set for the current study included 59 subjects (Fig. 1).
FDG-PET/CT imaging was performed using previously validated methods (11,12). Patients were asked to adhere to a low-carbohydrate diet for 24 h before the test and to fast overnight prior to imaging. Imaging was performed 2 h after administration of 10 mCi of 18F-FDG, and images were acquired in 3-dimensional mode over 15 min. The image data were attenuation-corrected and reconstructed using ordered-subsets expectation-maximization algorithm. Blood sugar concentration was <200 mg/dl at the time of imaging for all subjects.
Measurement of periodontal tissue FDG uptake with PET
PET and CT images were analyzed using previously detailed methods (21). Investigators were blinded to the clinical history, randomization details, and temporal sequence of imaging time points. Subsequently, the datasets (week 0, 4, and 12 images) were batch analyzed after manual coregistration of PET and CT images (Leonardo TrueD, Siemens, Forchheim, Germany) as previously reported (21). Coregistration was performed using anatomical landmarks such as teeth and periodontal tissue, brain, spinal cord, spine, and jaw. After coregistration, the periodontal tissues were identified and the maximum standardized uptake value (SUV) of FDG was measured by drawing a rectangular region of interest (ROI) around the teeth. The ROIs were drawn from the mesial surface of the first premolar to the distal surface of the second molar teeth in each of 4 quadrants (Fig. 2). Care was taken to avoid spill-over activity from the tongue, as well as from pharyngeal and buccal structures. Periodontal FDG uptake around anterior teeth (incisor and canine) and third molars (if present) were not assessed. The TBRs were derived from the ratio of the SUV of the periodontal tissue to background blood activity from the internal jugular vein. The interobserver and intraobserver correlations of periodontal TBR measurement (based on blinded analysis of 24 subjects) were 0.986 and 0.996, respectively. The inter-reader and intrareader variability was 4.58% and 2.36%, respectively.
Measurement of FDG uptake in carotid tissue
Carotid FDG uptake was measured using previously described methods (12). The ROIs were placed at each axial plane along the length of the carotid to measure the maximum SUV. The TBR was calculated as the ratio between the carotid arterial and the venous blood SUV measured in the internal jugular vein. Thereafter, FDG uptake (TBR) was calculated using an average of the maximum TBR activity for all of the axial segments that compose the vessel.
Assessment of periodontal bone loss
Contrast-enhanced CT imaging was performed once (at baseline or week 4) to provide additional anatomical information to ensure that the same locations within the arterial segments are measured across time. In 59 patients, the CT images included the oral cavity in the field of view, thus allowing for post-hoc evaluation of alveolar bones. Imaging parameters included rotation time of 420 ms or less, a tube current of ∼750 mAs, and voltage of 120 kVp. Image acquisition characteristics were section thicknesses of 0.75 mm and pitch of 0.2 to 0.4. Iopamidol 300 mg/ml or similar was used as an intravenous contrast agent and was infused at 5 to 6 mls/s. While the multisection CT image acquisition was optimized for arterial imaging, the current and voltage used for arterial imaging is substantially higher than that typically used for dental imaging (30). Evaluation of the periodontal CT images was performed by an experienced periodontist (T.V.) blinded to all PET data, clinical information, and treatment assignment. Alveolar bone resorption was semi-quantitatively assessed in each of the 4 dental quadrants: 0, 1, 2, or 3 for none, mild (limited to coronal one-third of the root), moderate (including the middle one-third of the root), or severe (to the apical one-third of the root) bone loss, respectively. Periodontium of anterior teeth (incisors and canines) and third molars were not evaluated for bone resorption scoring.
Assessment of blood biomarkers
High-sensitivity CRP, LDL-C, and high-density lipoprotein (HDL) concentrations were assessed in plasma at 0, 4, and 12 weeks. All serum biomarker analyses were performed in batches.
The “Generalized Estimating Equations” test was used to compare FDG uptake in dental quadrants with versus without severe PD (based on CT evidence of alveolar bone loss). The same test was employed to adjust for the covariates in that analysis. The Student t test was used to assess the impact of atorvastatin treatment (80 mg compared with 10 mg) on periodontal inflammation. Univariate associations were tested using Pearson's correlation coefficient. Linear regression was used to evaluate the independence of periodontal TBR as a predictor of periodontal bone loss, with PD risk factors as covariants. A forward-enter approach was employed to evaluate the robustness of these relationships, wherein the significant or near-significant (p < 0.10) variables identified in univariate analysis were entered. Between-group differences were based on observed data values, without adjusting for missing data. Unstandardized regression coefficients are reported as β and 95% confidence interval (CI). Statistical analysis was performed using SPSS version 20 (IBM, Armonk, New York). All reported p values are 2-tailed; statistical significance was set at p < 0.05. Multiplicity adjustments were not applied for secondary comparisons of interest; as such, nominal p values are reported for all comparisons.
A total of 163 patients were screened, and 83 patients were randomized. Twelve patients discontinued early due to: adverse experiences (n = 6), withdrawal of consent (n = 2), or protocol deviation or other reason (n = 4). Of the 83 patients randomized to the study, 71 subjects completed the study; among those, periodontal tissue images were available for 59 subjects. The demographic and clinical characteristics of the patients at the baseline are shown in Table 1.
Relationship between PD and periodontal FDG uptake at baseline
Periodontal FDG uptake at baseline was compared with CT measures of alveolar bone resorption. Mean baseline TBR was significantly higher in quadrants with versus without severe alveolar bone loss (dental quadrant TBR: 3.83 [95% CI: 3.36 to 4.30] vs. 3.18 [95% CI: 2.91 to 3.44], p = 0.004) (Fig. 3). The association between periodontal TBR and alveolar bone loss remained significant after adjusting for age and sex (β = 0.64, p = 0.005) and major risk factors of PD: diabetes mellitus and smoking (β = 0.65, p = 0.004) (31,32).
Statins and periodontal tissue inflammation
We observed a normal distribution of periodontal FDG uptake values across the subjects in both treatment groups at baseline and at weeks 4 and 12. In the entire cohort (before subset selection based on the presence of periodontitis at baseline), a significant reduction in periodontal FDG uptake was seen after 12 weeks of treatment with high-dose versus low-dose atorvastatin (mean change TBR: −0.29 ± 0.85 vs. 0.13 ± 0.68, atorvastatin 80 mg vs. 10 mg, p = 0.04) (Table 2). The impact of high-dose atorvastatin on PD activity remained significant after adjusting for: 1) age and sex (β = −0.45, p = 0.034); 2) diabetes mellitus and smoking (β = −0.43, p = 0.04); and 3) prior coronary artery disease, baseline HDL, low-density lipoprotein (LDL), and CRP levels (β = −0.45, p = 0.034).
Moreover, the effect of high-dose statin was more notable in subjects with imaging evidence of PD at baseline. In the first PD-based subset analysis, individuals with PD were identified based on the presence of PET evidence of active periodontitis (subjects with the highest 2 tertiles of baseline periodontal TBR). Between-group differences became more substantial within individuals with active periodontitis (by PET) at baseline (change TBR: −0.52 ± 0.94 vs. 0.22 ± 0.79, atorvastatin 80 mg vs. 10 mg, p = 0.01) (Fig. 4, Table 2). Furthermore, the difference in changes in PD activity between treatment groups was significant starting at 4 weeks (Fig. 4, Table 2). Similarly, in the second subgroup analysis, individuals with PD were identified based on CT evidence of alveolar bone loss to indicate a history of PD. In that analysis, subjects without moderate or severe alveolar bone loss in at least 1 tooth were excluded. In this second PD-based analysis, between-group differences remained significant in the subgroup of patients with moderate to severe periodontal bone loss at baseline as determined by CT (change in TBR: −0.19 ± 0.61 vs. 0.41 ± 0.73, atorvastatin 80 mg vs. 10 mg, p = 0.033) (Table 2).
Relationship between atherosclerotic inflammation and periodontal inflammation
Baseline FDG uptake (TBR) in periodontal tissue correlated with baseline carotid plaque TBR (Fig. 5). Additionally, after 12 weeks of statin therapy, changes in periodontal inflammation correlated with changes in carotid inflammation (Fig. 6). Moreover, subjects with a greater than median reduction of periodontal TBR demonstrated a significantly greater decrease of arterial inflammation after adjusting for changes of LDL-C and CRP (β = −0.29, p = 0.001).
PD inflammation versus lipids and CRP
Baseline PD activity (periodontal TBR) correlated inversely with baseline HDL concentration (R = −0.35, p = 0.007) but did not correlate with baseline CRP or baseline LDL. The presence of severe alveolar bone loss (by CT) was associated with higher CRP concentrations (β = 1.97, p = 0.022), after correcting for age, sex, smoking, and diabetes. Changes in PD activity did not correlate with changes in CRP, LDL or HDL.
This report demonstrates that 12 weeks of high-dose atorvastatin therapy significantly reduces periodontal inflammation. Between-group differences were more pronounced in individuals with PET imaging evidence of PD. The reduction in the PD signal was observed as early as 4 weeks after randomization and correlated with changes in FDG uptake within the wall of the carotid artery (a marker of arterial inflammation).
Periodontal FDG uptake as a marker of periodontitis
While evaluation of malignant and infectious oral lesions using FDG-PET is established in clinical practice, the assessment of PD using FDG-PET imaging is relatively novel. We have previously reported the correlation between periodontal FDG uptake and arterial plaque inflammation (21) and hypothesized that periodontal FDG uptake reflects dynamic periodontal inflammation and, thus, the severity of PD. Recently, Kito et al. (22) provided supportive evidence for this contention, demonstrating that periodontal FDG uptake is indeed correlated with PD severity as measured by the magnitude of bone resorption on radiographs, a destructive end result of inflammation (33). In the current study, we provide further confirmation of these findings and, importantly, provide additional evidence that periodontal FDG uptake reflects periodontal inflammation. However, in contrast to bone loss that identifies the longer-term consequences of severe PD, the FDG-PET signal likely reflects the current inflammatory burden within the target tissue and indicates ongoing, active PD.
Relationship between periodontitis and atherosclerosis
While an epidemiological association between PD and atherosclerosis is well known, the degree of influence of PD on atherosclerosis is not fully understood. Nevertheless, the consensus of 2 independent reviews was that PD is an independent risk factor for atherosclerosis (34,35). Imaging studies have also established a direct association between PD and carotid atherosclerosis by correlating increased intima-media thickness with the extent of PD (36). Importantly, the ICARAS (Inflammation and Carotid Artery–Risk from Atherosclerosis Study) (37) revealed that PD was associated with subsequent progression of atherosclerosis. In this study, we provide additional evidence of a link between PD and atherosclerosis by showing a significant correlation between PD and carotid imaging parameters at baseline (thus confirming prior studies) and additionally by demonstrating a strong association between changes of the 2 imaging parameters over a 12-week period upon atorvastatin treatment. The close association that we observed between the 2 tissues supports the hypothesis that periodontal and atherosclerotic inflammations (as assessed by FDG-PET arterial wall imaging) are inter-related, although the nature of that association is undefined.
A novel pleiotropic effect of statins
Although it was at first assumed that the beneficial impacts of statins were mediated via reduction of LDL-C, multiple studies have consistently suggested that not all actions can be accounted for by cholesterol reduction per se. For example, in the CARE (Cholesterol And Recurrent Events) trial (38), the magnitude of high-sensitivity CRP reduction associated with statins over a 5-year observation period was more pronounced than the amount that would be predicted by changes in LDL-C alone. In the PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) trial (39), the rapid event reduction after statin therapy was postulated to be in part due to non–lipid-related properties of statins. These cholesterol-independent or “pleiotropic” effects of statins have been attributed to several mechanisms, including improved endothelial function, decreased smooth muscle cell proliferation, reduced platelet function, and attenuated inflammation (40). Based on the findings of this study, we pose the possibility that statins may exert an additional pleiotropic effect: reduction of nonarterial inflammation, (i.e., within inflamed tissues such as the periodontium). We further postulate that a reduction in local periodontal inflammation (as an example of several clinical models of extra-arterial inflammation) may exert secondary benefits on the systemic arterial milieu, whereby reduction in inflammation within the periodontium leads to a reduction in proinflammatory mediators released by periodontal tissue into the systemic circulation; this, in turn, may lead to further reductions in atherosclerotic inflammation (Fig. 7).
Indeed, prior studies support the hypothesis that treatment of PD might yield benefits in atherosclerosis. For instance, PD treatment results in reduced carotid intima-media thickness (41), and improving oral health decreases both local and systemic markers of inflammation (42,43) and improves endothelial function (44,45). Additionally, other extravascular inflammatory diseases have similarly been linked to atherosclerotic disease. The most prominent example is rheumatoid arthritis (RA) (46,47). Atorvastatin therapy has proven beneficial in RA in terms of modulation of clinical and inflammatory markers (48). Further, treatment of RA and psoriasis with disease-modifying anti-inflammatory drugs (49) leads to a reduction in cardiovascular risk, thereby supporting the hypothesis that extravascular inflammation is an important and modifiable contributing factor for the promotion of atherosclerosis. However, the exact nature of the inter-relationship among statins, arterial inflammation, and periodontal inflammation remains elusive after the results of this study, and we cannot exclude the possibility that statins may affect both periodontal and arterial inflammation independently without a link between these 2 tissues.
Future randomized, controlled studies will be needed to examine the underlying mechanism of the association between localized inflammation of extra-arterial tissues and atherosclerosis; they will specifically be needed to test the hypothesis that localized (nonsystemic) treatment of extra-arterial inflammation reduces atherosclerotic inflammation and cardiovascular risk. These studies should also evaluate whether moderate doses of statins also confer anti-inflammatory benefits on the periodontium. Indeed, PD represents an ideal model to test this hypothesis, because treatment of periodontitis can be achieved via local intervention (plaque removal and scaling) without the need for systemic treatment.
If confirmed by larger prospective outcome studies, statins would prove to be a useful adjunctive treatment for PD, with efficacy seen within 1 month. Furthermore, the possible inter-relationship among periodontitis, atherosclerosis, and statins might prove to be of substantial importance due to the high prevalence of both periodontal and atherosclerotic diseases along with the widespread use of statins. Moreover, additional investigations to assess the inter-relationships between extra-arterial inflammation and atherosclerosis are warranted, considering the fact that knowledge derived from treatment of extra-arterial inflammatory disorders may lead to useful insights into the inflammatory mechanisms of atherosclerosis in general (47).
While our data suggest that high-dose atorvastatin is more effective than low-dose treatment in decreasing inflammation in atherosclerosis and PD, these findings do not allow determination of the efficacy of low-dose treatment relative to placebo. It is worth noting in this context that the majority of subjects that were randomized to atorvastatin 10 mg/day were previously on a low-dose statin prior to study entry, and, hence, they might not have experienced a boost in the effective statin dose over the course of the study. This might contribute to the observation that low-dose statin treatment was not associated with a reduction in periodontal FDG uptake. Nonetheless, the main observation of an effect of high-dose statin remains valid. Further, given that 50% of subjects randomized to atorvastatin 80 mg were previously on a low-dose statin, the impact of high-dose statin intervention in a statin naïve population might be more profound than seen in the current study. Last, the findings of the current study were derived from a post-hoc analysis of a population of subjects with PET/CT imaging evidence of atherosclerotic disease. Hence, extrapolation of the findings of this study to the broader population should be done cautiously. Future randomized clinical trials are warranted in order to evaluate the effects of statins on PD regardless of status of atherosclerosis.
We observed that high-dose atorvastatin is associated with a reduction in periodontal inflammation in this multicenter, double-blind trial. The impact of high-dose statins was greatest in individuals with evidence of active periodontitis and was evident after a 4-week treatment period. Furthermore, we observed a close association between reductions in periodontal and atherosclerotic inflammation. Accordingly, these results identify a potentially novel pleiotropic effect of statins and raise the possibility that an indirect benefit of statins on atherosclerosis may in part relate to a reduction in extra-arterial inflammation.
Merck & Co., Inc. provided funding for the study. The statistical analysis was conducted with consult from Harvard Catalyst which is supported by National Center for Research Resources and the National Center for Advancing Translational Sciences (NIH Award 8UL1TR000170-05). Drs. Alon and Shankar are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Dr. Alon owns stock in Merck Sharp & Dohme Corp. Dr. Farkouh's institution received grants from Merck Sharp & Dohme Corp. Dr. Rudd is supported by the NIHR Cambridge Biomedical Research Center. Drs. Fayad and Tawakol received consulting fees and their institutions received grants from Roche and Merck Sharp & Dohme Corp. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Subramanian and Emami contributed equally to this work. Drs. Van Dyke and Tawakol also contributed equally to this work.
- Abbreviations and Acronyms
- C-reactive protein
- computed tomography
- high-density lipoprotein
- low-density lipoprotein cholesterol
- periodontal disease
- positron emission tomography
- region of interest
- standardized uptake value
- target-to-background ratio
- Received May 4, 2013.
- Revision received July 25, 2013.
- Accepted August 12, 2013.
- American College of Cardiology Foundation
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