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Carotid artery atheromas in postmenopausal women
hirty-five million women are 55 years of age or older in the U.S. The physiological changes associated with menopause (for example, reduced levels of estrogen) and other processes associated with aging result in women being at a disproportionately high risk of developing stroke, the third leading cause of death in the United States. In 1991, women accounted for almost 61 percent of Americans who died of cerebrovascular disease; however, most epidemiologic studies have centered on identifying prevalence rates and risk factors in men.1 Stroke and its aftereffects cost the nation more than $30 billion each year.2 Moreover, Some identifying stroke-prone older women women at during the course of a routine dental high risk of examination would be a public health developing measure of great humanitarian significance. stroke can be The vast majority of strokes in postidentified in menopausal women, as in men, are the the dental result of ischemic cerebral injury caused office via by atherosclerotic disease (thrombus panoramic and embolus formation). Numerous radiography. studies have shown that men who have had a stroke almost always have an atherosclerotic lesion at the bifurcation of the common carotid artery. Although far fewer studies have been conducted among women, and almost all have involved small sample sizes, the data implicate high-grade stenotic lesions at the carotid bifurcation as the most likely cause of stroke.3,4 Atherosclerotic lesions at the carotid bifurcation
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JADA, Vol. 132, August 2001 Copyright ©1998-2001 American Dental Association. All rights reserved.
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ARTHUR H. FRIEDLANDER, D.D.S.; LISA ALTMAN, M.D.
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Their prevalence on panoramic radiographs and their relationship to atherogenic risk factors
Background. More than 60 percent of the deaths in the United States A D A attributed to stroke occur in J postmenopausal women. ✷ ✷ ® As estrogen levels decline, atherosclerotic lesions (that is, atheromas) deN C U A ING EDU 4 velop in the region of the RT carotid bifurcation and have ICLE been implicated as the precipitating cause in the majority of these strokes. Atheromas often are calcified and have been detected on the panoramic radiographs of neurologically asymptomatic male veterans; however, similar studies have not been conducted among female veterans. Methods. The authors assessed panoramic radiographs and medical records of 52 neurologically asymptomatic female veterans (mean age, 70.4 years), with a history of amenorrhea of more than 12 months’ duration, for atheromas and risk factors associated with atherosclerosis. Results. The radiographs of 16 subjects (31 percent) exhibited atheromas located in the neck about 2.0 centimeters inferior and posterior to the angle of the mandible. These findings were confirmed in all instances by the presence of atheromas on anteroposterior cervical spine radiographs. The medical histories of these subjects were heavily laden with atherogenic risk factors (hypertension, 94 percent; body mass index of 27 to 29.9 [characterized as overweight], 25 percent; body mass index of 30 or higher [characterized as obese], 25 percent; smoking more than 15 pack-years, 38 percent; hyperlipidemia, 69 percent; type 2 diabetes mellitus, 21 percent). Hypertension was significantly associated with the presence of atheromas. Conclusions. Some neurologically asymptomatic women at high risk of developing stroke can be identified in the dental office via panoramic radiography. Women whose X-rays show calcified carotid artery atheromas are almost always hypertensive and have medical histories heavily laden with other atherogenic risk factors. Clinical Implications. Dentists should refer patients with such calcifications to an appropriate physician for further evaluation and treatment. CON
Carotid artery atheromas in postmenopausal women
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frequently are calcified and have been shown to Subjects whose panoramic radiograph exhibited a be detectable on the panoramic dental radiocalcification in the area of the carotid bifurcation graphs of neurologically asymptomatic high-risk then underwent radiographic examination of the male veterans.5,6 A review of the literature, howanteroposterior view of the cervical spine for conever, reveals only two studies in which female firmation of the presence of an atheroma. Criteria participants (as well as male participants) were for the differential diagnosis of atheromas on assessed for atheroma formation on panoramic panoramic and cervical spine radiographs have radiographs.7,8 The mean ages (40 and 32 years) of been published elsewhere.6,9 7,8 the populations studied, however, were quite We reviewed the medical records of the study young, and so these subjects were at low risk of population for risk factors known to be associated experiencing atheroma formation. The prevalence with atherosclerosis in women. Specifically rate of atheroma formation among the women in assessed were demographic characteristics, these studies was 2 percent, but their atherogenic hypertension, excess weight/obesity, age at natrisk factors (that is, obesity, smoking, hypertenural or surgically induced menopause, type of oral sion, hyperlipidemia, diabetes mellitus) could not HRT (that is, estrogen alone or estrogen combe determined because their data were combined bined with progestin), lipid profile, diabetes melwith the data for men with atheromas. Informalitus and smoking habits. tion regarding menopause status, hormone Patients reported physician-diagnosed hyperreplacement therapy, or HRT, if any and laboratension or current use of antihypertensive meditory test results were not reported. cation. Being “overweight” was defined as having Therefore, we undertook this a body mass index, or BMI (calcuresearch project to determine the lated as kilograms/meter 2), of 27 to Atherosclerotic prevalence of atheromas on the 29.9, and “obesity” was defined as a lesions at the panoramic radiographs of an excluBMI of 30 or higher.10 Fasting plasma carotid bifurcation sively postmenopausal female populipid analyses included measurement lation aged 55 years and older and of total cholesterol levels (normal reffrequently are to identify all of their atherogenic erence range, 146 to 200 calcified and have risk factors. milligrams/deciliter) and low-density been detected lipoprotein, or LDL, cholesterol levels on the panoramic MATERIALS AND METHODS (normal reference range, 62 to 130 dental radiographs The study population of 52 subjects mg/dL), calculated according to the of neurologically was recruited from 567 consecuFriedewald equation.11 tively screened patients treated at We determined that subjects had asymptomatic the Women’s Health Clinic, Vetdiabetes if they reported having high-risk erans Affairs Outpatient Clinic, received a diagnosis from their physimale veterans. Sepulveda, Calif. Inclusion criteria cian, currently used insulin or oral were female sex, age 55 years or hypoglycemic medication, or had a older, a history of amenorrhea of at least 12 fasting plasma glucose level greater than 126 months’ duration and a standard panoramic mg/dL on two separate occasions.12 A positive radiograph of diagnostic quality. Exclusion crismoking history was defined as having smoked teria were a history of a transient ischemic attack more than 15 pack-years during a lifetime (that is, or a history of a cerebrovascular accident. the equivalent of one pack of cigarettes smoked per Equipment. A research dental assistant day for 15 years). obtained radiographs of the subjects using a We analyzed the data by compiling the demopanoramic X-ray system operated at 10 milgraphic information and calculating the prevalence liamperes and 75 kilovolts and dental film. The rates of calcified carotid artery atheromas and exposed radiographs were developed with an atherosclerosis-associated risk factors for the study automatic developer. population and for the subgroups with and without Methods. One of us (A.F.) examined the radioatheroma formation. In addition, we compared the graphs in subdued ambient light using transprevalence rates of atheroma formation between mitted light from a standard viewing box and a women who had been postmenopausal for 10 or rheostat-controlled 75-watt bulb (a “hot” light) for more years and had received HRT for more than the presence of calcified carotid artery atheromas. 50 percent of that time and women who had been JADA, Vol. 132, August 2001 Copyright ©1998-2001 American Dental Association. All rights reserved.
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Figure 1. Standard panoramic dental radiograph with calcified carotid arterial plaques visible in the right and left sides of the neck (arrows).
Figure 2. Cropped panoramic dental radiograph with two calcified carotid arterial plaques visible just anterior to the cervical spine in the left side of the neck (arrows).
postmenopausal for 10 or more years and had never received HRT. We used the Fisher exact test (categorical variables) or Student t test (continuous variables) to conduct statistical comparisons between subgroups with and without atheroma. RESULTS
The study population consisted of 49 white women and three African-American women (n = 52), with a mean age of 70.4 years and an age range of 55 to 90 years. A review of their medical histories revealed that 36 (69 percent) of the sub1132
jects were hypertensive, eight (15 percent) had a BMI of 27 to 29.9 and 15 (29 percent) had a BMI of 30 or greater. The majority (75 percent) of subjects had gone through natural (physiological) menopause at a mean age of 49.3 years, and 25 percent had gone through surgical (artificial) menopause after a hysterectomy (surgical removal of the uterus and cervix) and an accompanying oophorectomy (surgical removal of both ovaries) at a mean age of 38.2 years. Hormone replacement therapy. At the time that subjects underwent radiography, they had been postmenopausal for a mean of 24 years (range, six to 43 years). Thirty-seven (71 percent) of the women were receiving HRT, with 22 (42 percent) receiving estrogen alone for a mean of 8.5 years (range, one to 38 years) and 15 (29 percent) receiving estrogen and progestin for a mean of 5.8 years (range, six months to 20 years). One subject had received a course of estrogen alone for two years, followed by a six-year course of estrogen and progestin. Risk factors. Atherogenic risk factors were common, with 32 subjects (62 percent) having an elevated total serum cholesterol level (mean level, 238 mg/dL), 23 (42 percent) having an elevated LDL cholesterol level (mean level, 154 mg/dL) and 11 (19 percent) having type 2 diabetes mellitus. Smoking also was common, with 15 (29 percent) of the 52 subjects reporting having smoked during their lives. These subjects had smoked a mean of 37.5 pack-years, with a range of 15 to 65 years. Panoramic radiographs. The panoramic radiographs of 16 white subjects (31 percent), with a mean age of 72.1 years (range, 56 to 84 years), exhibited calcified carotid artery disease. Eight subjects had unilateral opacities and eight had bilateral opacities (Figures 1 and 2). Anteroposterior cervical spine radiographs confirmed that each of these 16 women had calcified carotid artery atheromas; however, for two of the eight subjects whose panoramic radiographs showed unilateral atheromas, bilateral atheromas were found on the anteroposterior film. A review of the medical histories of the 16 women with calcified carotid atheromas revealed that 15 (94 percent) were hypertensive, four (25 percent) had a BMI between 27 and 29.9 (characterized as overweight) and four (25 percent) had a BMI of 30 or greater (characterized as obese). Twelve (75 percent) of the subjects had gone through physiological menopause at a mean age
JADA, Vol. 132, August 2001 Copyright ©1998-2001 American Dental Association. All rights reserved.
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of 46.3 years, and four (25 percent) had gone through surgical menopause at a mean age of 43.5 years. At the time we detected the atheroma via panoramic radiography, subjects had been postmenopausal for a mean of 22.4 years, with a range of three to 50 years. Twelve (75 percent) of the 16 women were receiving HRT, with eight (50 percent) receiving estrogen alone (mean duration, 5.4 years [range, two to 15 years]) and three (19 percent) receiving estrogen and progestin (mean duration, four years [range, two to six years]). One subject (6 percent) received estrogen alone for two years, followed by a six-year course of estrogen and progestin. Atherogenic risk factors were common among the 16 women with atheromas: nine subjects (56 percent) had an elevated total serum cholesterol level (mean level, 245 mg/dL), eight (50 percent) had an elevated LDL cholesterol level (mean level, 151 mg/dL) and three (19 percent) had type 2 diabetes mellitus. Smoking also was common, with six subjects (38 percent) reporting that they had smoked during their lives. These subjects had smoked a mean of 27 pack-years, with a range of 15 to 65 years. Statistical analysis. Our analysis of discrete risk factors for atherosclerosis performed between the groups of women with and without atheroma formation demonstrated that hypertension was a significant risk factor for the development of arterial disease. However, we found that “ever use” of HRT was unrelated to the presence or absence of atheromas in this study sample. Thirteen (25 percent) of the 52 subjects in the study reported that they had received long-term HRT (mean time, 14.3 years; mean number of postmenopausal years, 20.5). Panoramic radiography showed that two (15 percent) of these women had atheromas. In contrast, 15 women reported that they had never received HRT (mean number of postmenopausal years, 14). Panoramic radiography showed that three (21 percent) of these women had atheromas. Thus, the difference in prevalence rates between the two groups of subjects was not statistically significant. We calculated a combined score for risk factors by totaling the number of risk factors that were positive for each subject: hypertension, being overweight (or obese), elevated cholesterol (or LDL) level, diabetes mellitus and smoking (scores ranged from 0 to 5). As shown in the table, the mean number of positive risk factors (2.6,
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standard deviation = 1.5) for women with atheroma formation was not different from that for women without atheromas (2.1, standard deviation = 1.1). DISCUSSION
Clinicians can identify some women at high risk of developing stroke in the dental office. In our study, standard panoramic dental radiographs detected the presence of calcified cervical carotid artery disease in approximately 31 percent of postmenopausal women with no history of transient ischemic attack or stroke. Our analysis of women with and without atheroma formation demonstrated that hypertension was a significant risk factor for the development of atheromas, but HRT did not appear to influence the development of these lesions. The carotid artery calcifications were located within the soft tissues of the neck, approximately 2 centimeters inferior and posterior to the angle of the mandible at about the level of the lower margin of the third cervical vertebra (where discernible). Their distinctive appearance (single or multiple punctuate or verticolinear calcifications) and location readily distinguished them from other confounding opacities (that is, hyoid bone, salivary calculi, phleboliths, calcified lymph nodes, tip of the epiglottis, styloid process and associated ligaments). The results of our study are consistent with those of a recent high-resolution ultrasonographic study of 2,588 postmenopausal women, which demonstrated that 49 percent of subjects had carotid artery plaques.13 Our results are somewhat more modest because panoramic radiographs can detect only those lesions that have significant deposits of calcium, while ultrasonography can detect early lesions that are devoid of calcium or that have minimal amounts of calcium.14 The women in our study were about 70 years of age, and other studies15,16 have noted that the age range of 66 to 70 years is the crucial period for women to develop significant atherosclerotic lesions (that is, stenosis of 40 percent or greater) at the carotid bifurcation. Stenotic lesions of this magnitude are capable of reducing cerebral blood flow and are associated with a yearly risk of cerebral infarction of approximately 5 percent.17 The authors of these studies13-17 noted, as did we, that hypertension, a disorder common in women at the age of menopause, was a significant risk factor for
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TABLE
RISK-FACTOR ANALYSIS FOR ATHEROSCLEROSIS IN POSTMENOPAUSAL WOMEN. RISK FACTOR
ATHEROMAS PRESENT (n = 16)
ATHEROMAS ABSENT (n = 36)
STUDENT t TEST (P VALUE)
Mean Age at Time of Radiography (Years)
72.1
69.5
.884 (.38)
Mean No. of Years Since Menopause Began
22.4
23.8
.387 (.70)
Mean No. of Years of Estrogen Treatment
5.1
10.9
.945 (.35) .
Mean No. of Years of Estrogen and Progestin Treatment
4.3
6.3
.539 (.59)
Mean No. of Postmenopausal Years Without Treatment for Subjects Who Received HRT*
18.5
17.6
.232 (.82)
Mean Sum of Risk Factors (Range, 0 to 5)
2.6
2.1
1.32 (.19)
No. of Subjects Who Never Received HRT
4
11
NS†
No. of Subjects Who Received Estrogen‡
9
14
NS†
No. of Subjects Who Received Estrogen and Progestin‡
4
11
NS†
No. of Subjects With Hypertension
15
21
(.011) (Fisher exact test)
No. of Subjects Who Were Overweight
4
4
NS†
No. of Subjects Who Were Obese
4
11
NS†
No. of Subjects With Elevated Total Cholesterol (> 200 mg/dL§)
9
23
NS†
No. of Subjects With Elevated Serum LowDensity Cholesterol (> 130 mg/dL)
8
15
NS†
No. of Subjects With Diabetes
3
8
NS†
No. of Subjects Who Smoked ≥ 15 Pack-Years**
6
9
NS†
* HRT: Hormone replacement therapy. † NS: Not significant (Fisher exact test). ‡ One subject received estrogen therapy for two years, followed by estrogen and progestin therapy for five years, and is included in both categories. § mg/dL: Milligrams per deciliter. ** 15 pack-years is equivalent to one pack of cigarettes smoked per day for 15 years.
the development of atherosclerosis in the area of the carotid bifurcation. Hypertension disrupts the integrity of the 1134
carotid vessel’s endothelial lining and initiates plaque formation. Serum lipoproteins and platelet-derived growth factor, or PDGF, pass
JADA, Vol. 132, August 2001 Copyright ©1998-2001 American Dental Association. All rights reserved.
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through the damaged and hyperpermeable endothelium. The lipoproteins lodge in the intima and the PDGFs cause proliferation of smooth muscle cells. The thickened and elevated lesion calcifies primarily at the junction of the intima and media, and protrudes into the vessel lumen, altering the flow of blood.18 Postmenopausal women also are at high risk of developing carotid artery atherosclerosis because they frequently develop an atherogenic blood lipid profile at the time menses cease. Reduced levels of circulating estrogen are associated with an increase in hepatic lipase activity and a decrease in LDL catabolism, which result in increased levels of LDL cholesterol and reduced levels of HDL cholesterol.19-21 Reduced levels of circulating estrogen also have been shown in animal models to be associated with enhanced myointimal hyperplasia.22-24 Although many studies have demonstrated the efficacy of HRT to delay the onset or halt the progression of carotid artery atherosclerosis, our study did not, but this might be the result of having had a small sample size.25-29 Identifying a calcified carotid artery atheroma on a panoramic radiograph is of major clinical significance. In 1994, Friedlander and colleagues30 observed that the panoramic radiographs of patients who had suffered an ischemic stroke were 10 times more likely to exhibit a calcified carotid artery atheroma than were radiographs of similarly aged, neurologically asymptomatic people. In 1996, in response to the observations of Friedlander and Friedlander,31 Crouse32 noted that atheromas detected on panoramic radiographs were likely to be indicative of generalized atherosclerosis and that patients with such lesions required an intensive medical evaluation of their carotid and coronary arteries. Woodworth and colleagues33 found that the presence of atheromas on the panoramic radiographs of high-risk patients is a significant predictor of death from cardiovascular disease. CONCLUSION
The results of this study show that some older women with calcified carotid artery atheromas can be identified in the dental office via panoramic radiography. Patients with such calcifications may be at risk of experiencing stroke and should be referred to an appropriate physician for confirmation of the findings and determination of the extent of disease. The control of risk factors, administration of medications and prophylactic
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surgical removal of the plaque, in selected patients, are safe and reliable methods of reducing the incidence of cerebrovascular accidents. ■ Dr. Friedlander is the associate chief of staff and the director, Graduate Medical Education, Veterans Affairs Greater Los Angeles Healthcare System; director, Quality Assurance, Hospital Dental Service, Medical Center at the University of California Los Angeles; and a professor, Oral and Maxillofacial Surgery, University of California Los Angeles School of Dentistry. Address reprint requests to Dr. Friedlander, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail “arthur. [email protected]. gov”.
Dr. Altman is the director of the Women’s Health Clinic at the Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda Division, Sepulveda, Calif., and a clinical associate professor, Department of Medicine, University of California Los Angeles School of Medicine.
1. American Heart Association. Heart and stroke facts: 1995 statistical supplement. Dallas: American Heart Association; 1994:11. 2. Dobkin B. The economic impact of stroke. Neurology 1995;45(2 suppl 1):S6-9. 3. Ryglewicz D, Rosenfeld A, BaranskaGieruszczak M, Czyrny M, Lechowicz W. Carotid artery disease in patients with ischemic stroke: results of year-long observation conducted within the framework of prospective epidemiological studies, Warsaw, 1991-1992. Neurol Neurochir Pol 1998;32(2): 255-64. 4. Rothwell PM, Slattery J, Warlow CP. Clinical and angiographic predictors of stroke and death from carotid endarterectomy: systematic review. BMJ 1997;315(7122):1571-7. 5. Friedlander AH, Baker JD. Panoramic radiography: an aid in detecting patients at risk of cerebrovascular accident. JADA 1994;
125:1598-603. 6. Friedlander AH. Identification of stroke-prone patients by panoramic and cervical spine radiography. Dentomaxillofac Radiol 1995;24(3):160-4. 7. 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. JADA 1997;128:977-84. 8. Lewis DA, Brooks SL. Carotid artery calcification in a general dental population: a retrospective study of panoramic radiographs. Gen Dent 1999;47(1):98-103. 9. Friedlander AH. Panoramic radiography: the differential diagnosis of carotid artery atheromas. Spec Care Dentist 1995;15(6):223-7. 10. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report— National Institutes of Health. Obes Res 1998;6(supplement 2): 51S-209S. 11. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18(6):499-502. 12. Standards of medical care for patients with diabetes mellitus— American Diabetes Association. Diabetes Care 1997;20:1183-97. 13. Joakimsen O, Bonaa KH, Stensland-Bugge E, Jacobsen BK. Population-based study of age at menopause and ultrasound assessed carotid atherosclerosis: the Tromso Study. J Clin Epidemiol 2000;53(5): 525-30. 14. Foley WD. Color doppler flow imaging. Boston: Andover Medical Publishers; 1991:1-65. 15. Willeit J, Kiechl S. Prevalence and risk factors of asymptomatic extracranial carotid artery atherosclerosis: a population-based study. Arterioscler Thromb 1993;13(5):661-8. 16. Prati P, Vanuzzo D, Casaroli M, et al. Prevalence and determinants of carotid atherosclerosis in a general population. Stroke 1992; 23(12):1705-11. 17. Winslow CM, Solomon DH, Chassin MR, Kosecoff J, Merrick NJ, Brook RH. The appropriateness of carotid endarterectomy. N Engl J Med 1988;318(12):721-7. 18. Mitchell ME, Sidawy AN. The pathophysiology of atherosclerosis. Semin Vasc Surg 1998;11(3):134-41. 19. Krauss RM, Perlman JA, Ray R, Petitti D. Effects of estrogen dose and smoking on lipid and lipoprotein levels in postmenopausal women. Am J Obstet Gynecol 1988;158:1606-11. 20. Applebaum-Bowden D, McLean P, Steinmetz A, et al. Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen
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administration in postmenopausal women. J Lipid Res 1989;30(2): 1895-906. 21. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325(17):1196-204. 22. Sack MN, Rader DJ, Cannon RO 3rd. Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet 1994;343(8892):269-70. 23. Haarbo J, Leth-Espensen P, Stender S, Christiansen C. Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits. J Clin Invest 1991;87:1274-9. 24. Cheng LP, Kuwahara M, Jacobsson J, Foegh ML. Inhibition of myointimal hyperplasia and macrophage infiltration by estradiol in aorta allografts. Transplantation 1991;52(6):967-72. 25. Espeland MA, Applegate W, Furberg CD, Lefkowitz D, Rice L, Hunninghake D. Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. ACAPS Investigators. Asymptomatic Carotid Atherosclerosis Progression Study. Am J Epidemiol 1995;142(10):1011-9. 26. Akkad A, Hartshorne T, Bell PR, al-Azzawi F. Carotid plaque regression on oestrogen replacement: a pilot study. Eur J Vasc Endovasc Surg 1996;11(3):347-8.
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27. Westendorp IC, Veld BA, Bots ML, et al. Hormone replacement therapy and intima-media thickness of the common carotid artery: the Rotterdam Study. Stroke 1999;30(12):2562-7. 28. Jonas HA, Kronmal RA, Psaty BM, et al. Current estrogen-progestin and estrogen replacement therapy in elderly women: association with carotid atherosclerosis. CHS Collaborative Research Group. Cardiovascular Health Study. Ann Epidemiol 1996;6(4):314-23. 29. McGrath BP, Liang YL, Teede H, Shiel LM, Cameron JD, Dart A. Age-related deterioration in arterial structure and function in postmenopausal women: impact of hormone replacement therapy. Arterioscler Thromb Vasc Biol 1998;18(7):1149-56. 30. Friedlander AH, Manesh F, Wasterlain CG. Prevalence of detectable carotid artery calcifications on panoramic radiographs of recent stroke victims. Oral Surg Oral Med Oral Pathol 1994;77(6): 669-73. 31. Friedlander AH, Friedlander IK. Panoramic dental radiography: an aid in detecting individuals prone to stroke. Br Dent J 1996;181(1): 23-6. 32. Crouse JR 3rd. Heart of the matter in cerebral arterial sclerosis. Lancet 1996;348(9030):766. 33. Woodworth W, Genco RJ, Knowler W, Pettitt M, Shlossman R, Dunford J. Calcified carotid atherosclerotic plaque as a predictor of CVD death. J Dent Res 2000;79(special issue):524.
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JADA, Vol. 132, August 2001 Copyright ©1998-2001 American Dental Association. All rights reserved.
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ARTHUR H. FRIEDLANDER, D.D.S.; LISA ALTMAN, M.D.
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Their prevalence on panoramic radiographs and their relationship to atherogenic risk factors
Background. More than 60 percent of the deaths in the United States A D A attributed to stroke occur in J postmenopausal women. ✷ ✷ ® As estrogen levels decline, atherosclerotic lesions (that is, atheromas) deN C U A ING EDU 4 velop in the region of the RT carotid bifurcation and have ICLE been implicated as the precipitating cause in the majority of these strokes. Atheromas often are calcified and have been detected on the panoramic radiographs of neurologically asymptomatic male veterans; however, similar studies have not been conducted among female veterans. Methods. The authors assessed panoramic radiographs and medical records of 52 neurologically asymptomatic female veterans (mean age, 70.4 years), with a history of amenorrhea of more than 12 months’ duration, for atheromas and risk factors associated with atherosclerosis. Results. The radiographs of 16 subjects (31 percent) exhibited atheromas located in the neck about 2.0 centimeters inferior and posterior to the angle of the mandible. These findings were confirmed in all instances by the presence of atheromas on anteroposterior cervical spine radiographs. The medical histories of these subjects were heavily laden with atherogenic risk factors (hypertension, 94 percent; body mass index of 27 to 29.9 [characterized as overweight], 25 percent; body mass index of 30 or higher [characterized as obese], 25 percent; smoking more than 15 pack-years, 38 percent; hyperlipidemia, 69 percent; type 2 diabetes mellitus, 21 percent). Hypertension was significantly associated with the presence of atheromas. Conclusions. Some neurologically asymptomatic women at high risk of developing stroke can be identified in the dental office via panoramic radiography. Women whose X-rays show calcified carotid artery atheromas are almost always hypertensive and have medical histories heavily laden with other atherogenic risk factors. Clinical Implications. Dentists should refer patients with such calcifications to an appropriate physician for further evaluation and treatment. CON
Carotid artery atheromas in postmenopausal women
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frequently are calcified and have been shown to Subjects whose panoramic radiograph exhibited a be detectable on the panoramic dental radiocalcification in the area of the carotid bifurcation graphs of neurologically asymptomatic high-risk then underwent radiographic examination of the male veterans.5,6 A review of the literature, howanteroposterior view of the cervical spine for conever, reveals only two studies in which female firmation of the presence of an atheroma. Criteria participants (as well as male participants) were for the differential diagnosis of atheromas on assessed for atheroma formation on panoramic panoramic and cervical spine radiographs have radiographs.7,8 The mean ages (40 and 32 years) of been published elsewhere.6,9 7,8 the populations studied, however, were quite We reviewed the medical records of the study young, and so these subjects were at low risk of population for risk factors known to be associated experiencing atheroma formation. The prevalence with atherosclerosis in women. Specifically rate of atheroma formation among the women in assessed were demographic characteristics, these studies was 2 percent, but their atherogenic hypertension, excess weight/obesity, age at natrisk factors (that is, obesity, smoking, hypertenural or surgically induced menopause, type of oral sion, hyperlipidemia, diabetes mellitus) could not HRT (that is, estrogen alone or estrogen combe determined because their data were combined bined with progestin), lipid profile, diabetes melwith the data for men with atheromas. Informalitus and smoking habits. tion regarding menopause status, hormone Patients reported physician-diagnosed hyperreplacement therapy, or HRT, if any and laboratension or current use of antihypertensive meditory test results were not reported. cation. Being “overweight” was defined as having Therefore, we undertook this a body mass index, or BMI (calcuresearch project to determine the lated as kilograms/meter 2), of 27 to Atherosclerotic prevalence of atheromas on the 29.9, and “obesity” was defined as a lesions at the panoramic radiographs of an excluBMI of 30 or higher.10 Fasting plasma carotid bifurcation sively postmenopausal female populipid analyses included measurement lation aged 55 years and older and of total cholesterol levels (normal reffrequently are to identify all of their atherogenic erence range, 146 to 200 calcified and have risk factors. milligrams/deciliter) and low-density been detected lipoprotein, or LDL, cholesterol levels on the panoramic MATERIALS AND METHODS (normal reference range, 62 to 130 dental radiographs The study population of 52 subjects mg/dL), calculated according to the of neurologically was recruited from 567 consecuFriedewald equation.11 tively screened patients treated at We determined that subjects had asymptomatic the Women’s Health Clinic, Vetdiabetes if they reported having high-risk erans Affairs Outpatient Clinic, received a diagnosis from their physimale veterans. Sepulveda, Calif. Inclusion criteria cian, currently used insulin or oral were female sex, age 55 years or hypoglycemic medication, or had a older, a history of amenorrhea of at least 12 fasting plasma glucose level greater than 126 months’ duration and a standard panoramic mg/dL on two separate occasions.12 A positive radiograph of diagnostic quality. Exclusion crismoking history was defined as having smoked teria were a history of a transient ischemic attack more than 15 pack-years during a lifetime (that is, or a history of a cerebrovascular accident. the equivalent of one pack of cigarettes smoked per Equipment. A research dental assistant day for 15 years). obtained radiographs of the subjects using a We analyzed the data by compiling the demopanoramic X-ray system operated at 10 milgraphic information and calculating the prevalence liamperes and 75 kilovolts and dental film. The rates of calcified carotid artery atheromas and exposed radiographs were developed with an atherosclerosis-associated risk factors for the study automatic developer. population and for the subgroups with and without Methods. One of us (A.F.) examined the radioatheroma formation. In addition, we compared the graphs in subdued ambient light using transprevalence rates of atheroma formation between mitted light from a standard viewing box and a women who had been postmenopausal for 10 or rheostat-controlled 75-watt bulb (a “hot” light) for more years and had received HRT for more than the presence of calcified carotid artery atheromas. 50 percent of that time and women who had been JADA, Vol. 132, August 2001 Copyright ©1998-2001 American Dental Association. All rights reserved.
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Figure 1. Standard panoramic dental radiograph with calcified carotid arterial plaques visible in the right and left sides of the neck (arrows).
Figure 2. Cropped panoramic dental radiograph with two calcified carotid arterial plaques visible just anterior to the cervical spine in the left side of the neck (arrows).
postmenopausal for 10 or more years and had never received HRT. We used the Fisher exact test (categorical variables) or Student t test (continuous variables) to conduct statistical comparisons between subgroups with and without atheroma. RESULTS
The study population consisted of 49 white women and three African-American women (n = 52), with a mean age of 70.4 years and an age range of 55 to 90 years. A review of their medical histories revealed that 36 (69 percent) of the sub1132
jects were hypertensive, eight (15 percent) had a BMI of 27 to 29.9 and 15 (29 percent) had a BMI of 30 or greater. The majority (75 percent) of subjects had gone through natural (physiological) menopause at a mean age of 49.3 years, and 25 percent had gone through surgical (artificial) menopause after a hysterectomy (surgical removal of the uterus and cervix) and an accompanying oophorectomy (surgical removal of both ovaries) at a mean age of 38.2 years. Hormone replacement therapy. At the time that subjects underwent radiography, they had been postmenopausal for a mean of 24 years (range, six to 43 years). Thirty-seven (71 percent) of the women were receiving HRT, with 22 (42 percent) receiving estrogen alone for a mean of 8.5 years (range, one to 38 years) and 15 (29 percent) receiving estrogen and progestin for a mean of 5.8 years (range, six months to 20 years). One subject had received a course of estrogen alone for two years, followed by a six-year course of estrogen and progestin. Risk factors. Atherogenic risk factors were common, with 32 subjects (62 percent) having an elevated total serum cholesterol level (mean level, 238 mg/dL), 23 (42 percent) having an elevated LDL cholesterol level (mean level, 154 mg/dL) and 11 (19 percent) having type 2 diabetes mellitus. Smoking also was common, with 15 (29 percent) of the 52 subjects reporting having smoked during their lives. These subjects had smoked a mean of 37.5 pack-years, with a range of 15 to 65 years. Panoramic radiographs. The panoramic radiographs of 16 white subjects (31 percent), with a mean age of 72.1 years (range, 56 to 84 years), exhibited calcified carotid artery disease. Eight subjects had unilateral opacities and eight had bilateral opacities (Figures 1 and 2). Anteroposterior cervical spine radiographs confirmed that each of these 16 women had calcified carotid artery atheromas; however, for two of the eight subjects whose panoramic radiographs showed unilateral atheromas, bilateral atheromas were found on the anteroposterior film. A review of the medical histories of the 16 women with calcified carotid atheromas revealed that 15 (94 percent) were hypertensive, four (25 percent) had a BMI between 27 and 29.9 (characterized as overweight) and four (25 percent) had a BMI of 30 or greater (characterized as obese). Twelve (75 percent) of the subjects had gone through physiological menopause at a mean age
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of 46.3 years, and four (25 percent) had gone through surgical menopause at a mean age of 43.5 years. At the time we detected the atheroma via panoramic radiography, subjects had been postmenopausal for a mean of 22.4 years, with a range of three to 50 years. Twelve (75 percent) of the 16 women were receiving HRT, with eight (50 percent) receiving estrogen alone (mean duration, 5.4 years [range, two to 15 years]) and three (19 percent) receiving estrogen and progestin (mean duration, four years [range, two to six years]). One subject (6 percent) received estrogen alone for two years, followed by a six-year course of estrogen and progestin. Atherogenic risk factors were common among the 16 women with atheromas: nine subjects (56 percent) had an elevated total serum cholesterol level (mean level, 245 mg/dL), eight (50 percent) had an elevated LDL cholesterol level (mean level, 151 mg/dL) and three (19 percent) had type 2 diabetes mellitus. Smoking also was common, with six subjects (38 percent) reporting that they had smoked during their lives. These subjects had smoked a mean of 27 pack-years, with a range of 15 to 65 years. Statistical analysis. Our analysis of discrete risk factors for atherosclerosis performed between the groups of women with and without atheroma formation demonstrated that hypertension was a significant risk factor for the development of arterial disease. However, we found that “ever use” of HRT was unrelated to the presence or absence of atheromas in this study sample. Thirteen (25 percent) of the 52 subjects in the study reported that they had received long-term HRT (mean time, 14.3 years; mean number of postmenopausal years, 20.5). Panoramic radiography showed that two (15 percent) of these women had atheromas. In contrast, 15 women reported that they had never received HRT (mean number of postmenopausal years, 14). Panoramic radiography showed that three (21 percent) of these women had atheromas. Thus, the difference in prevalence rates between the two groups of subjects was not statistically significant. We calculated a combined score for risk factors by totaling the number of risk factors that were positive for each subject: hypertension, being overweight (or obese), elevated cholesterol (or LDL) level, diabetes mellitus and smoking (scores ranged from 0 to 5). As shown in the table, the mean number of positive risk factors (2.6,
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standard deviation = 1.5) for women with atheroma formation was not different from that for women without atheromas (2.1, standard deviation = 1.1). DISCUSSION
Clinicians can identify some women at high risk of developing stroke in the dental office. In our study, standard panoramic dental radiographs detected the presence of calcified cervical carotid artery disease in approximately 31 percent of postmenopausal women with no history of transient ischemic attack or stroke. Our analysis of women with and without atheroma formation demonstrated that hypertension was a significant risk factor for the development of atheromas, but HRT did not appear to influence the development of these lesions. The carotid artery calcifications were located within the soft tissues of the neck, approximately 2 centimeters inferior and posterior to the angle of the mandible at about the level of the lower margin of the third cervical vertebra (where discernible). Their distinctive appearance (single or multiple punctuate or verticolinear calcifications) and location readily distinguished them from other confounding opacities (that is, hyoid bone, salivary calculi, phleboliths, calcified lymph nodes, tip of the epiglottis, styloid process and associated ligaments). The results of our study are consistent with those of a recent high-resolution ultrasonographic study of 2,588 postmenopausal women, which demonstrated that 49 percent of subjects had carotid artery plaques.13 Our results are somewhat more modest because panoramic radiographs can detect only those lesions that have significant deposits of calcium, while ultrasonography can detect early lesions that are devoid of calcium or that have minimal amounts of calcium.14 The women in our study were about 70 years of age, and other studies15,16 have noted that the age range of 66 to 70 years is the crucial period for women to develop significant atherosclerotic lesions (that is, stenosis of 40 percent or greater) at the carotid bifurcation. Stenotic lesions of this magnitude are capable of reducing cerebral blood flow and are associated with a yearly risk of cerebral infarction of approximately 5 percent.17 The authors of these studies13-17 noted, as did we, that hypertension, a disorder common in women at the age of menopause, was a significant risk factor for
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TABLE
RISK-FACTOR ANALYSIS FOR ATHEROSCLEROSIS IN POSTMENOPAUSAL WOMEN. RISK FACTOR
ATHEROMAS PRESENT (n = 16)
ATHEROMAS ABSENT (n = 36)
STUDENT t TEST (P VALUE)
Mean Age at Time of Radiography (Years)
72.1
69.5
.884 (.38)
Mean No. of Years Since Menopause Began
22.4
23.8
.387 (.70)
Mean No. of Years of Estrogen Treatment
5.1
10.9
.945 (.35) .
Mean No. of Years of Estrogen and Progestin Treatment
4.3
6.3
.539 (.59)
Mean No. of Postmenopausal Years Without Treatment for Subjects Who Received HRT*
18.5
17.6
.232 (.82)
Mean Sum of Risk Factors (Range, 0 to 5)
2.6
2.1
1.32 (.19)
No. of Subjects Who Never Received HRT
4
11
NS†
No. of Subjects Who Received Estrogen‡
9
14
NS†
No. of Subjects Who Received Estrogen and Progestin‡
4
11
NS†
No. of Subjects With Hypertension
15
21
(.011) (Fisher exact test)
No. of Subjects Who Were Overweight
4
4
NS†
No. of Subjects Who Were Obese
4
11
NS†
No. of Subjects With Elevated Total Cholesterol (> 200 mg/dL§)
9
23
NS†
No. of Subjects With Elevated Serum LowDensity Cholesterol (> 130 mg/dL)
8
15
NS†
No. of Subjects With Diabetes
3
8
NS†
No. of Subjects Who Smoked ≥ 15 Pack-Years**
6
9
NS†
* HRT: Hormone replacement therapy. † NS: Not significant (Fisher exact test). ‡ One subject received estrogen therapy for two years, followed by estrogen and progestin therapy for five years, and is included in both categories. § mg/dL: Milligrams per deciliter. ** 15 pack-years is equivalent to one pack of cigarettes smoked per day for 15 years.
the development of atherosclerosis in the area of the carotid bifurcation. Hypertension disrupts the integrity of the 1134
carotid vessel’s endothelial lining and initiates plaque formation. Serum lipoproteins and platelet-derived growth factor, or PDGF, pass
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through the damaged and hyperpermeable endothelium. The lipoproteins lodge in the intima and the PDGFs cause proliferation of smooth muscle cells. The thickened and elevated lesion calcifies primarily at the junction of the intima and media, and protrudes into the vessel lumen, altering the flow of blood.18 Postmenopausal women also are at high risk of developing carotid artery atherosclerosis because they frequently develop an atherogenic blood lipid profile at the time menses cease. Reduced levels of circulating estrogen are associated with an increase in hepatic lipase activity and a decrease in LDL catabolism, which result in increased levels of LDL cholesterol and reduced levels of HDL cholesterol.19-21 Reduced levels of circulating estrogen also have been shown in animal models to be associated with enhanced myointimal hyperplasia.22-24 Although many studies have demonstrated the efficacy of HRT to delay the onset or halt the progression of carotid artery atherosclerosis, our study did not, but this might be the result of having had a small sample size.25-29 Identifying a calcified carotid artery atheroma on a panoramic radiograph is of major clinical significance. In 1994, Friedlander and colleagues30 observed that the panoramic radiographs of patients who had suffered an ischemic stroke were 10 times more likely to exhibit a calcified carotid artery atheroma than were radiographs of similarly aged, neurologically asymptomatic people. In 1996, in response to the observations of Friedlander and Friedlander,31 Crouse32 noted that atheromas detected on panoramic radiographs were likely to be indicative of generalized atherosclerosis and that patients with such lesions required an intensive medical evaluation of their carotid and coronary arteries. Woodworth and colleagues33 found that the presence of atheromas on the panoramic radiographs of high-risk patients is a significant predictor of death from cardiovascular disease. CONCLUSION
The results of this study show that some older women with calcified carotid artery atheromas can be identified in the dental office via panoramic radiography. Patients with such calcifications may be at risk of experiencing stroke and should be referred to an appropriate physician for confirmation of the findings and determination of the extent of disease. The control of risk factors, administration of medications and prophylactic
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surgical removal of the plaque, in selected patients, are safe and reliable methods of reducing the incidence of cerebrovascular accidents. ■ Dr. Friedlander is the associate chief of staff and the director, Graduate Medical Education, Veterans Affairs Greater Los Angeles Healthcare System; director, Quality Assurance, Hospital Dental Service, Medical Center at the University of California Los Angeles; and a professor, Oral and Maxillofacial Surgery, University of California Los Angeles School of Dentistry. Address reprint requests to Dr. Friedlander, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail “arthur. [email protected]. gov”.
Dr. Altman is the director of the Women’s Health Clinic at the Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda Division, Sepulveda, Calif., and a clinical associate professor, Department of Medicine, University of California Los Angeles School of Medicine.
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125:1598-603. 6. Friedlander AH. Identification of stroke-prone patients by panoramic and cervical spine radiography. Dentomaxillofac Radiol 1995;24(3):160-4. 7. 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. JADA 1997;128:977-84. 8. Lewis DA, Brooks SL. Carotid artery calcification in a general dental population: a retrospective study of panoramic radiographs. Gen Dent 1999;47(1):98-103. 9. Friedlander AH. Panoramic radiography: the differential diagnosis of carotid artery atheromas. Spec Care Dentist 1995;15(6):223-7. 10. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report— National Institutes of Health. Obes Res 1998;6(supplement 2): 51S-209S. 11. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18(6):499-502. 12. Standards of medical care for patients with diabetes mellitus— American Diabetes Association. Diabetes Care 1997;20:1183-97. 13. Joakimsen O, Bonaa KH, Stensland-Bugge E, Jacobsen BK. Population-based study of age at menopause and ultrasound assessed carotid atherosclerosis: the Tromso Study. J Clin Epidemiol 2000;53(5): 525-30. 14. Foley WD. Color doppler flow imaging. Boston: Andover Medical Publishers; 1991:1-65. 15. Willeit J, Kiechl S. Prevalence and risk factors of asymptomatic extracranial carotid artery atherosclerosis: a population-based study. Arterioscler Thromb 1993;13(5):661-8. 16. Prati P, Vanuzzo D, Casaroli M, et al. Prevalence and determinants of carotid atherosclerosis in a general population. Stroke 1992; 23(12):1705-11. 17. Winslow CM, Solomon DH, Chassin MR, Kosecoff J, Merrick NJ, Brook RH. The appropriateness of carotid endarterectomy. N Engl J Med 1988;318(12):721-7. 18. Mitchell ME, Sidawy AN. The pathophysiology of atherosclerosis. Semin Vasc Surg 1998;11(3):134-41. 19. Krauss RM, Perlman JA, Ray R, Petitti D. Effects of estrogen dose and smoking on lipid and lipoprotein levels in postmenopausal women. Am J Obstet Gynecol 1988;158:1606-11. 20. Applebaum-Bowden D, McLean P, Steinmetz A, et al. Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen
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administration in postmenopausal women. J Lipid Res 1989;30(2): 1895-906. 21. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325(17):1196-204. 22. Sack MN, Rader DJ, Cannon RO 3rd. Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet 1994;343(8892):269-70. 23. Haarbo J, Leth-Espensen P, Stender S, Christiansen C. Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits. J Clin Invest 1991;87:1274-9. 24. Cheng LP, Kuwahara M, Jacobsson J, Foegh ML. Inhibition of myointimal hyperplasia and macrophage infiltration by estradiol in aorta allografts. Transplantation 1991;52(6):967-72. 25. Espeland MA, Applegate W, Furberg CD, Lefkowitz D, Rice L, Hunninghake D. Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. ACAPS Investigators. Asymptomatic Carotid Atherosclerosis Progression Study. Am J Epidemiol 1995;142(10):1011-9. 26. Akkad A, Hartshorne T, Bell PR, al-Azzawi F. Carotid plaque regression on oestrogen replacement: a pilot study. Eur J Vasc Endovasc Surg 1996;11(3):347-8.
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27. Westendorp IC, Veld BA, Bots ML, et al. Hormone replacement therapy and intima-media thickness of the common carotid artery: the Rotterdam Study. Stroke 1999;30(12):2562-7. 28. Jonas HA, Kronmal RA, Psaty BM, et al. Current estrogen-progestin and estrogen replacement therapy in elderly women: association with carotid atherosclerosis. CHS Collaborative Research Group. Cardiovascular Health Study. Ann Epidemiol 1996;6(4):314-23. 29. McGrath BP, Liang YL, Teede H, Shiel LM, Cameron JD, Dart A. Age-related deterioration in arterial structure and function in postmenopausal women: impact of hormone replacement therapy. Arterioscler Thromb Vasc Biol 1998;18(7):1149-56. 30. Friedlander AH, Manesh F, Wasterlain CG. Prevalence of detectable carotid artery calcifications on panoramic radiographs of recent stroke victims. Oral Surg Oral Med Oral Pathol 1994;77(6): 669-73. 31. Friedlander AH, Friedlander IK. Panoramic dental radiography: an aid in detecting individuals prone to stroke. Br Dent J 1996;181(1): 23-6. 32. Crouse JR 3rd. Heart of the matter in cerebral arterial sclerosis. Lancet 1996;348(9030):766. 33. Woodworth W, Genco RJ, Knowler W, Pettitt M, Shlossman R, Dunford J. Calcified carotid atherosclerotic plaque as a predictor of CVD death. J Dent Res 2000;79(special issue):524.
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