Relation of Mitral Annular Calcium and Coronary Calcium (from the Multi-Ethnic Study of Atherosclerosis [MESA])

Relation of Mitral Annular Calcium and Coronary Calcium (from the Multi-Ethnic Study of Atherosclerosis [MESA]) Yasmin S. Hamirani, MDa,*, Khurram Nasir, MPH, MDb,c, Roger S. Blumenthal, MDc, Junichiro Takasu, MDa, David Shavelle, MDa, Richard Kronmal, PhDd, and Matthew Budoff, MDa Atherosclerosis is a complex diffuse disorder. The close correlation between coronary artery calcium (CAC) score on computed tomogram and extent and severity of coronary atherosclerosis is well established. It has been suggested that mitral annular calcification (MAC) may be a manifestation of generalized atherosclerosis. The MESA population included a population-based sample of 4 ethnic groups (12% Chinese, 38% white, 22% Hispanic, and 28% black) of 6,814 women and men 45 to 84 years of age. Computed tomographic scans were performed for all participants. The calcium score of each lesion was calculated by multiplying lesion area by a density factor derived from maximal Hounsfield units. A total calcium score was determined by summing individual lesion scores at each anatomic site. Relative risk regression was used to model the probability of MAC as a function of CAC >0 and CAC categories (0, 1 to 99, 100 to 399, and >400) with the referent group being CAC 0. The final study population consisted of 6,814 subjects (mean age 62 ⴞ 10 years, 47% men). Overall 9% and 50% had detectable MAC and CAC, respectively. Of those with absent CAC, only 4% had MAC, whereas 9%, 19%, and 15% had MAC scores with increasing CAC scores of 1 to 99, 100 to 399, and >400, respectively (p <0.0001 for trend). After taking into account demographics and other risk factors, the prevalence ratio of MAC in those with mild CAC (1 to 99) was 2.13 (95% confidence interval 1.69 to 2.69) and increased to 7.57 (95% confidence interval 5.95 to 9.62) for CAC >400. Similar statistically significant increased risk of MAC was found when CAC was assessed as a continuous variable. In conclusion, we observed a strong association between MAC and increasing burden of CAC. This association weakened but persisted after adjustment for age, gender, and other traditional cardiovascular risk factors. These findings suggest that presence of MAC is an indicator of atherosclerotic burden rather than just a degenerative change of the mitral valve. Published by Elsevier Inc. (Am J Cardiol 2011;107:1291–1294)

Mitral annular calcium (MAC) is long-term fibrous degenerative calcium of the mitral valve support ring,1 which is frequent in women and elderly patients.2,3 It has been suggested that MAC may be a manifestation of generalized atherosclerosis and could be an aid toward diagnosing coronary artery disease (CAD).4 Whether there is an association between presence of MAC and coronary artery calcium (CAC) on computed tomogram has not been well studied. The few studies that have been done have shown a strong positive correlation between severe MAC and CAC across men and women.5 However, mild MAC has not shown the same association.5 In this substudy of the Multi-Ethnic Study of Atherosclerosis (MESA) population, we looked at

a

Los Angeles Biomedical Research Institute at Harbor–UCLA, Torrance, California; bBoston Medical Center, Boston, Massachusetts; cJohns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore, Maryland; dUniversity of Washington, Seattle, Washington. Manuscript received October 12, 2010; revised manuscript received and accepted January 6, 2011. This research was supported by Grant R01 HL071739 and Contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. *Corresponding author: Tel: 505-272-4253; fax: 505-272-4356. E-mail address: [email protected] (Y.S. Hamirani). 0002-9149/11/$ – see front matter Published by Elsevier Inc. doi:10.1016/j.amjcard.2011.01.005

the correlation between presence of MAC and CAC and whether it varies across various ethnic groups and between men and women. We also studied the strength of the association of cardiovascular disease (CVD) traditional and novel risk factors with MAC compared to CAC. Methods MESA patients with baseline MAC and CAC computed tomographic (CT) scans were studied. Patients on dialysis were excluded from the study. The MESA cohort consists of 6,814 men and women 45 to 84 years of age who were recruited from 6 communities in the United States and were free of clinically evident CVD at time of enrollment. The main objective of MESA is to determine characteristics of subclinical CVD and its progression. Participants were excluded if they had a history of coronary bypass surgery, balloon angioplasty, heart valve replacement, pacemaker or defibrillator implantation, or any other cardiac surgery. The study was designed to include sufficient numbers of white, African-American, Hispanic, and Chinese subjects. Sampling and recruitment procedures have been previously described in detail.6 Participants were enrolled from August 1, 2000 through July 30, 2002. Institutional review boards at all participating centers approved the study, and all participants gave informed consent. www.ajconline.org

1292

The American Journal of Cardiology (www.ajconline.org)

Table 1 Characteristics of MESA absence/presence of mitral annular calcium Variable Age (years) Men Race White Chinese Black Hispanic Smoker Former Current Body mass index (kg/m2) Systolic blood pressure (mm Hg) Hypertension Diabetes mellitus Family history of heart attack Total cholesterol (mg/dl) Low-density lipoprotein (mg/dl) High-density lipoprotein (mg/dl) Triglycerides (mg/dl) Lipid-lowering medications High-sensitivity Creactive protein (mg/L) Coronary artery calcium (AU)

MAC 0 (n ⫽ 6,170)

CAC ⬎0 (n ⫽ 644)

p Value

61 ⫾ 10 2,955 (48%)

72 ⫾ 11 258 (40%)

⬍0.001 ⬍0.001

2,309 (38%) 766 (12%) 1,753 (28%) 1,342 (22%)

315 (49%) 37 (6%) 141 (22%) 151 (23%)

⬍0.001

2,234 (36%) 828 (13%) 28 ⫾ 5

253 (39%) 59 (9%) 29 ⫾ 6

⬍0.008

126 ⫾ 21 2,655 (43%) 827 (13%) 2,438 (40%)

135 ⫾ 23 403 (63%) 144 (22%) 296 (46%)

0.003 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

194 ⫾ 35 117 ⫾ 31

195 ⫾ 38 115 ⫾ 33

0.439 0.09

51 ⫾ 15

52 ⫾ 15

0.08

111 (787–161) 479 (8%)

113 (80–161) 165 (15%)

1.88 (0.83–4.25) 2.21 (0.94–4.40)

0 (0–63)

118 (4–447)

⬍0.001 ⬍0.001 0.02

⬍0.0001

Duplicate CT scans were performed using an Imatron C-150XL CT scanner (GE-Imatron, South San Francisco, California) at 3 sites or multidetector CT scanners (4 slices) at 3 sites. The specific scanning methods employed in the MESA study have been reported.7 All studies were analyzed at the MESA CT reading center at Harbor–UCLA (Torrance, California). The calcium score of each lesion was calculated by multiplying the lesion area by a density factor derived from the maximal Hounsfield units within this area, as described by Agatston et al.8 The density factor was assigned in the following manner: 1 for lesions whose maximal density was 130 to 199 HU, 2 for lesions 200 to 299 HU, 3 for lesions 300 to 399 HU, and 4 for lesions ⬎400 HU. A total calcium score (Agatston) was determined by summing individual lesion scores at each anatomic site. MAC was measured and quantified using the same lesion definition as for coronary calcification. MAC was assessed on every level of the mitral annulus and the sum of calcification was reported. MAC score (using Agatston and volume scorings) was assessed in every patient. Absence of any calcification in that region was scored 0. MAC was dichotomized as present (Agatston score ⬎0) or absent (Agatston score 0). Distributions of demographics and cardiovascular risk factors were compared across these groups. Differences in characteristics were compared using

Figure 1. Prevalence of mitral annular calcium according to coronary artery calcium scores 0 (white bars), 1 to 99 (light gray bars), 100 to 399 (dark gray bars), and ⱖ400 (black bars).

analysis of variance for continuous variables and chi-square tests for categorical variables. In the analysis treating MAC score as a continuous variable, we used the logarithm of the mitral valve calcium score plus 1 (log [MAC ⫹ 1]). Prevalence ratios were estimated from exponentiation of ␤ from the regression model y ⫽ exp(XT␤). We assumed Gaussian error and used robust SEEs. Using this method we assessed the relation between MAC and presence of CAC and with increasing CAC score categories in a hierarchal fashion. Covariates were entered into the regression model in stages. First, we determined unadjusted relative risk followed by adjusting for demographics age, gender, and race/ ethnicity (Model 1). Second, adjusting was done for other risk factors: body mass index, total cholesterol, high-density lipoprotein cholesterol, low density lipoprotein cholesterol, lipid-lowering medication, smoking, systolic blood pressure, hypertension, diabetes mellitus, triglycerides, family history of heart attack, and high-sensitivity C-reactive protein (Model 2). We also categorized subjects with any MAC into tertiles and compared the association of higher MAC categories (comparison group MAC 0) to increasing CAC cutoffs using ordinal regression analysis. Ordinal regression permits logistic regression to be applied to non-normal data without loss of information associated with collapsing continuous data to a binary outcome. Statistical analyses were performed with STATA 10.0 for Windows (STATA Corporation, College Station, Texas). Results The study population consisted of 6,814 subjects with no previous coronary disease. Cohort participants were 38% white (n ⫽ 2,622), 28% black (n ⫽ 1,894), 22% Hispanic (n ⫽ 1493), and 12% Chinese (n ⫽ 803). MAC was present in 644 (9%) of the cohort and CAC was present in 3,398 (50%) of the study cohort. Baseline characteristics concerning presence/absence of MAC are listed in Table 1. Subjects with MAC were significantly more likely to be older, women, white, had a higher prevalence of hypertension, diabetes, and family history of CAD. In addition, increased high-sensitivity C-reactive protein was associated with presence of MAC (Table 1).

Coronary Artery Disease/MAC and CAC—Correlation Table 2 Association of presence of mitral annular calcium with coronary artery calcium in unadjusted and multivariable adjusted analyses CAC

0 ⬎0 0 1–99 100–399 ⱖ400 Ln(CAC ⫹ 1)

Relative Risk (95% CI) Model 1*

Model 2†

Model 3‡

1.00 (reference) 3.85 (3.18–4.66) 1.00 (reference) 2.13 (1.69–2.69) 5.07 (4.01–6.41) 7.57 (5.95–9.62) 1.39 (1.33–1.46)

1.00 (reference) 1.68 (1.31–2.31) 1.00 (reference) 1.11 (0.82–1.45) 2.05 (1.52–2.75) 2.77 (2.06–3.73) 1.20 (1.14–1.26)

1.00 (reference) 1.66 (1.27–2.14) 1.00 (reference) 1.14 (0.83–1.56) 2.09 (1.53–2.85) 2.58 (1.85–3.60) 1.19 (1.12–1.25)

* Unadjusted. Adjusted for age, gender, and race. ‡ Adjusted for age, gender, race, smoking, hypertension, diabetes mellitus, family history of heart attack, low-density lipoprotein, high-density lipoprotein, body mass index, lipid-lowering medications, and C-reactive protein. Ln ⫽ natural logarithm. †

Nearly 1/2 of the study population had no coronary calcification (CAC 0, n ⫽ 3,416, 50%), whereas 26%, 14%, and 10% had CAC scores of 1 to 99, 100 to 399, and ⱖ400, respectively. As shown in Figure 1, likelihood of MAC ⬎0 increases linearly with greater CAC burden. Of those with absent CAC, only 4% had MAC, whereas 9%, 18%, and 25% had some MAC with increasing CAC scores of 1 to 99, 100 to 399, and ⱖ400, respectively (p ⬍0.0001 for trend). Similar relations existed among all ethnic groups (Figure 1). Table 2 presents prevalence ratios for MAC according to presence of any CAC in multivariate analyses. No significant ethnic-by-CAC interaction for MAC prevalence was found. We also examined the association of increasing CAC scores with presence of MAC. In the various ethnic groups, analyses of prevalence ratio with presence of severe CAC (ⱖ400) compared to those without CAC showed ratios of 2.89 (95% confidence interval [CI] 1.69 to 4.95) for Caucasians, 1.95 (95% CI 0.99 to 3.81) for African-Americans, and 3.05 (95% CI 1.51 to 6.15) for Hispanics in Model 3, respectively. Similar statistically significant increased risk of MAC was found when CAC was assessed as a continuous variable (Table 2), with no significant ethnic-by-CAC interaction noted. No gender differences in association of MAC with CAC were noted in our study. When MAC was assessed as a continuous variable (log [MAC ⫹ 1]), a significant association was noted with increasing logarithmically transformed CAC scores (beta coefficient 0.08, 95% CI 0.06 to 0.10, p ⬍0.0001) after adjusting for demographics and risk factors (Model 2). In addition, compared to no MAC, a higher odds ratio for higher MAC tertiles was noted with CAC score categories (CAC 1 to 99, 1.25, 95% CI 0.96 to 1.61; CAC 100 to 399, 2.28, 95% CI 1.73 to 3.01; CAC ⱖ400, 2.79, 95% CI 2.08 to 3.74). Discussion Our study demonstrates that MAC is independently associated with increasing severity of coronary atherosclerosis as measured by CAC in all racial groups. This relation

1293

persisted even after taking into account age, gender, and other traditional coronary heart disease risk factors. Prevalence of CAC appears to follow a pattern similar to that of coronary heart disease, with a strongly increasing prevalence with age and much higher prevalence in men compared to women.7 Coronary calcium has also been shown to be related to traditional coronary risk factors.9 –11 Studies have suggested that MAC is a manifestation of diffuse atherosclerosis of the vascular system.11–19 An association between MAC and cardiovascular calcifications as assessed by multiple techniques including computed tomography, echocardiography, and conventional chest x-ray film and CVD risk factors is similarly suggested.17,18,20,21 Recent data have clearly shown that cardiovascular calcification is a strong predictor of the presence of CAD.22–24 Acarturk et al25 studied 123 patients with significant CAD and found MAC identified CAD with a sensitivity and specificity of 60% and 56%, respectively, and with negative and positive predictive values of 52% and 64%, respectively. Absence of MAC was found to be a stronger predictor for absence of CAD than all conventional risk factors, except absence of diabetes mellitus. Tenebaum et al21 performed 1 of the few studies that aimed to study a direct correlation between CAC and MAC. This study included 522 hypertensive patients with a mean age of 65 ⫾ 6 years and found a strong association between advanced MAC and severe CAC in known CAD. No association with trivial MAC was seen. The same group21 looked at gender differences in the association of MAC and CAC (522 patients, 284 men and 238 postmenopausal women, 52 to 80 years of age, mean 65 ⫾ 6). Prevalence of any type of CAC was significantly higher in men (p ⫽ 0.001) but prevalence of advanced MAC was prominently seen in women. Adler et al26 found MAC to be independently associated with advanced CAC (odds ratio 2.6, 95% CI 1.3 to 5.2, p ⫽ 0.005). A significant difference was also found between groups for prevalence of proved CAD (30% vs 16%, p ⫽ 0.008). The present study found a significant correlation of MAC with CAC in unadjusted and adjusted models. Previous studies have lacked ethnic diversity and are limited by small samples. Our study adds to the current literature by supporting the finding that presence of MAC is an indicator of atherosclerotic burden rather than just a degenerative change in all ethnic/racial subgroups. In our study nearly 1/4 of subjects with a CAC score ⱖ400 had MAC. Although presence and severity of calcification in coronary arteries has been clearly established as an indicator for an adverse CVD outcome, the incremental prognostic value of MAC, especially for presence of very high CAC scores, is not yet known. Continuation of the MESA study will provide additional outcome data on the prognostic value of MAC. The ability to evaluate MAC at no additional cost on noncontrast CT scans performed primarily for assessing CAC burden will need to be evaluated in follow-up studies. Our study findings need to be interpreted in light of the following limitations. The MESA sample may not be completely generalizable to the entire population because participating subjects tended to be healthier overall than the general population. Also, overall only 12% of our cohort

1294

The American Journal of Cardiology (www.ajconline.org)

was Chinese, so these estimates are more variable than those for another race/ethnicity. In addition, the cross-sectional nature of the study limits the inference of whether the probability of MAC development is higher with increased CAC burden and will need to evaluate in follow-up studies. Acknowledgment: The authors thank the other investigators, staff, and participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www. mesa-nhlbi.org. 1. Fulkerson PK, Beaver BM, Auseon JC, Graber HL. Calcification of the mitral annulus: etiology, clinical associations, complications and therapy. Am J Med 1979;66:967–977. 2. Savage DD, Garrison RJ, Castelli WP, McNamara PM, Anderson SJ, Kannel WB, Feinleib M. Prevalence of submitral (anular) calcium and its correlates in a general population-based sample (the Framingham Study). Am J Cardiol 1983;51:1375–1378. 3. Aronow WS, Ahn C, Kronzon I. Prevalence of echocardiographic findings in 554 men and in 1,243 women aged ⬎60 years in a long-term health care facility. Am J Cardiol 1997;79:379 –380. 4. Kanjanauthai S, Nasir K, Katz R, Rivera JJ, Takasu J, Blumenthal RS, Eng J, Budoff MJ. Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2010;213:558 –562. 5. Acarturk E, Bozkurt A, Cayli M, Demir M. Mitral annular calcification and aortic valve calcification may help in predicting significant coronary artery disease. Angiology 2003;54:561–567. 6. Bild DE, Bluemke DA, Burke GL, Detrano R, Diez Roux AV, Folsom AR, Greenland P, Jacob DR Jr, Kronmal R, Liu K, Nelson JC, O’Leary D, Saad MF, Shea S, Szklo M, Tracy RP. Multi-ethnic Study of Atherosclerosis: objectives and design. Am J Epidemiol 2002;156: 871– 881. 7. Carr JJ, Nelson JC, Wong ND, McNitt-Gray M, Arad Y, Jacobs DR Jr, Sidney S, Bild DE, Williams OD, Detrano RC. Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study. Radiology 2005;234:35– 43. 8. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827– 832. 9. Wong ND, Kouwabunpat D, Vo AN, Detrano RC, Eisenberg H, Goel M, Tobis JM. Coronary calcium and atherosclerosis by ultrafast computed tomography in asymptomatic men and women: relation to age and risk factors. Am Heart J 1994;127:422– 430. 10. Mahoney LT, Thompson BH, Stanford W, Burns TL, Witt JD, Rost CA, Lauer RM. Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine Study. J Am Coll Cardiol 1996;27:277– 284. 11. Bild DE, Folsom AR, Lowe LP, Sidney S, Kiefe C, Westfall AO, Zheng JZ, Rumberger J. Prevalence and correlates of coronary calci-

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

fication in black and white young adults: the Coronary Artery risk Development in Young Adults (CARDIA) Study. Arterioscler Thromb Vasc Biol 2001;21:852– 857. 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. Kallikazaros I, Tsioufis C, Sideris S, Stefanadis C, Toutouzas P. Carotid artery disease as a marker for the presence of severe coronary artery disease in patients evaluated for chest pain. Stroke 1999;30: 1002–1007. Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb 1991;11:1245–1249. Rosfors S, Hallerstam S, Jensen-Urstad K, Zetterling M, Carlstrom C. Relationship between intima-media thickness in the common carotid artery and atherosclerosis in the carotid bifurcation. Stroke 1998;29: 1378 –1382. Willeit J, Kiechl S. Prevalence and risk factors of asymptomatic extracranial carotid artery atherosclerosis. A population-based study. Arterioscler Thromb 1993;13:661– 666. Iribarren C, Sidney S, Sternfeld B, Browner WS. Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease. JAMA 2000;283:2810 –2815. Kamensky G, Lisy L, Polak E, Piknova E, Plevova N. Mitral annular calcifications and aortic plaques as predictors of increased cardiovascular mortality. J Cardiol 2001;37:21–26. Rubin DC, Hawke MW, Plotnick GD. Relation between mitral annular calcium and complex intraaortic debris. Am J Cardiol 1993;71:1251– 1252. Savage DD, Garrison RJ, Castelli WP, McNamara PM, Anderson SJ, Kannel WB, Feinleib M. Prevalence of submitral (anular) calcium and its correlates in a general population-based sample (the Framingham Study). Am J Cardiol 1983;51:1375–1378. Tenebaum A, Shemesh J, Fisman EZ, Motro M. Advanced mitral annular calcification is associated with severe coronary calcification on fast dual spiral computed tomography. Invest Radiol 2000;35:193– 198. Sharma R, Pellerin D, Gaze DC, Mehta RL, Gregson H, Streather CP, Collinson PO, Brecker SJ. Mitral annular calcification predicts mortality and coronary artery disease in end stage renal disease. Atherosclerosis 2007;191:348 –354. Willens HJ, Chirinos JA, Schob A, Veerani A, Perez AJ, Chakko S. The relation between mitral annular calcification and mortality in patients undergoing diagnostic coronary angiography. Echocardiography 2006;23:717–722. Atar S, Jeon DS, Luo H, Siegel RJ. Mitral annular calcification: a marker of severe coronary artery disease in patients under 65 years old. Heart 2003;89:161–164. Acarturk E, Bozkurt A, Cayli M, Demir M. Mitral Annular Calcification and Aortic valve Calcification may help in predicting significant coronary artery disease. Angiology 2003;54:561–567. Adler Y, Fisman EZ, Shemesh J, Tanne D, Hovav B, Motro M, Schwammenthal E, Tenenbaum A. Usefulness of helical computed tomography in detection of mitral annular calcification as a marker of coronary artery disease. Int J Cardiol 2005;101:371–376.