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 ± 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.
Mitral annular calcium (MAC) is long-term fibrous degenerative calcium of the mitral valve support ring, which is frequent in women and elderly patients. It has been suggested that MAC may be a manifestation of generalized atherosclerosis and could be an aid toward diagnosing coronary artery disease (CAD). 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. However, mild MAC has not shown the same association. In this substudy of the Multi-Ethnic Study of Atherosclerosis (MESA) population, we looked at 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. 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.
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.
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. 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 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 β from the regression model y = exp(X T β). 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 ).
| Variable | MAC 0 | CAC >0 | p Value |
|---|---|---|---|
| (n = 6,170) | (n = 644) | ||
| Age (years) | 61 ± 10 | 72 ± 11 | <0.001 |
| Men | 2,955 (48%) | 258 (40%) | <0.001 |
| Race | |||
| White | 2,309 (38%) | 315 (49%) | <0.001 |
| Chinese | 766 (12%) | 37 (6%) | |
| Black | 1,753 (28%) | 141 (22%) | |
| Hispanic | 1,342 (22%) | 151 (23%) | |
| Smoker | |||
| Former | 2,234 (36%) | 253 (39%) | <0.008 |
| Current | 828 (13%) | 59 (9%) | |
| Body mass index (kg/m 2 ) | 28 ± 5 | 29 ± 6 | 0.003 |
| Systolic blood pressure (mm Hg) | 126 ± 21 | 135 ± 23 | <0.001 |
| Hypertension | 2,655 (43%) | 403 (63%) | <0.001 |
| Diabetes mellitus | 827 (13%) | 144 (22%) | <0.001 |
| Family history of heart attack | 2,438 (40%) | 296 (46%) | <0.001 |
| Total cholesterol (mg/dl) | 194 ± 35 | 195 ± 38 | 0.439 |
| Low-density lipoprotein (mg/dl) | 117 ± 31 | 115 ± 33 | 0.09 |
| High-density lipoprotein (mg/dl) | 51 ± 15 | 52 ± 15 | 0.08 |
| Triglycerides (mg/dl) | 111 (787–161) | 113 (80–161) | <0.001 |
| Lipid-lowering medications | 479 (8%) | 165 (15%) | <0.001 |
| High-sensitivity C-reactive protein (mg/L) | 1.88 (0.83–4.25) | 2.21 (0.94–4.40) | 0.02 |
| Coronary artery calcium (AU) | 0 (0–63) | 118 (4–447) | <0.0001 |
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 ≥400, 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 ≥400, 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.
| CAC | Relative Risk (95% CI) | ||
|---|---|---|---|
| Model 1 ⁎ | Model 2 † | Model 3 ‡ | |
| 0 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| >0 | 3.85 (3.18–4.66) | 1.68 (1.31–2.31) | 1.66 (1.27–2.14) |
| 0 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 1–99 | 2.13 (1.69–2.69) | 1.11 (0.82–1.45) | 1.14 (0.83–1.56) |
| 100–399 | 5.07 (4.01–6.41) | 2.05 (1.52–2.75) | 2.09 (1.53–2.85) |
| ≥400 | 7.57 (5.95–9.62) | 2.77 (2.06–3.73) | 2.58 (1.85–3.60) |
| Ln(CAC + 1) | 1.39 (1.33–1.46) | 1.20 (1.14–1.26) | 1.19 (1.12–1.25) |
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