- Email: [email protected]
Aortic valve sclerosis, mitral annular calcium, and aortic root sclerosis as markers of atherosclerosis in men
Aortic Valve Sclerosis, Mitral Annular Calcium, and Aortic Root Sclerosis as Markers of Atherosclerosis in Men Kirsten Tolstrup,
MD,
Carlos A. Roldan, MD, Clifford R. Qualls, Michael H. Crawford, MD
PhD,
and
Aortic valve sclerosis (AVS) and mitral annular calcium (MAC) as detected by transthoracic echocardiography have been associated with atherosclerosis. Aortic root sclerosis (ARS) may have a similar association, but has not been studied. This study evaluates, by transesophageal echocardiography, the association of AVS, MAC, and ARS with aortic atheromatous disease and cardiovascular disease. Multiplane transesophageal echocardiography with evaluation of AVS, MAC, ARS, and aortic atheromatous disease by 2 experienced observers unaware of clinical data was performed in 157 male patients >50 years old. The presence of cardiovascular disease, defined as coronary, carotid, or peripheral artery disease, was determined by specific criteria. The prevalence of AVS, MAC, ARS, and aortic atheromatous disease was 42%, 30%, 48%, and 71%, respectively.
The presence of AVS, MAC, or ARS was highly associated with aortic atheromatous disease (odds ratio 4.9 to 12.0, confidence interval 1.4 to 35.8, p <0.001). ARS was also associated with cardiovascular disease (odds ratio 2.2, confidence interval 1.0 to 4.5, p ⴝ 0.038). The presence of AVS, MAC, or ARS had a sensitivity of 77%, specificity of 72%, a positive predictive value of 88%, and a negative predictive value of 55% for aortic atheromatous disease. We concluded that the prevalence of AVS, MAC, or ARS by transesophageal echocardiography in men is common, and their presence is highly associated with aortic atheromatous disease and coronary, carotid, or peripheral artery disease. 䊚2002 by Excerpta Medica, Inc. (Am J Cardiol 2002;89:1030 –1034)
he presence of aortic atheromatous disease by transesophageal echocardiography is highly assoT ciated with coronary artery disease. The purpose of
esophageal echocardiography with a Hewlett-Packard 2500 multiplane imaging system (Andover, Massachusetts). The aortic valve was scanned in the short-axis view from the outflow tract to the aortic root and in the long-axis view 90° to 120° perpendicular to the shortaxis view. MAC was evaluated and measured from the 2- and 4-chamber views. The presence of ARS was assessed visually from the short- and long-axis views of the aortic root. Left ventricular function and wall motion were visually assessed. Two experienced observers unaware of the patients’ clinical data interpreted all studies. Fifty of the studies (32%) were randomly selected for inter- and intraobserver variabilities in the detection of abnormalities of valves and aorta. Criteria for echocardiographic interpretation: AVS: Each cusp was scored from 0 to 4 (Table 1).8 Grades 0 and 1 were classified as normal, grade 2 as mildly sclerotic, grade 3 as moderately sclerotic, and grade 4 as severely sclerotic. The highest score for a given cusp was assigned as the overall degree of AVS. MAC: The annulus was graded as normal, mildly (⬍5 mm), moderately (5 to 10 mm), or severely calcified (⬎10 mm) (Table 1). ARS: ARS was considered present when the anterior or posterior wall demonstrated increased echoreflectance and thickness of ⬎2.2 mm.9 Aortic atheromatous disease: The ascending, transverse, and descending aorta were scored from normal to severely diseased (grade 0 to 3)10 (Table 1). The highest score was assigned as the overall degree of aortic atheromatous disease. Clinical data: All patients’ atherogenic risk factors were determined: systemic hypertension (blood pres-
1–7
this study was to evaluate the association of aortic valve sclerosis (AVS), mitral annular calcium (MAC), and aortic root sclerosis (ARS) with aortic atheromatous disease and cardiovascular disease in a male population that would be expected to have a high incidence of these conditions. We hypothesized that ARS may also be related to atherosclerosis.
METHODS
Study population: We identified 362 patients from our echocardiographic database who underwent multiplane transesophageal echocardiography for clinical indications from January 1996 to August 1999 at the Albuquerque Veterans Affairs Medical Center. We excluded 57 patients who were ⬍50 years old, 64 who had poorly visualized thoracic aortas, 9 who had nondegenerative aortic valve disease, 13 patients with aortic stenosis (peak velocity ⬎2 m/s), 46 patients with duplicate and/or missing studies, and 16 women. Therefore, the final study population consisted of 157 male patients ⱖ50 years old with native trileaflet aortic valves. Echocardiography: All patients underwent transFrom the Veterans Affairs Medical Center and University of New Mexico, Albuquerque, New Mexico. Manuscript received October 1, 2001; revised manuscript received and accepted January 24, 2002. Address for reprints: Carlos A. Roldan, MD, Veterans Affairs Medical Center, Cardiology 5B-111, 2100 Ridgecrest Dr. SE, Albuquerque, New Mexico 87108. E-mail: [email protected].
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©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 May 1, 2002
0002-9149/02/$–see front matter PII S0002-9149(02)02270-1
TABLE 1 Classification of Aortic Valve Sclerosis (AVS), Mitral Annular Calcium (MAC), and Aortic Atheromatous Disease (AAD) Grade
AVS
MAC
AAD
0 1 2 3 4
No thickening Slight 1 reflectance, thickness ⬍2 mm Mild 1 reflectance, thickness 2–4 mm Generalized hyper-reflectance, thickness ⬎4 mm Markedly hyper-reflectant masses, thickness ⬎6 mm
Normal ⬍5 mm 5–10 mm ⬎10 mm
Normal, ⬍2 mm intimal thickness Intimal thickness 2–4 mm Intimal thickness ⬎4 mm Any protruding/mobile plaque
TABLE 2 Clinical Characteristics of Patients With and Without Aortic Valve Sclerosis (AVS), Mitral Annular Calcium (MAC), and Aortic Root Sclerosis (ARS) AVS
MAC
ARS
Characteristics
Present (n ⫽ 66)
Absent (n ⫽ 91)
Present (n ⫽ 44)
Absent (n ⫽ 104)
Present (n ⫽ 74)
Absent (n ⫽ 80)
Mean age ⫾ SD (yrs) Hypertension Diabetes mellitus 1 Cholesterol Smoking Mean EF ⫾ SD (%)
69 ⫾ 8* 85% 30% 69% 83% 51 ⫾ 13
66 ⫾ 9 76% 24% 61% 86% 50 ⫾ 15
68 ⫾ 9 88% 45%† 64% 90% 48 ⫾ 15‡
67 ⫾ 8 76% 17% 63% 83% 52 ⫾ 13
68 ⫾ 8 83% 31% 66% 87% 49 ⫾ 14§
66 ⫾ 8 76% 22% 62% 84% 53 ⫾ 13
*p ⫽ 0.012 for the comparison of patients with and without AVS; †p ⬍0.001 for the comparison of patients with and without MAC. ‡ p ⫽ 0.068; §p ⫽ 0.078. EF ⫽ ejection fraction.
sure ⬎140/90 mm Hg or on antihypertensive medication), diabetes mellitus (hyperglycemia or on diabetes medication), hypercholesterolemia as per National Cholesterol Education Program II guidelines11 or on lipid-lowering therapy, and past or present tobacco use. In all patients, cardiovascular disease was determined by chart review as the presence of coronary, carotid, or peripheral artery disease. Coronary artery disease was defined as: ⬎30% luminal diameter narrowing of ⱖ1 coronary artery by angiography, history of coronary revascularization, an abnormal myocardial perfusion scan or dobutamine stress echocardiogram, regional left ventricular akinesia and/or dyskinesia on echocardiogram, or pathologic Q waves on 12-lead electrocardiogram. Carotid artery disease was considered present by a positive carotid duplex study (plaques or ⬎15% stenosis), a positive angiogram, or documented carotid endarterectomy. Peripheral vascular disease was defined as an ankle-brachial index ⬍1, a positive angiogram, presence of abdominal aortic aneurysm, or a history of peripheral vascular surgery. Statistical analysis: Fisher’s exact test was used to evaluate differences in the patients’ baseline characteristics and to determine associations between AVS, MAC, ARS, and aortic atheromatous disease or cardiovascular disease. Multivariable stepwise logistic regression analysis was done with echocardiographic findings and cardiovascular risks as candidate factors. Univariable logistic analysis was assessed with and without adjustment for age and diabetes. Odds ratios and 95% confidence intervals were calculated. Interand intraobserver variabilities were assessed by paired t tests and correlation. Continuous variables are ex-
pressed as mean ⫾ SD. A p value ⱕ0.05 was considered significant.
RESULTS
Population clinical characteristics: The mean age of the 157 men in the study group was 67 ⫾ 8 years (range 50 to 84). Atherogenic risk factors were frequent: systemic hypertension was seen in 80%, diabetes mellitus in 27%, hypercholesterolemia in 64%, and smoking in 85%. The mean left ventricular ejection fraction was 51 ⫾ 14%.
Echocardiographic findings: PREVALENCE AND SEVERITY OF AVS, MAC, ARS, AND AORTIC ATHEROMATOUS DISEASE: Of the 157 patients, 66 had AVS (42%). Of
these 66 patients, 82% had mild and 18% had moderate AVS. All patients with severe AVS had an aortic valve peak velocity ⬎2 m/s, and were excluded. MAC was identified in 44 patients (30%), 73% of whom had mild, 20% had moderate, and 7% had severe MAC. ARS was found in 74 patients (48%). A total of 98 patients (64%) had ⱖ1 of the 3 abnormalities. Aortic atheromatous disease was detected in 112 patients (71%), and was most prevalent and severe in the aortic arch and descending aorta. Atheromas in all 3 aortic sites were present in 38 patients (24%). ASSOCIATION OF PATIENT CLINICAL CHARACTERISTICS WITH ECHOCARDIOGRAPHIC FINDINGS: Patients with
AVS were older than those without AVS. Patients with MAC had a higher prevalence of diabetes mellitus than those without MAC (Table 2). The prevalence of other cardiovascular risk factors was similar among the groups. ASSOCIATION OF AVS, MAC, AND ARS WITH ATHEROSCLEROSIS: The presence of AVS, MAC, and ARS was
highly associated with aortic atheromatous disease by
CORONARY ARTERY DISEASE/NON-ARTERIAL ATHEROSCLEROTIC MARKERS
1031
TABLE 3 Association of Aortic Valve Sclerosis (AVS), Mitral Annular Calcium (MAC), and Aortic Root Sclerosis (ARS) With Aortic Atheromatous Disease Unadjusted
Age Adjusted
Adjusted for Age and Diabetes Mellitus
Variable
Odds Ratio (95% CI)
p Value
Odds Ratio (95% CI)
p Value
Odds Ratio (95% CI)
p Value
AVS MAC ARS
7.50 (2.9–19.1) 4.49 (1.6–12.3) 8.24 (3.4–20.1)
⬍0.001 0.004 ⬍0.001
6.61 (2.4–18.0) 6.24 (1.9–20.7) 11.6 (4.0–33.3)
⬍0.001 0.003 ⬍0.001
6.82 (2.4–19.2) 4.88 (1.4–17.1) 12.00 (4.0–35.8)
⬍0.001 0.013 ⬍0.001
CI ⫽ confidence interval.
univariable analysis even when adjusted for age and diabetes mellitus (Table 3 and Figure 1). The presence of AVS, MAC, or ARS, age ⬎65 years, and diabetes mellitus were the best predictors of aortic atheromatous disease by multivariable analysis (p ⬍0.001, p ⬍0.001, and p ⫽ 0.047, respectively). By univariable analysis, ARS was significantly associated with cardiovascular disease (Table 4). By multivariable analysis, ARS entered the model second after age (p ⫽ 0.047), followed by hypertension (p ⫽ 0.094). DIAGNOSTIC VALUE OF AVS, MAC, AND ARS FOR ATHEROSCLEROSIS: The presence of AVS, MAC, and ARS
when evaluated separately, although highly associated with aortic atheromatous disease, had poor sensitivity and negative predictive values for aortic atheromatous disease. However, the specificity and positive predictive values were high. The presence of AVS, MAC, or ARS was a much better predictor of atheromatous disease than each individual abnormality (Figure 2). The diagnostic value of these lesions for cardiovascular disease was poor (Figure 3). Intra- and interobserver agreement: The interobserver agreements for the presence of AVS, MAC, ARS, and aortic atheromatous disease were 75%, 74%, 74%, and 88%, respectively (kappa 0.37 to 0.73, p ⬍0.05). The overall intraobserver agreements for AVS, MAC, and aortic atheromatous disease were 86%, 81%, and 88%, respectively (kappa 0.50 to 0.75, p ⬍0.05).
DISCUSSION
FIGURE 1. A, transesophageal echocardiogram of a 62-year-old male demonstrating (from left to right) MAC (arrow), AVS (arrow), and ARS (arrowheads). B, severe, protruding (arrowheads) and mobile (arrow) aortic arch atheromatous disease was detected. Ao ⴝ aorta; LA ⴝ left atrium, LV ⴝ left ventricle.
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Major findings: The major finding of this study is that the presence of AVS, MAC, or ARS by transesophageal echocardiography in men is highly associated with aortic atheromatous disease and cardiovascular disease. Patients with AVS, MAC, or ARS had a 5- to 12-fold higher risk of aortic atheromatous disease than those without any of these lesions. These lesions were also significantly associated with other cardiovascular diseases, although not as strongly as with atheromatous disease. To our knowledge, this is the first study to demonstrate a direct association of AVS, MAC, and ARS with aortic atheromatous disease and cardiovascular disease. These data not only confirm the association of AVS and MAC with atherosclerosis, as suggested by previous studies, but also demonstrate that ARS is a strong predictor of atherosclerosis. MAY 1, 2002
TABLE 4 Association of Aortic Valve Sclerosis (AVS), Mitral Annular Calcium (MAC), and Aortic Root Sclerosis (ARS) With Cardiovascular Disease Unadjusted
Age Adjusted
Adjusted for Age and Diabetes Mellitus
Variable
Odds Ratio (95% CI)
p Value
Odds Ratio (95% CI)
p Value
Odds Ratio (95% CI)
p Value
AVS MAC ARS
1.47 (0.8–2.8) 1.85 (0.9–4.0) 2.29 (1.2–4.5)
0.26 0.12 0.017
1.19 (0.6–2.4) 1.73 (0.8–3.9) 2.11 (1.1–4.3)
0.64 0.18 0.037
1.36 (0.7–2.8) 1.47 (0.6–3.5) 2.17 (1.0–4.5)
0.42 0.38 0.038
Abbreviation as in Table 3.
FIGURE 2. Diagnostic value of AVS, MAC, and ARS for aortic atheromatous disease. NPV ⴝ negative predictive value; PPV ⴝ positive predictive value.
FIGURE 3. Diagnostic value of AVS, MAC, and ARS for cardiovascular disease. Abbreviations as in Figure 2.
Prevalence of AVS, MAC, ARS, and aortic atheromatous disease: The prevalence of AVS and MAC in-
creases with age and the 2 conditions often coexist.12–16 AVS affects 21% to 26% of persons ⬎65 years of age, and has a prevalence of 55% in the ninth to tenth decade. The prevalence of MAC is 20% in the seventh decade and increases up to 60% in the ninth decade. The prevalence of AVS, MAC, and ARS (42%, 30%, and 48%, respectively) in this study of men ⱖ50 years old was higher than reported in previous studies for this age group. There are several reasons for this: (1) we utilized transesophageal echocardiography for detection of these abnormalities; (2) the prevalence of risk factors for cardiovascular disease was high; (3) we studied a male veteran population17; and (4) there was a potential bias toward higher prevalence rates due to the inability to dissociate the evaluation of AVS, MAC, ARS, and aortic atheromatous disease during echocardiographic interpretation.
Most published studies have utilized transthoracic echocardiography for the detection of AVS and MAC, which likely has lower sensitivity and specificity compared with transesophageal echocardiography. One population study18 utilizing transesophageal echocardiography showed a similar prevalence of AVS (37%) as in the present study. In the Cardiovascular Health Study,15 the prevalences of hypertension, diabetes mellitus, and past or present tobacco use were lower (44%, 10%, and 53%, respectively) than in this study (80%, 27%, and 85%, respectively). The presence of risk factors was self-reported in the Cardiovascular Health Study, which may have accounted for underestimation of the prevalence rates. Also, the previously reported prevalence rates of atherogenic risk factors have been based on population studies, which had a predominance of women.12,15,16 The prevalence of aortic atheromatous disease in our study was high (71%). This probably reflects the study of a male population with a high-risk factor profile for atherosclerotic disease, and the selection of patients undergoing transesophageal echocardiography, which implies a higher risk for cardiovascular disease. In conclusion, sclerotic cardiac lesions are associated with atherosclerosis and may predict an increased risk for cardiac morbidity and mortality.14,16,19 –25 Therefore, the recognition of these lesions should lead to aggressive modification of atherogenic risk factors and consideration of further evaluation for the detection of cardiovascular disease. Acknowledgment: The investigators would like to thank Frank T. Gurule and Aggie Schaeffer for their echocardiographic technical assistance.
1. Witteman JC, Kannel WB, Wolf PA, Grobbee DE, Hofman A, D’Agustino RB, Cobb JC. Aortic calcified plaques and cardiovascular disease (the Framingham study). Am J Cardiol 1990;66:1060 –1064. 2. Fazio GP, Redberg RF, Winslow T, Schiller NB. Transesophageal echocardiographically detected atherosclerotic aortic plaque is a marker for coronary artery disease. J Am Coll Cardiol 1993;21:144 –150. 3. Matsumura Y, Takata J, Yabe T, Furuno T, Chikamori T, Dori YL. Atherosclerotic aortic plaque detected by transesophageal echocardiography: its significance and limitations as a marker for coronary artery disease in the elderly. Chest 1997;112:81–86. 4. Khoury Z, Schwartz R, Gottlieb S, Chenzbraun A, Stern S, Keren A. Relation of coronary artery disease to atherosclerotic disease in the aorta, carotid, and femoral arteries evaluated by ultrasound. Am J Cardiol 1997;80:1429 –1433. 5. Tribouilloy C, Peltier M, Colas L, Rida Z, Rey JL, Lesbre JP. Multiplane transesophageal echocardiographic absence of thoracic aortic plaque is a powerful predictor for absence of significant coronary artery disease in valvular patients, even in the elderly. A large prospective study. Eur Heart J 1997;18:1478 – 1483. 6. Tribouilloy C, Peltier M, Rey JL, Ruiz V, Lesbre JP. Use of transesophageal
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echocardiography to predict significant coronary artery disease in aortic stenosis. Chest 1998;13:671–675. 7. Parthenakis FI, Kochiadakis GE, Skalidis EI, Kanakaraki MK, Mezilis NE, Kanoupakis EM, Vardas PE, Nihoyannopoulos P. Aortic atherosclerotic lesions in the thoracic aorta detected by multiplane transesophageal echocardiography as a predictor of coronary artery disease in elderly patients. Clin Cardiol 2000;23: 734 –739. 8. Shively BK, Charlton GA, Crawford MH, Chaney RK. Flow dependence of valve area in aortic stenosis: relation to valve morphology. J Am Coll Cardiol 1998;31:654 –660. 9. Roldan CA, Chavez J, Wiest PW, Qualls CR, Crawford MH. Aortic root disease and valve disease associated with ankylosing spondylitis. J Am Coll Cardiol 1998;32:1397–1404. 10. Ferrari E, Vidal R, Chevallier T, Baudouy M. Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants. J Am Coll Cardiol 1999;33:1317–1322. 11. National Cholesterol Education Program. Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. NIH Pub. No 93–3095. Bethesda, MD: National Heart, Lung, and Blood Institute. 1993. 12. Lindroos M, Kupari M, Heikkila¨ J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol 1993;21:1220 –1225. 13. Boon A, Cheriex E, Lodder J, Kessels F. Cardiac valve calcification: characteristics of patients with calcification of the mitral annulus or aortic valve. Heart 1997;78:472–474. 14. Adler Y, Herz I, Vaturi M, Fusman R, Shohat-Zabarski R, Fink N, Porter A, Shapira Y, Assali A, Sagie A. Mitral annular calcium detected by transthoracic echocardiography is a marker for high prevalence and severity of coronary artery disease in patients undergoing coronary angiography. Am J Cardiol 1998;82: 1183–1186. 15. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM. Clinical factors associated with calcific aortic valve disease: cardiovascular health study. J Am Coll Cardiol 1997;29:630 –634.
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16. Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovic DS. Association of aortic valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 1999;341:142–147. 17. Strong JP. Coronary atherosclerosis in soldiers. JAMA 1986;256:2863–2866. 18. Agmon Y, Khandheria BK, Meissner I, Sicks JD, O’Fallon WM, Wiebers DO, Whisnant JP, Seward JB, Tajik AJ. Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study. J Am Coll Cardiol 2001;38:827–834. 19. Aronow WS, Ahn C, Kronzon I. Association of mitral annular calcium with symptomatic peripheral arterial disease in older persons. Am J Cardiol 2001;88: 333–334. 20. Aronow WS, Ahn C, Shirani J, Kronzon I. Comparison of frequency of new coronary events in older subjects with and without valvular aortic sclerosis. Am J Cardiol 1999;83:599 –600. 21. Mohler ER, Sheridan MJ, Nichols R, Harvey WP, Waller BF. Development and progression of aortic valve stenosis: atherosclerosis risk factors—a causal relationship? A clinical morphologic study. Clin Cardiol 1991;14:995–999. 22. Aronow WS, Schwartz KS, Koenigsberg M. Correlation of serum lipids, calcium and phosphorus, diabetes mellitus, aortic valve stenosis and history of systemic hypertension with presence or absence of mitral annular calcium in persons older than 62 years in a long-term health care facility. Am J Cardiol 1987;59:381–382. 23. Wierzbicki A, Shetty C. Aortic stenosis: an atherosclerotic disease? J Heart Valve Dis 1999;8:416 –423. 24. Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M, Maurer G, Baumgartner H. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000;343:611–617. 25. Jeong D, Atar S, Brasch AV, Luo H, Mirocha J, Naqvi TZ, Kraus R, Berman DS, Siegel RJ. Association of mitral annulus calcification, aortic valve sclerosis and aortic root calcification with abnormal myocardial perfusion single photon emission tomography in subjects age ⱕ65 years old. J Am Coll Cardiol 2001; 38:1988 –1993.
MAY 1, 2002
MD,
Carlos A. Roldan, MD, Clifford R. Qualls, Michael H. Crawford, MD
PhD,
and
Aortic valve sclerosis (AVS) and mitral annular calcium (MAC) as detected by transthoracic echocardiography have been associated with atherosclerosis. Aortic root sclerosis (ARS) may have a similar association, but has not been studied. This study evaluates, by transesophageal echocardiography, the association of AVS, MAC, and ARS with aortic atheromatous disease and cardiovascular disease. Multiplane transesophageal echocardiography with evaluation of AVS, MAC, ARS, and aortic atheromatous disease by 2 experienced observers unaware of clinical data was performed in 157 male patients >50 years old. The presence of cardiovascular disease, defined as coronary, carotid, or peripheral artery disease, was determined by specific criteria. The prevalence of AVS, MAC, ARS, and aortic atheromatous disease was 42%, 30%, 48%, and 71%, respectively.
The presence of AVS, MAC, or ARS was highly associated with aortic atheromatous disease (odds ratio 4.9 to 12.0, confidence interval 1.4 to 35.8, p <0.001). ARS was also associated with cardiovascular disease (odds ratio 2.2, confidence interval 1.0 to 4.5, p ⴝ 0.038). The presence of AVS, MAC, or ARS had a sensitivity of 77%, specificity of 72%, a positive predictive value of 88%, and a negative predictive value of 55% for aortic atheromatous disease. We concluded that the prevalence of AVS, MAC, or ARS by transesophageal echocardiography in men is common, and their presence is highly associated with aortic atheromatous disease and coronary, carotid, or peripheral artery disease. 䊚2002 by Excerpta Medica, Inc. (Am J Cardiol 2002;89:1030 –1034)
he presence of aortic atheromatous disease by transesophageal echocardiography is highly assoT ciated with coronary artery disease. The purpose of
esophageal echocardiography with a Hewlett-Packard 2500 multiplane imaging system (Andover, Massachusetts). The aortic valve was scanned in the short-axis view from the outflow tract to the aortic root and in the long-axis view 90° to 120° perpendicular to the shortaxis view. MAC was evaluated and measured from the 2- and 4-chamber views. The presence of ARS was assessed visually from the short- and long-axis views of the aortic root. Left ventricular function and wall motion were visually assessed. Two experienced observers unaware of the patients’ clinical data interpreted all studies. Fifty of the studies (32%) were randomly selected for inter- and intraobserver variabilities in the detection of abnormalities of valves and aorta. Criteria for echocardiographic interpretation: AVS: Each cusp was scored from 0 to 4 (Table 1).8 Grades 0 and 1 were classified as normal, grade 2 as mildly sclerotic, grade 3 as moderately sclerotic, and grade 4 as severely sclerotic. The highest score for a given cusp was assigned as the overall degree of AVS. MAC: The annulus was graded as normal, mildly (⬍5 mm), moderately (5 to 10 mm), or severely calcified (⬎10 mm) (Table 1). ARS: ARS was considered present when the anterior or posterior wall demonstrated increased echoreflectance and thickness of ⬎2.2 mm.9 Aortic atheromatous disease: The ascending, transverse, and descending aorta were scored from normal to severely diseased (grade 0 to 3)10 (Table 1). The highest score was assigned as the overall degree of aortic atheromatous disease. Clinical data: All patients’ atherogenic risk factors were determined: systemic hypertension (blood pres-
1–7
this study was to evaluate the association of aortic valve sclerosis (AVS), mitral annular calcium (MAC), and aortic root sclerosis (ARS) with aortic atheromatous disease and cardiovascular disease in a male population that would be expected to have a high incidence of these conditions. We hypothesized that ARS may also be related to atherosclerosis.
METHODS
Study population: We identified 362 patients from our echocardiographic database who underwent multiplane transesophageal echocardiography for clinical indications from January 1996 to August 1999 at the Albuquerque Veterans Affairs Medical Center. We excluded 57 patients who were ⬍50 years old, 64 who had poorly visualized thoracic aortas, 9 who had nondegenerative aortic valve disease, 13 patients with aortic stenosis (peak velocity ⬎2 m/s), 46 patients with duplicate and/or missing studies, and 16 women. Therefore, the final study population consisted of 157 male patients ⱖ50 years old with native trileaflet aortic valves. Echocardiography: All patients underwent transFrom the Veterans Affairs Medical Center and University of New Mexico, Albuquerque, New Mexico. Manuscript received October 1, 2001; revised manuscript received and accepted January 24, 2002. Address for reprints: Carlos A. Roldan, MD, Veterans Affairs Medical Center, Cardiology 5B-111, 2100 Ridgecrest Dr. SE, Albuquerque, New Mexico 87108. E-mail: [email protected].
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©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 May 1, 2002
0002-9149/02/$–see front matter PII S0002-9149(02)02270-1
TABLE 1 Classification of Aortic Valve Sclerosis (AVS), Mitral Annular Calcium (MAC), and Aortic Atheromatous Disease (AAD) Grade
AVS
MAC
AAD
0 1 2 3 4
No thickening Slight 1 reflectance, thickness ⬍2 mm Mild 1 reflectance, thickness 2–4 mm Generalized hyper-reflectance, thickness ⬎4 mm Markedly hyper-reflectant masses, thickness ⬎6 mm
Normal ⬍5 mm 5–10 mm ⬎10 mm
Normal, ⬍2 mm intimal thickness Intimal thickness 2–4 mm Intimal thickness ⬎4 mm Any protruding/mobile plaque
TABLE 2 Clinical Characteristics of Patients With and Without Aortic Valve Sclerosis (AVS), Mitral Annular Calcium (MAC), and Aortic Root Sclerosis (ARS) AVS
MAC
ARS
Characteristics
Present (n ⫽ 66)
Absent (n ⫽ 91)
Present (n ⫽ 44)
Absent (n ⫽ 104)
Present (n ⫽ 74)
Absent (n ⫽ 80)
Mean age ⫾ SD (yrs) Hypertension Diabetes mellitus 1 Cholesterol Smoking Mean EF ⫾ SD (%)
69 ⫾ 8* 85% 30% 69% 83% 51 ⫾ 13
66 ⫾ 9 76% 24% 61% 86% 50 ⫾ 15
68 ⫾ 9 88% 45%† 64% 90% 48 ⫾ 15‡
67 ⫾ 8 76% 17% 63% 83% 52 ⫾ 13
68 ⫾ 8 83% 31% 66% 87% 49 ⫾ 14§
66 ⫾ 8 76% 22% 62% 84% 53 ⫾ 13
*p ⫽ 0.012 for the comparison of patients with and without AVS; †p ⬍0.001 for the comparison of patients with and without MAC. ‡ p ⫽ 0.068; §p ⫽ 0.078. EF ⫽ ejection fraction.
sure ⬎140/90 mm Hg or on antihypertensive medication), diabetes mellitus (hyperglycemia or on diabetes medication), hypercholesterolemia as per National Cholesterol Education Program II guidelines11 or on lipid-lowering therapy, and past or present tobacco use. In all patients, cardiovascular disease was determined by chart review as the presence of coronary, carotid, or peripheral artery disease. Coronary artery disease was defined as: ⬎30% luminal diameter narrowing of ⱖ1 coronary artery by angiography, history of coronary revascularization, an abnormal myocardial perfusion scan or dobutamine stress echocardiogram, regional left ventricular akinesia and/or dyskinesia on echocardiogram, or pathologic Q waves on 12-lead electrocardiogram. Carotid artery disease was considered present by a positive carotid duplex study (plaques or ⬎15% stenosis), a positive angiogram, or documented carotid endarterectomy. Peripheral vascular disease was defined as an ankle-brachial index ⬍1, a positive angiogram, presence of abdominal aortic aneurysm, or a history of peripheral vascular surgery. Statistical analysis: Fisher’s exact test was used to evaluate differences in the patients’ baseline characteristics and to determine associations between AVS, MAC, ARS, and aortic atheromatous disease or cardiovascular disease. Multivariable stepwise logistic regression analysis was done with echocardiographic findings and cardiovascular risks as candidate factors. Univariable logistic analysis was assessed with and without adjustment for age and diabetes. Odds ratios and 95% confidence intervals were calculated. Interand intraobserver variabilities were assessed by paired t tests and correlation. Continuous variables are ex-
pressed as mean ⫾ SD. A p value ⱕ0.05 was considered significant.
RESULTS
Population clinical characteristics: The mean age of the 157 men in the study group was 67 ⫾ 8 years (range 50 to 84). Atherogenic risk factors were frequent: systemic hypertension was seen in 80%, diabetes mellitus in 27%, hypercholesterolemia in 64%, and smoking in 85%. The mean left ventricular ejection fraction was 51 ⫾ 14%.
Echocardiographic findings: PREVALENCE AND SEVERITY OF AVS, MAC, ARS, AND AORTIC ATHEROMATOUS DISEASE: Of the 157 patients, 66 had AVS (42%). Of
these 66 patients, 82% had mild and 18% had moderate AVS. All patients with severe AVS had an aortic valve peak velocity ⬎2 m/s, and were excluded. MAC was identified in 44 patients (30%), 73% of whom had mild, 20% had moderate, and 7% had severe MAC. ARS was found in 74 patients (48%). A total of 98 patients (64%) had ⱖ1 of the 3 abnormalities. Aortic atheromatous disease was detected in 112 patients (71%), and was most prevalent and severe in the aortic arch and descending aorta. Atheromas in all 3 aortic sites were present in 38 patients (24%). ASSOCIATION OF PATIENT CLINICAL CHARACTERISTICS WITH ECHOCARDIOGRAPHIC FINDINGS: Patients with
AVS were older than those without AVS. Patients with MAC had a higher prevalence of diabetes mellitus than those without MAC (Table 2). The prevalence of other cardiovascular risk factors was similar among the groups. ASSOCIATION OF AVS, MAC, AND ARS WITH ATHEROSCLEROSIS: The presence of AVS, MAC, and ARS was
highly associated with aortic atheromatous disease by
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TABLE 3 Association of Aortic Valve Sclerosis (AVS), Mitral Annular Calcium (MAC), and Aortic Root Sclerosis (ARS) With Aortic Atheromatous Disease Unadjusted
Age Adjusted
Adjusted for Age and Diabetes Mellitus
Variable
Odds Ratio (95% CI)
p Value
Odds Ratio (95% CI)
p Value
Odds Ratio (95% CI)
p Value
AVS MAC ARS
7.50 (2.9–19.1) 4.49 (1.6–12.3) 8.24 (3.4–20.1)
⬍0.001 0.004 ⬍0.001
6.61 (2.4–18.0) 6.24 (1.9–20.7) 11.6 (4.0–33.3)
⬍0.001 0.003 ⬍0.001
6.82 (2.4–19.2) 4.88 (1.4–17.1) 12.00 (4.0–35.8)
⬍0.001 0.013 ⬍0.001
CI ⫽ confidence interval.
univariable analysis even when adjusted for age and diabetes mellitus (Table 3 and Figure 1). The presence of AVS, MAC, or ARS, age ⬎65 years, and diabetes mellitus were the best predictors of aortic atheromatous disease by multivariable analysis (p ⬍0.001, p ⬍0.001, and p ⫽ 0.047, respectively). By univariable analysis, ARS was significantly associated with cardiovascular disease (Table 4). By multivariable analysis, ARS entered the model second after age (p ⫽ 0.047), followed by hypertension (p ⫽ 0.094). DIAGNOSTIC VALUE OF AVS, MAC, AND ARS FOR ATHEROSCLEROSIS: The presence of AVS, MAC, and ARS
when evaluated separately, although highly associated with aortic atheromatous disease, had poor sensitivity and negative predictive values for aortic atheromatous disease. However, the specificity and positive predictive values were high. The presence of AVS, MAC, or ARS was a much better predictor of atheromatous disease than each individual abnormality (Figure 2). The diagnostic value of these lesions for cardiovascular disease was poor (Figure 3). Intra- and interobserver agreement: The interobserver agreements for the presence of AVS, MAC, ARS, and aortic atheromatous disease were 75%, 74%, 74%, and 88%, respectively (kappa 0.37 to 0.73, p ⬍0.05). The overall intraobserver agreements for AVS, MAC, and aortic atheromatous disease were 86%, 81%, and 88%, respectively (kappa 0.50 to 0.75, p ⬍0.05).
DISCUSSION
FIGURE 1. A, transesophageal echocardiogram of a 62-year-old male demonstrating (from left to right) MAC (arrow), AVS (arrow), and ARS (arrowheads). B, severe, protruding (arrowheads) and mobile (arrow) aortic arch atheromatous disease was detected. Ao ⴝ aorta; LA ⴝ left atrium, LV ⴝ left ventricle.
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Major findings: The major finding of this study is that the presence of AVS, MAC, or ARS by transesophageal echocardiography in men is highly associated with aortic atheromatous disease and cardiovascular disease. Patients with AVS, MAC, or ARS had a 5- to 12-fold higher risk of aortic atheromatous disease than those without any of these lesions. These lesions were also significantly associated with other cardiovascular diseases, although not as strongly as with atheromatous disease. To our knowledge, this is the first study to demonstrate a direct association of AVS, MAC, and ARS with aortic atheromatous disease and cardiovascular disease. These data not only confirm the association of AVS and MAC with atherosclerosis, as suggested by previous studies, but also demonstrate that ARS is a strong predictor of atherosclerosis. MAY 1, 2002
TABLE 4 Association of Aortic Valve Sclerosis (AVS), Mitral Annular Calcium (MAC), and Aortic Root Sclerosis (ARS) With Cardiovascular Disease Unadjusted
Age Adjusted
Adjusted for Age and Diabetes Mellitus
Variable
Odds Ratio (95% CI)
p Value
Odds Ratio (95% CI)
p Value
Odds Ratio (95% CI)
p Value
AVS MAC ARS
1.47 (0.8–2.8) 1.85 (0.9–4.0) 2.29 (1.2–4.5)
0.26 0.12 0.017
1.19 (0.6–2.4) 1.73 (0.8–3.9) 2.11 (1.1–4.3)
0.64 0.18 0.037
1.36 (0.7–2.8) 1.47 (0.6–3.5) 2.17 (1.0–4.5)
0.42 0.38 0.038
Abbreviation as in Table 3.
FIGURE 2. Diagnostic value of AVS, MAC, and ARS for aortic atheromatous disease. NPV ⴝ negative predictive value; PPV ⴝ positive predictive value.
FIGURE 3. Diagnostic value of AVS, MAC, and ARS for cardiovascular disease. Abbreviations as in Figure 2.
Prevalence of AVS, MAC, ARS, and aortic atheromatous disease: The prevalence of AVS and MAC in-
creases with age and the 2 conditions often coexist.12–16 AVS affects 21% to 26% of persons ⬎65 years of age, and has a prevalence of 55% in the ninth to tenth decade. The prevalence of MAC is 20% in the seventh decade and increases up to 60% in the ninth decade. The prevalence of AVS, MAC, and ARS (42%, 30%, and 48%, respectively) in this study of men ⱖ50 years old was higher than reported in previous studies for this age group. There are several reasons for this: (1) we utilized transesophageal echocardiography for detection of these abnormalities; (2) the prevalence of risk factors for cardiovascular disease was high; (3) we studied a male veteran population17; and (4) there was a potential bias toward higher prevalence rates due to the inability to dissociate the evaluation of AVS, MAC, ARS, and aortic atheromatous disease during echocardiographic interpretation.
Most published studies have utilized transthoracic echocardiography for the detection of AVS and MAC, which likely has lower sensitivity and specificity compared with transesophageal echocardiography. One population study18 utilizing transesophageal echocardiography showed a similar prevalence of AVS (37%) as in the present study. In the Cardiovascular Health Study,15 the prevalences of hypertension, diabetes mellitus, and past or present tobacco use were lower (44%, 10%, and 53%, respectively) than in this study (80%, 27%, and 85%, respectively). The presence of risk factors was self-reported in the Cardiovascular Health Study, which may have accounted for underestimation of the prevalence rates. Also, the previously reported prevalence rates of atherogenic risk factors have been based on population studies, which had a predominance of women.12,15,16 The prevalence of aortic atheromatous disease in our study was high (71%). This probably reflects the study of a male population with a high-risk factor profile for atherosclerotic disease, and the selection of patients undergoing transesophageal echocardiography, which implies a higher risk for cardiovascular disease. In conclusion, sclerotic cardiac lesions are associated with atherosclerosis and may predict an increased risk for cardiac morbidity and mortality.14,16,19 –25 Therefore, the recognition of these lesions should lead to aggressive modification of atherogenic risk factors and consideration of further evaluation for the detection of cardiovascular disease. Acknowledgment: The investigators would like to thank Frank T. Gurule and Aggie Schaeffer for their echocardiographic technical assistance.
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