Prevalence of calcified carotid artery atheromas on the panoramic images of patients with syndrome Z, coexisting obstructive sleep apnea, and metabolic syndrome
Tina I. Chang, DMD, MD,aJeffrey M. Tanner, DDS,bNancy D. Harada, PhD,cNeal R. Garrett, PhD,dand Arthur H. Friedlander, DMD,eLos Angeles, California
VETERANS AFFAIRS GREATER LOS ANGELES HEALTHCARE SYSTEM, UNIVERSITY OF CALIFORNIA, LOS ANGELES, AND RONALD REAGAN UCLA MEDICAL CENTER
Objectives.The objective of this study was to compare the prevalence of calcified carotid artery atheromas (CCAAs) on panoramic images of individuals (n⫽ 31) with obstructive sleep apnea (OSA) with individuals (n ⫽ 117) with syndrome Z (SZ: OSA with concomitant metabolic syndrome [MetS]).
Study design.Images of patients with OSA or SZ referred from the Sleep Service to Dentistry were evaluated. Descriptive statistics and t tests (Bonferroni correction) were conducted to determine significant differences between atheroma prevalence and proatherogenic factors (age, apnea-hypopnea index, body mass index, lipid profile, blood pressure, glucose) between OSA and SZ groups.
Results.Individuals with OSA had an atheroma prevalence of 35% and those with SZ 42% (P⫽ .52). Individuals with SZ also had significantly more severe atherogenic profiles (obesity, dyslipidemia, hyperglycemia) than OSA patients (Pⱕ .05).
Greatest CCAA prevalence (63%) was evidenced by SZ patients with severe OSA and moderate MetS.
Conclusion.Individuals with SZ have significantly greater atherogenic burden and slightly higher prevalence of CCAAs when compared with individuals with OSA. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:134-141)
The obesity epidemic sweeping the United States has resulted in a significant number of these obese individ- uals developing obstructive sleep apnea (OSA).1The disorder is most often seen in persons with an upper
airway narrowed by parapharyngeal fat deposits and is characterized by recurrent episodes of absent (apnea) or diminished airflow (hypopnea) owing to loss of pha- ryngeal tone, resulting in obstruction during sleep de- spite persistent respiratory effort. Approximately 20%
of American adults have mild OSA, defined as 5 or more apneas plus hypopneas per hour of sleep (i.e., the apnea-hypopnea index [AHI]ⱖ5) and 7% have mod- erate to severe OSA (AHIⱖ15).2
The obesity epidemic has also resulted in the devel- opment of metabolic syndrome (MetS). MetS is the concurrence of multiple metabolic abnormalities asso- ciated with the development and progression of athero- sclerosis. It is typified by the clustering of 3 to 5 quantitatively defined risk markers that include obesity signified by increased body mass index (BMI), dyslip- idemia, hypertension, and hyperglycemia. The preva- lence rates of MetS among men and women (agesⱖ20 years) are 33.7% and 35.4%, respectively.3
Individuals having either OSA or MetS are at high risk of suffering an adverse cardiovascular event be- cause of the associated proatherogenic elements. Con- temporaneous epidemiologic studies have noted that these illnesses are responsible for more than 38,000 yearly deaths from myocardial infarction (MI) and stroke.4-6 Recently it has been determined that an un- known number of Americans simultaneously have both diseases, with the illness termed Syndrome Z (SZ).7 The proatherogenic elements harbored by individuals having these combined illnesses places them at even
The financial support of this project was limited to the full-time salaries paid to the authors by the Department of Veterans Affairs and the University of California. Elements of this investigation were conducted in a facility constructed with support from Research Facilities Improve- ment Program Grant Number C06 RR-14529-01 from the National Center for Research Resources, National Institutes of Health.
aDirector, Fellowship and Inpatient Oral and Maxillofacial Surgery, Veterans Affairs Greater Los Angeles Healthcare System; Instructor, Oral and Maxillofacial Surgery, School of Dentistry, University of California, Los Angeles.
bFellow, Oral and Maxillofacial Surgery Section, Dental Service, Veterans Affairs Greater Los Angeles Healthcare System.
cGraduate Medical Education, member of the Geriatric Research Education and Clinical Center, Veterans Affairs Greater Los Angeles Healthcare System; Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles.
dProfessor, Division of Advanced Prosthodontics, Biomaterials and Hos- pital Dentistry, School of Dentistry, University of California, Los An- geles.
eAssociate Chief of Staff and Director of Graduate Medical Education, Veterans Affairs Greater Los Angeles Healthcare System; Director of Quality Assurance, Hospital Dental Service, Ronald Reagan UCLA Medical Center; and Professor-in-Residence of Oral and Maxillofacial Surgery, School of Dentistry, University of California, Los Angeles.
Received for publication Mar 10, 2011; returned for revision May 31, 2011; accepted for publication Jul 26, 2011.
Published by Elsevier Inc.
2212-4403/$ - see front matter doi:10.1016/j.tripleo.2011.07.039
greater risk of succumbing to adverse cardiovascular events.8
In 2010, the American Academy of Sleep Medicine issued a Practice Parameters statement, which con- cluded that certain groups of patients with OSA who were intolerant to positive airway pressure could be effectively treated by fabrication of oral appliances or maxilla-mandibular advancement.9 Diagnostic proce- dures to determine how best to perform these dental interventions almost always require obtaining a pan- oramic radiograph. These images also have the capa- bility of demonstrating calcified atherosclerotic lesions (atheromas) of the carotid artery (Figure 1).10,11Med- ical and dental researchers have previously demon- strated that these atheromas are surrogate markers of coronary artery atherosclerosis and an independent sign heralding future myocardial infarction and stroke.12-14 A previous study evaluated the panoramic radio- graphs (analogue) of 54 patients with OSA for the presence of atheromas and noted a 22% prevalence15; however, it was conducted before the use of digital radiography with image-enhancing capabilities (i.e., altering brightness, contrast, and magnification) and before the medical profession’s recognition that some of these individuals may have had occult MetS also and therefore in fact had SZ.16,17It was decided to revisit this issue by segregating patients solely with OSA from those with SZ and determining the prevalence rates of calcified carotid artery atheromas (CCAAs) on the digital images of each group of indi- viduals. The hypothesis was that those with SZ would have a greater prevalence of CCAAs on their images compared with those with OSA alone.
MATERIALS AND METHODS Patients studied
After receiving institutional review board approval for the study, the Medical Center’s comprehensive elec- tronic medical record system was queried and the chart of every patient referred to the dental service for treat- ment of OSA by the Sleep Medicine service between July 1, 2007, and June 30, 2010, was retrieved, yielding a total of 490 patients. Each of these charts was re- viewed by one of the authors (J.T.) to determine the patient’s eligibility to be enrolled into the study. Inclu- sion criteria were the following: (1) a diagnosis of OSA by the Sleep Medicine Service in which the AHI was 5 or more events per hour of electroencephalographic sleep based on either a full, attended, overnight sleep study in the Veterans Affairs sleep laboratory using polysomnography or a multichannel home sleep test and a patient complaint of excessive daytime sleepi- ness18; (2) a digital panoramic image of diagnostic quality. Exclusion criteria included: (1) being of female gender given the paucity of such individuals in the Veterans Affairs system, (2) individuals diagnosed as having OSA at another institution, (3) laboratory data that were not recorded within 1 year before the sleep study, (4) evidence of calcified submandibular or cer- vical lymphadenopathy on which single or multiple nodes were described on palpation as being “hard and movable” on either the head and neck component of the physician’s physical examination or the dentist’s max- illofacial examination. Based on these criteria, the final analytical sample consisted of 216 patients.
For each patient in the analytical sample, the follow- ing data elements were abstracted from the medical record: age, AHI, BMI, triglycerides, high-density li- poprotein (HDL), blood pressure (BP) readings, and fasting serum glucose values.
The data were first analyzed to classify patients into OSA severity levels based on the AHI as follows: (1) mild: AHI 5 to 14, (2) moderate: AHI 15 to 30, and (3) severe: AHI of 31 or higher.19Apnea was defined as the complete cessation of airflow, and hypopnea was de- fined as a discernable reduction in airflow for 10 sec- onds or more accompanied by a decrease in oxygen saturation of at least 4%.
Criteria for diagnosing MetS in the analytical sample were based on recommendations proposed by the Adult Treatment Panel III (ATPIII),20with later modification of the serum glucose level by the American Heart Association.21The diagnosis was established when 3 of the 5 following risk markers or medications to control them were evidenced: (1) BMI of 30 kg/m2or higher, (2) triglycerides of 150 mg/dL or higher, (3) HDL 40 mg/dL or lower, (4) hypertension: systolic BP of 130 mm Hg or higher or diastolic BP of 85 mm Hg or Fig. 1. A panoramic radiograph digitally enhanced with the
manufacturer provided software evidencing bilateral carotid artery atheromas (arrows). Note the globular and vertical opacities on the patient’s right just inferior to the greater horn of the hyoid bone, and in a similar location on the left note the semicircular opacity. The patient, a 63-year-old man, was diagnosed with moderate OSA and mild MetS (SZ) by the Sleep Medicine Service using overnight polysomnog- raphy (AHI⫽ 20.2), clinical examination, and laboratory data (BMI⫽ 36.2).
higher, (5) insulin resistance defined as fasting serum glucose of 100 mg/dL or higher. The severity of each patient’s MetS was categorized by summing the num- ber of risk markers evidenced. The presence of 3 risk markers was deemed mild MetS, 4 was deemed mod- erate MetS, and 5 was termed severe MetS.22Note that we replaced the ATPIII recommended waist circumfer- ence measurement of 102 cm or larger with a BMI value based on the recommendations of the World Health Organization23and the American Association of Endocrinologists24 because of its ready clinical availability and simplicity as well as studies showing that using BMI has the same identification and prog- nostic values as waist circumference.25,26 Those in- dividuals having 3 or more metabolic risk markers and an AHI greater than 5 were assigned a diagnosis of SZ.
Of the 216 patients initially enrolled, there were 148 panoramic images that were of satisfactory qual- ity (not over- or underexposed) and demonstrated an area of interest that extended 2.5 cm inferior and 2.5 cm posterior to the cortical rim of the midpoint of the mandibular angle. The senior author (A.H.F.) re- viewed each radiograph by altering the brightness, contrast, and magnification to determine the presence or absence of atheroma(s) in this area of interest using previously published criteria.27 Confounding radiopacities frequently imaged in the area (i.e., hy- oid bone, epiglottis, stylomandibular ligament, sty- lohyoid ligament, calcified triticeous cartilage, sub- mandibular gland sialoliths, and phleboliths) were excluded by their appearance. Individuals identified with atheroma(s) were assigned a designation of
“present” as opposed to “absent.” This investigator was masked as to which cohort (OSA vs SZ) each digital image belonged (Figure 1).
De-identified data were entered into an electronic spreadsheet and checked for accuracy before importing the file into statistical software for analysis. Descriptive statistics were run to assess univariate measures of central tendency and dispersion of age and the clinical variables for the sample as a whole, and by OSA versus SZ groupings. To determine whether age and the clin- ical variables were significantly different between in- dividuals with OSA and individuals with SZ, t tests for independent groups, corrected for multiple tests (Bon- ferroni; SAS procedure MULTTEST), were used. Chi- square analysis was used to evaluate the relationship between atheromas and presence of OSA and SZ. Cross tabulations and chi-square analyses were conducted to determine the prevalence of atheromas by OSA severity levels. Finally, cross-tabulations were run to assess the
distribution of atheromas by OSA severity and number of metabolic syndrome risk markers. Analyses were conducted using PASW Statistics version 18 (release 18.0.0 2009, IBM Corporation, Somers, NY) and SAS version 9.1 (SAS version 9.1. SAS Institute Inc., Cary, NC).
The study group consisted of 31 individuals with OSA and 117 with SZ (Table I). Those with SZ were ap- proximately 5 years older (P ⫽ .27) and evidenced significantly greater obesity, dyslipidemia, and hyper- glycemia than those with OSA. Individuals with SZ evidenced atheromas (Figure 2) on their panoramic images more frequently (49/117, 42%) than individuals with OSA (11/31, 35%); however, this difference was not statistically significant (P⫽ .52).
Table I. Patient characteristics (n⫽ 148)
OSA (n⫽ 31)
Syndrome Z (n⫽ 117)
P value (Bonferroni)
Age, y .2707
⫾ SD 56⫾ 12 61⫾ 12
Range 30–82 26–91
Body mass index (kg/m2)
⫾ SD 28⫾ 3 32⫾ 6
Range 22–39 21–50
Apnea-hypopnea index, events/h
⫾ SD 26⫾ 19 26⫾ 18
Range 5–81 5–101
Triglycerides, mg/dL* .0440
⫾ SD 113⫾ 67 169⫾ 106
Range 39–298 39–677
HDL-C, mg/dL* .0369
⫾ SD 45⫾ 13 38⫾ 11
Range 22–75 20–92
Systolic blood pressure (mm Hg)†
⫾ SD 126⫾ 14 125⫾ 14
Range 105–176 94–186
Diastolic blood pressure, mm Hg†
⫾ SD 76⫾ 9 74⫾ 10
Range 56–91 42–99
Fasting glucose (mg/dL)‡
⫾ SD range 96⫾ 23 124⫾ 46
Range 53–175 78–366
OSA, obstructive sleep apnea; HDL-C, high-density lipoprotein-cho- lesterol.
*Results acquired while individuals were receiving dyslipidemic medications.
†Results acquired while individuals were receiving antihypertensive medications.
‡Results acquired while individuals were receiving antihyperglyce- mic medications.
Individuals with OSA were equally distributed among severity levels (Table II). Counterintuitively, and without ready explanation, those with mild OSA manifested the highest prevalence (55%) of CCAA on their images, but this difference was not statistically significant (P⫽ .19).
Among the individuals with SZ, most (57%; 67/117) had mild MetS irrespective of OSA severity level (Ta- ble III). The largest group (n⫽ 29) of patients had both mild OSA and mild MetS. In this group of patients, 10 (35%) of the 29 had CCAA. As the severity of OSA increased among individuals with mild MetS, the prev- alence of CCAAs increased linearly from 35% to 50%.
Individuals having the severe form of OSA and con- comitant moderate MetS manifested the highest prev- alence (63%) of atheromas.
In the United States, the first and third most common causes of death (myocardial infarction and ischemic stroke, respectively) are almost always the result of atherosclerosis and thus explains the relevance of our findings.28 Specifically, in this study we determined that (1) individuals having comorbid OSA and MetS, that is SZ, have a greater prevalence of calcified carotid artery atherosclerotic lesions on their panoramic images than individuals solely with OSA; (2) individuals with SZ have significantly more severe atherogenic profiles (obesity, dyslipidemia, hyperglycemia) than individu- als solely with OSA; and (3) more than half of indi- viduals with SZ having both severe OSA and moderate MetS have CCAAs on their panoramic images. These findings are consistent with a study by Drager et al.,29 who, using ultrasound to evaluate the carotid artery in the bifurcation region, noted that individuals with SZ
had a prevalence of atherosclerotic plaque that was almost twice (10.0% vs 19.6%) as common as those having solely MetS. Drager et al.’s observations,29like those in our study, likely result from the additive proatherogenic effect present in individuals having both OSA and MetS.
In earlier studies of patient populations with OSA, calcified atheromas have been visualized in the carotid artery on cephalometric radiographs30 and also in the coronary artery on electron beam computerized tomog- raphy31 and 3-dimensional intravascular ultrasound.32 Given the medical profession’s relatively recent under- standing of the relationship between OSA and MetS, however, it may be assumed that some of the individ- uals enrolled in the 3 previously cited studies had the combined entity, namely SZ.
OSA and associated atherogenic mechanisms Chronic intermittent hypoxia (IH) (decrement in blood oxygen saturation) caused by OSA-associated apneic and hypopneic events stimulates carotid chemoreceptors to activate the sympathetic nervous system (SNS) and re- lease norepinephrine.33The norepinephrine causes vaso- constriction in the peripheral vascular bed, resulting in a surge in blood pressure, which causes hypertension that damages the blood vessel’s lining and walls fostering atheroma formation.34The repetitive process of IH alter- nating with rapid reoxygenation/reperfusion is responsible for the excessive production of reactive oxygen species (ROS; oxidative stress) that react negatively with nitric oxide produced by vascular endothelium, preventing the expected homeostatic dilatation response and thereby fur- thering vessel wall damage and atheroma develop- ment.35,36
ROS also increase expression of transcription fac- tors, such as nuclear factor kappa, which upregulate the production of proinflammatory cytokines, such as C-re- active protein.37,38 Synergistically, the transcription factors and cytokines upregulate the production of che- moattractant protein and adhesion molecules that facil- itate the recruitment and accumulation of monocytes Fig. 2. A panoramic radiograph digitally enhanced with the
manufacturer provided software evidencing bilateral carotid artery atheromas (arrows). Note the multiple globular contig- uous opacities that lie adjacent to and for the most part inferior to the greater horn of the hyoid bone. The patient, a 68-year-old man, was diagnosed with severe OSA and mod- erate MetS (SZ) by the Sleep Medicine Service using over- night polysomnography (AHI⫽ 48.8), clinical examination, and laboratory data (BMI⫽ 33.4).
Table II. Distribution by severity level of individuals (n ⫽ 31) with OSA and of calcified carotid artery atheromas on the panoramic images
Severity of OSA
No. of individuals
Prevalence of atheromas
Mild (AHI 5-14) 11 6*/11† (55%‡)
Moderate (AHI 15-30) 10 2*/10† (20%‡)
Severe (AHIⱖ31) 10 3*/10† (30%‡)
OSA, obstructive sleep apnea; AHI, apnea-hypopnea index.
*Number of individuals classified as having atheroma(s).
†Total number of individuals within OSA severity level.
‡Proportion of individuals with atheroma within OSA severity level.
and platelets onto the endothelial surface.39-41 Adher- ence of the monocytes to the damaged and dysfunc- tional endothelium enables their entrance into the ves- sel wall where they are transformed into macrophages.
The macrophages then take up the oxidized (promoted by ROS) low-density lipoprotein (LDL), leading to foam cell formation. Simultaneously, platelet-derived growth factor causes hypertrophy of vascular smooth muscle cells, which likewise accumulate oxidized lip- ids.42These noted processes result in the development of atherosclerotic lesions in the carotid artery and often even more advanced lesions in the coronary arteries.43
Atherogenic mechanisms associated with MetS in conjunction with OSA (SZ)
Hyperglycemia, one of the key elements in MetS, arises in part from insulin resistance, which is defined as insulin producing less than the expected biological ef- fect. This hyperglycemic state is worsened by the OSA hypoxia activation of the SNS resulting in the release of catecholamines that increase glycogen breakdown, in- duce gluconeogenesis, decrease insulin sensitivity, and reduce insulin-mediated glucose uptake. The previ- ously formed ROS elicit release of tumor necrosis factor alpha, which inhibits glucose uptake and the storage of free fatty acids (FFA) by the adipocytes within the abdominal adipose tissues.44 Thus ham- pered, the adipocytes release large amounts of FFA into the systemic circulation.45 Muscle cells take up much (but not all) of the FFA, but as they become glutted with FFAs, they also become insulin resistant. With the muscle cells unable to adequately uptake glucose, hy- perglycemia is further exacerbated and, in response, the beta cells of the pancreases are stimulated and produce additional insulin (hyperinsulinemia).46 The residual FFA that was unable to be absorbed by the muscle cells is diverted to the liver via the portal vein where it stimulates the synthesis, assembly, and secretion of lipoproteins that promote atherogenesis (raised triglyc- erides, low concentrations of HDL cholesterol, and small, dense LDL cholesterol).47-49 Hypertension is
now reinforced in the SZ state by a number of other mechanisms, including hyperinsulinemia stimulation of SNS,50overabundance of FFAs that exert a constrictive effect on blood vessels,51 and impairment of insulin’s usual vasodilatory effect.52Furthermore, as previously noted, hypertension disrupts the integrity of the endo- thelial lining of the coronary and carotid blood vessels, permitting ingress of elements associated with ather- oma development.53
The results of our study suggest that dentists should carefully review panoramic images for the presence of CCAA when patients present for treatment of OSA.
This effort is critically important because in a previous study of neurologically asymptomatic males older than 50 without SZ, 23% of individuals with ultrasound- confirmed CCAAs had hemodynamically (ⱖ50%) sig- nificant stenosis in the carotid bulb or internal carotid artery.54 In addition to the stroke-causing potential of hemodynamically significant lesions, the mere presence of any-sized calcified atheroma on panoramic images has great prognostic significance. Specifically, in an- other previous control study it was demonstrated that CCAAs were true independent markers of elevated vascular risk often heralding near-term (⬍3 years) MI, need for coronary artery revascularization surgery, hos- pitalization for intractable angina, transient ischemic attack, and stroke.14
The prognostic implications of carotid artery athero- sclerotic plaques on panoramic images established by these earlier investigations are consistent with a number of B-mode ultrasound studies that have likewise shown that these plaques are a very strong predictor of future adverse cardiovascular/cerebrovascular events. The Tromsø Study conducted among 6179 Norwegians (mean age 60) dem- onstrated that the adjusted relative risk (RR; 95% confi- dence interval [CI]) for first-ever MI between the highest carotid plaque tertile versus no plaque was 1.56 (1.04- 2.36) in men and 3.95 (2.16-7.19) in women.55 The CAFES-CAVE study conducted among 10000 Italians Table III. Distribution of calcified carotid artery atheromas on the panoramic images of patients with syndrome Z (n⫽ 117) relative to severity level of OSA and MetS
Severity of metabolic syndrome by number of RMs Severity of OSA
Mild (RM 3) (n⫽ 67)
Moderate (RM 4) (n⫽ 35)
Severe (RM 5) (n⫽ 15)
Mild (AHI 5-14) (n⫽ 39) 10a/29* (35%†) 3‡/6* (50 %†) 2‡/4* (50%†)
Moderate (AHI 15-30) (n⫽ 37) 8‡/22* (36%†) 5‡/13* (39%†) 0‡/2* (0 %†)
Severe (AHIⱖ31) (n ⫽ 41) 8‡/16* (50%†) 10a/16* (63%†) 3‡/9* (33%†)
OSA, obstructive sleep apnea; MetS, metabolic syndrome; RM, risk marker; AHI, apnea-hypopnea index.
*Total number of individuals within OSA / MetS severity level.
†Proportion of individuals with atheroma within OSA/MetS severity level.
‡Number of individuals with atheroma(s).
(6055 males, 3945 females; mean age 53.2) substanti- ated that the presence of both nonstenotic and stenotic plaques in the carotid bifurcation identified subjects at moderate and high risk of future nonfatal and fatal cardiovascular events.56 Similarly, the Kuopio, Fin- land, Ischemic Heart Disease study of 1288 men (be- tween ages 42 and 60) demonstrated that carotid bulb plaque was a major risk factor for nonfatal and fatal MI in men with nonstenotic and stenotic plaque 4.15 (95% CI, 1.51-11.47; P ⬍ .01) and 6.71 (95% CI, 1.33-33.91; P ⬍ .01), respectively, when compared with men free of any structural changes in the carotid wall.57 Likewise, the Northern Manhattan carotid artery ultrasound study of 1118 stroke-free multieth- nic subjects (59% women, mean age 68) substanti- ated the fact that those with calcified carotid artery plaque in comparison with those without, had a sig- nificantly increased risk of combined adverse vascu- lar outcome (ischemic stroke, MI, or vascular death) (hazard ratio 2.5, 95% CI, 1.0-5.8).58
Several methodological issues should be considered in the interpretation of our study results. First, the data were collected retrospectively rather than prospec- tively. Second, we had to adapt the ATPIII definition of the MetS to the data elements available in our local medical center’s records. Specifically, we used obesity as defined by BMI as a proxy for central obesity, which is classically identified by waist measurement. This alteration may have classified some patients with obe- sity who did not have abdominal obesity, or missed some patients with central obesity, as this is not always captured by a high BMI. In addition, our findings are based on a male population in one Veterans Affairs health care system and cannot be generalized to the US population or to women. Finally, although the sample size for the OSA group was limited, post hoc power analysis of the primary variables related to classically identified major atherogenic risk factors yielded power of 71% to 99% to detect a change of 30% in fasting glucose level, 20% change in BMI, a 20% decrease in HDL, and 15% changes in blood pressure.59 For trig- lycerides, a change from 113 to 180 (59%) would yield a power of 71%. These power estimates were made using alpha levels corrected for multiple comparisons.
In summary, our research has identified a very high prevalence of atherosclerotic lesions on the panoramic images of a cadre of patients presenting for dental treatment of OSA. A large number of these individuals also had MetS, qualifying them for a diagnosis of SZ.
This latter group of individuals had an even greater prevalence of CCAAs on their images. CCAAs have previously been shown to herald adverse cardiovascular and cerebrovascular events, and, therefore, the findings in this most recent study are consistent with epidemi-
ologic studies that have shown that this group of indi- viduals is at uniquely high risk of future MI and stroke.
In conclusion, the dental profession must be prepared to assist in the management of a new cadre of high-risk patients and recognize that one of its most frequently used diagnostic tools may identify a preclinical indica- tor of future adverse cardiovascular events. It is there- fore incumbent on the profession to be uniquely vigi- lant for the presence of CCAAs when evaluating the panoramic images of patients with sleep-disordered breathing and if a lesion is identified, refer the individ- ual back to his or her physician with a detailed note describing the findings.
1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230-5.
2. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health prospective. Am J Respir Crit Care Med 2002;165:1217-39.
3. Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U.S. Dia- betes Care 2005;28:2745-9.
4. Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J 2006;28:596-602.
5. Capampangan DJ, Wellik KE, Parish JM, Aguilar MI, Snyder CR, Wingerchuk D, et al. Is obstructive sleep apnea an indepen- dent risk factor for stroke? A critically appraised topic. Neurol- ogist 2010;16:269-73.
6. Butt M, Dwivedi G, Khair O, Lip GY. Obstructive sleep apnea and cardiovascular disease. Int J Cardiol 2010;139:7-16.
7. Wilcox I, McNamara SG, Collins FL, Grunstein RR, Sullivan CE. “Syndrome Z”: the interaction of sleep apnea, vascular risk factors and heart disease. Thorax 1998;53:S25-8.
8. Lam JC, Ip MS. Obstructive sleep apnea and the metabolic syndrome. Expert Rev Respir Med 2009;3:177-86.
9. Aurora RN, Casey KR, Kristo D, Auerbach S, Bista SR, Chow- dhuri S, et al. Practice parameters for the surgical modifications of the upper airway for obstructive sleep apnea in adults. Sleep 2010;33:1408-13.
10. Carter LC, Haller AD, Nadarajah V, Calamel AD, Aguirre A.
Use of panoramic radiography among an ambulatory dental population to detect patients at risk of stroke. J Am Dent Assoc 1997;128:977-84.
11. Lewis DA, Brooks SL. Carotid artery calcification in a general dental population: a retrospective study of panoramic radio- graphs. Gen Dent 1999;47:98-103.
12. Nossen J, Vierzigmann T, Weiss W, Lang E. [Calcified plaque of the extracranial carotid arteries in comparison with traditional risk factors as a predictor for relevant coronary artery stenosis.]
Herz 2001;26:454-60. German.
13. Griniatsos J, Damaskos S, Tsekouras N, Klonaris C, Georgopou- los S. Correlation of calcified carotid plaques detected by pan- oramic radiograph with risk factors for stroke development. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:600-3.
14. Friedlander AH, Cohen SN. Panoramic radiographic atheromas portend adverse vascular events. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:830-5.
15. Friedlander AH, Friedlander IK, Yueh R, Littner MR. The prev- alence of carotid atheromas seen on panoramic radiographs of
patients with obstructive sleep apnea and their relation to risk factors for atherosclerosis. J Oral Maxillofac Surg 1999;57:
16. Nock NL, Li L, Larkin EK, Patel SR, Redline S. Empirical evidence for “Syndrome Z”: a hierarchical 5-factor model of the metabolic syndrome incorporating sleep disturbance measures.
17. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 2004;25:735-41.
18. Whittle AT, Finch SP, Mortimore IL, MacKay TW, Douglas NJ.
Use of home sleep studies for diagnosis of the sleep apnoea/
hypopnoea syndrome. Thorax 1997;52:1068-73.
19. American Academy of Sleep Medicine. The AASM Manual for the Scoring of Sleep and Associated Events. Rules, Terminology and Technical Specifications. Westchester (IL): American Acad- emy of Sleep Medicine; 2007:1-59.
20. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
21. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C;
National Heart, Lung, and Blood Institute; American Heart As- sociation. Definition of metabolic syndrome: report of the Na- tional Heart, Lung, and Blood Institute/American Heart Associ- ation Conference on Scientific Issues Related to Definition.
Arterioscler Thromb Vasc Biol 2004;24:e13-8.
22. Solymoss BC, Bourassa MG, Campeau L, Sniderman A, Marcil M, Lespérance J, et al. Effect of increasing metabolic syndrome score on atherosclerotic risk profile and coronary artery disease angiographic severity. Am J Cardiol 2004;93:159-64.
23. Alberti KG, Zimmet PZ. Definition, diagnosis, and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-53.
24. Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Han- delsman Y, et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003;9:237-52.
25. McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C, Reaven G. Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann Intern Med 2003;139:802-9.
26. Malik S, Wong ND, Franklin SS, Kamath TV, L’Italien GJ, Pio JR, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004;110:1245-50.
27. Friedlander AH. Panoramic radiography: the differential diagno- sis of carotid atheromas. Spec Care Dent 1995;15:223-7.
28. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Heart disease and stroke statistics—2011 Update: A report from the American Heart Association. Circu- lation 2011;123:e18-209.
29. Drager LF, Bortolotto LA, Maki-Nunes C, Trombetta IC, Alves MJ, Fraga RF, et al. The incremental role of obstructive sleep apnoea on markers of atherosclerosis in patients with metabolic syndrome. Atherosclerosis 2010;208:490-5.
30. Tsuda H, Almeida FR, Tsuda T, Moritsuchi Y, Lowe AA.
Cephalometric calcified carotid artery atheromas in patients with obstructive sleep apnea. Sleep Breath 2010;14:365-70.
31. Sorajja D, Gami AS, Somers VK, Behrenbeck TR, Garcia- Touchard A, Lopez-Jimenez F. Independent association between
obstructive sleep apnea and subclinical coronary artery disease.
32. Turmel J, Sériès F, Boulet LP, Poirier P, Tardif JC, Rodés- Cabeau J, et al. Relationships between atherosclerosis and the sleep apnea syndrome: an intravascular ultrasound study. Int J Cardiol 2009;132:203-9.
33. González-Martín MC, Vega-Agapito V, Prieto-Lloret J, Agapito MT, Castañeda J, Gonzalez C. Effects of intermittent hypoxia on blood gases, plasma, catecholamine and blood pressure. Adv Exp Med Biol 2009;648:319-28.
34. Rouwet EV, Tintu AN, Schellings MW, van Bilsen M, Lutgens E, Hofstra L, et al. Hypoxia induces aortic hypertrophic growth, left ventricular dysfunction, and sympathetic hyperinnervation of peripheral arteries in the chick embryo. Circulation 2002;105:
35. Peng Y, Yuan G, Overholt JL, Kumar GK, Prabhakar NR.
Systemic and cellular responses to intermittent hypoxia: evi- dence for oxidative stress and mitochondrial dysfunction. Adv Exp Med Biol 2003;536:559-64.
36. Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winn- icki M, Accurso V, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102:2607-10.
37. Lavie L, Lavie P. Molecular mechanisms of cardiovascular dis- ease in OSAHS: the oxidative stress link. Eur Respir J 2009;33:1467-84.
38. Ryan S, Taylor CT, McNicholas WT. Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Thorax 2009;64:631-6.
39. Lévy P, Pépin JL, Arnaud C, Baguet JP, Dematteis M, Mach F.
Obstructive sleep apnea and atherosclerosis. Prog Cardiovasc Dis 2009;51:400-10.
40. Ryan S, McNicholas WT. Inflammatory cardiovascular risk markers in obstructive sleep apnoea syndrome. Cardiovasc He- matol Agents Med Chem 2009;7:76-81.
41. Quercioli A, Mach F, Montecucco F. Inflammation accelerates atherosclerotic processes in obstructive sleep apnea syndrome (OSAS). Sleep Breath 2010;14:261-9.
42. Lattimore JD, Wilcox I, Nakhla S, Langenfeld M, Jessup W, Celermajer DS. Repetitive hypoxia increases lipid loading in human macrophages—a potentially atherogenic effect. Athero- sclerosis 2005;179:255-9.
43. Schulz R, Seeger W, Fegbeutel C, Hüsken H, Bödeker RH, Tillmanns H, et al. Changes in extracranial arteries in obstructive sleep apnoea. Eur Respir J 2005;25:69-74.
44. Punjabi NM, Ahmed MM, Polotsky VY, Beamer BA, O’Donnell CP. Sleep-disordered breathing, glucose intolerance, and insulin resistance. Respir Physiol Neurobiol 2003;136:167-78.
45. Ginsberg HN. Treatment of patients with the metabolic syn- drome. Am J Cardiol 2003;91:29E-39E.
46. Isomaa B. A major health hazard: the metabolic syndrome. Life Sci 2003;73:2395-411.
47. Fisher EA, Ginsberg HN. Complexity in the secretory pathway:
the assembly and secretion of apolipoprotein B-containing lipo- proteins. J Biol Chem 2002;277:17377-80.
48. Berglund L, Hyson D. Cholesterol absorption and the metabolic syndrome: a new look at an old area. Arterioscler Thromb Vasc Biol 2003;23:1314-16.
49. McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001;86:713-8.
50. Sowers JR, Frohlich ED. Insulin and insulin resistance: impact on blood pressure and cardiovascular disease. Med Clin North Am 2004;88:63-82.
51. Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, et al. Elevation of free fatty acids induces inflammation and
impairs vascular reactivity in healthy subjects. Diabetes 2003;
52. Tooke JE, Hannemann MM. Adverse endothelial function and the insulin resistance syndrome. J Intern Med 2000;247:425-31.
53. Hulthe J, Bokemark L, Wikstrand J, Fagerberg B. The metabolic syndrome, LDL particle size, and atherosclerosis: the Athero- sclerosis and Insulin Resistance (AIR) study. Arterioscler Thromb Vasc Biol 2000;20:2140-7.
54. Friedlander AH, Garrett NR, Chin EE, Baker JD. Ultrasono- graphic confirmation of carotid artery atheromas diagnosed via panoramic radiography. J Am Dent Assoc 2005;136:635-40.
55. Johnsen SH, Mathiesen EB, Joakimsen O, Stensland E, Wils- gaard T, Løchen ML, et al. Carotid atherosclerosis is a stronger predictor of myocardial infarction in women than in men: a 6-year follow-up study of 6226 persons: the Tromsø study.
56. Belcaro G, Nicolaides AN, Ramaswami G, Cesarone MR, De Sanctis M, Incandela L, et al. Carotid and femoral ultrasound morphology screening and cardiovascular events in low risk
subjects: a 10-year follow-up study (the CAFES-CAVE study(1)). Atherosclerosis 2001;156:379-87.
57. Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb 1991;11:1245-9.
58. Prabhakaran S, Singh R, Zhou X, Ramas R, Sacco RL, Rundek T.
Presence of calcified carotid plaque predicts vascular events: the Northern Manhattan Study. Atherosclerosis 2007;195:e197-201.
59. Kannel WB. The Framingham Study: its 50-year legacy and future promise. J Atheroscler Thromb 2000;6:60-6.
Arthur H. Friedlander, DMD
Associate, Chief of Staff and Director Graduate Medical Education VA Greater Los Angeles Healthcare System
11301 Wilshire Boulevard Los Angeles, CA 90073 E-mail:firstname.lastname@example.org