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1.  Associations of Left Ventricular Hypertrophy with Prevalent and Incident Valve Calcification: The Multi-Ethnic Study of Atherosclerosis 
JACC. Cardiovascular imaging  2012;5(8):781-788.
We aim to evaluate the relationship between percent of predicted left ventricular mass (%PredLVM) and valve calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).
Cardiac valve calcification has been associated with left ventricular hypertrophy (LVH), which portends cardiovascular events. However, this relationship and its mediators are poorly understood.
MESA is a longitudinal cohort study of men and women aged 45-84 years without clinical cardiovascular disease in whom serial cardiac magnetic resonance and computed tomography imaging were performed. The relationships between baseline %PredLVM and the prevalence, severity, and incidence of aortic valve (AVC) and mitral annulus calcification (MAC) were determined by regression modeling.
Prevalent AVC was observed in 630 and MAC in 442 of 5,042 subjects (median 55.9 and 71.1 Agatston units, respectively). After adjustment for age, gender, body mass index, ethnicity, socioeconomic status, physical activity, diabetes, cholesterol levels, blood pressure, smoking, kidney function, serum lipids, and antihypertensive and statin medications, %PredLVM was associated with prevalent AVC (OR=1.18 per SD increase in %PredLVM [95%CI 1.08 – 1.30]; p=0.0004) and MAC (OR=1.18 [95%CI 1.06 – 1.32]; p=0.002). Similarly, %PredLVM was associated with increased severity of prevalent AVC (risk difference = 0.26 [95%CI 0.15 – 0.38]; p<0.0001) and MAC (risk difference = 0.20 [95%CI 0.03 – 0.37]; p=0.02). During follow-up (mean 2.4±0.9 years), 153 subjects (4%) developed AVC and 198 (5%) MAC. %PredLVM was associated with incident AVC (OR=1.24 [95%CI 1.04 – 1.47]; p=0.02) and MAC (OR=1.18 [1.01-1.40]; p=0.04). Further adjustment for inflammatory markers and coronary artery calcification did not attenuate these associations. Specifically, concentric LVH most strongly predicted incident valve calcification.
Within the MESA cohort, LVH was associated with prevalence, severity, and incidence of valve calcification independent of hypertension and other identified confounders.
PMCID: PMC3426868  PMID: 22897991
aortic valve; calcification; left ventricular mass; mitral valve annulus
2.  Computed Tomography-Derived Cardiovascular Risk Markers, Incident Cardiovascular Events, and All-Cause Mortality in Non- Diabetics. The Multi-Ethnic Study of Atherosclerosis 
We assess the improvement in discrimination afforded by the addition thoracic aorta calcium (TAC), aortic valve calcification (AVC), mitral annular calcification (MAC), pericardial adipose tissue volume (PAT) and liver attenuation (LA) to Framingham risk score(FRS) + coronary artery calcium (CAC) for incident CHD/CVD in a multi ethnic cohort.
Methods and Results
A total 5745(2710 were intermediate Framingham risk, 210 CVD and 155 CHD events) 251 had adjudicated CHD, 346 had CVD events, 321 died after 9 years of follow-up. Cox proportional hazard, receiver operator curve (ROC) and net reclassification improvement (NRI) analyses.
In the whole cohort and also when the analysis was restricted to only the intermediate risk participants: CAC, TAC, AVC and MAC were all significantly associated with incident CVD/CHD/ mortality; CAC had the strongest association. When added to the FRS, CAC had the highest area under the curve (AUC) for the prediction of incident CHD/CVD; LA had the least. The addition of TAC, AVC, MAC, PAT and LA to FRS + CAC all resulted in a significant reduction in AUC for incident CHD [0.712 vs. 0.646, 0.655, 0.652, 0.648 and 0.569; all p<0.01 respectively] in participants with intermediate FRS. The addition of CAC to FRS resulted in an NRI of 0.547 for incident CHD in the intermediate risk group. The NRI when TAC, AVC, MAC, PAT and LA were added to FRS + CAC were 0.024, 0.026, 0.019, 0.012 and 0.012 respectively, for incident CHD in the intermediate risk group. Similar results were obtained for incident CVD in the intermediate risk group and also when the whole cohort was used instead of the intermediate FRS group.
The addition of CAC to the FRS provides superior discrimination especially in intermediate risk individuals compared with the addition of TAC, AVC, MAC, PAT or LA for incident CHD/CVD. Compared with FRS + CAC, the addition of TAC, AVC, MAC, PAT or LA individually to FRS + CAC worsens the discrimination for incident CHD/CVD. These CT risk markers are unlikely to be useful for improving cardiovascular risk prediction.
PMCID: PMC4150859  PMID: 23689526
cardiac CT derived risk factors; coronary heart disease; cardiovascular events; risk prediction
3.  Associations between Aspirin and other non-steroidal anti-inflammatory drugs and aortic valve or coronary artery calcification: The Multi-Ethnic Study of Atherosclerosis and the Heinz Nixdorf Recall Study 
Atherosclerosis  2013;229(2):310-316.
The association between non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence of valvular and arterial calcification is not well established despite known associations between these drugs and cardiovascular events.
To compare the association between the baseline use of aspirin with other NSAID class medications with the incidence and prevalence of aortic valve calcification (AVC) and coronary artery calcium (CAC).
The relationship of NSAID use to AVC and CAC detected by computed tomography was assessed in 6,814 participants within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling. Results were adjusted for age, sex, ethnicity, study site, anti-hypertensive medication use, education, income, health insurance status, diabetes, smoking, exercise, body mass index, blood pressure, serum lipids, inflammatory markers, fasting glucose, statin medication use, and a simple diet score. Medication use was assessed by medication inventory at baseline which includes the use of non-prescription NSAIDs. MESA collects information on both incident and prevalent calcification. The 4,814 participants of the Heinz Nixdorf Recall (HNR) Study, a German prospective cohort study with similar measures of calcification, were included in this analysis to enable replication.
Mean age of the MESA participants was 62 years (51% female). After adjustment for possible confounding factors, a possible association between aspirin use and incident AVC (Relative Risk(RR): 1.60; 95%Confidence Interval (CI): 1.19–2.15) did not replicate in the HNR cohort (RR: 1.06; 95%CI: 0.87–1.28). There was no significant association between aspirin use and incident CAC in the MESA cohort (RR 1.08; 95%CI: 0.91–1.29) or in the HNR cohort (RR 1.24; 95%CI: 0.87–1.77). Non-aspirin NSAID use was not associated with either AVC or CAC in either cohort. There were no associations between regular cardiac dose aspirin and incident calcification in either cohort.
Baseline NSAID use, as assessed by medication inventory, appears to have no protective effect regarding the onset of calcification in either coronary arteries or aortic valves.
PMCID: PMC3724227  PMID: 23880181
Non-steroidal anti-inflammatory drugs; aspirin; aortic valve calcification; coronary artery calcification; Multi-Ethnic Study of Atherosclerosis; Heinz Nixdorf Recall Study
4.  Association of mitral annulus calcification, aortic valve calcification with carotid intima media thickness 
Mitral annular calcification (MAC) and aortic annular calcification (AVC) may represent a manifestation of generalized atherosclerosis in the elederly. Alterations in vascular structure, as indexed by the intima media thickness (IMT), are also recognized as independent predictors of adverse cardiovascular outcomes.
To examine the relationship between the degree of calcification at mitral and/or aortic valve annulus and large artery structure (thickness).
We evaluated 102 consecutive patients who underwent transthoracic echocardiography and carotid artery echoDoppler for various indications; variables measured were: systemic blood pressure (BP), pulse pressure (PP=SBP-DBP), body mass index (BMI), fasting glucose, total, HDL, LDL chlolesterol, triglycerides, cIMT. The patients were divided according to a grading of valvular/annular lesions independent scores based on acoustic densitometry: 1 = annular/valvular sclerosis/calcification absence; 2 = annular/valvular sclerosis; 3 = annular calcification; 4 = annular-valvular calcification; 5 = valvular calcification with no recognition of the leaflets.
Patient score was the highest observed for either valvular/annulus. Mean cIMT increased linearly with increasing valvular calcification score, ranging from 3.9 ± 0.48 mm in controls to 12.9 ± 1.8 mm in those subjects scored 5 (p < 0.0001). In the first to fourth quartile of cIMT values the respective maximal percentual of score were: score 1: 76.1%, score 2: 70.1%, score 4: 54.3% and score 5: 69.5% (p > 0.0001).
MAC and AVC score can identify subgroups of patients with different cIMT values which indicate different incidence and prevalence of systemic artery diseases. This data may confirm MAC-AVC as a useful important diagnostic parameter of systemic atherosclerotic disease.
PMCID: PMC526215  PMID: 15471552
carotid artery disease; heart disease; atherosclerosis; imaging
5.  Aortic Valve Calcium Independently Predicts Coronary and Cardiovascular Events in a Primary Prevention Population 
Jacc. Cardiovascular Imaging  2012;5(6):619-625.
This study aimed to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population.
Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial and it is unknown if this association extends to younger individuals.
We performed a prospective analysis of 6,685 participants in the Multi-Ethnic Study of Atherosclerosis. All subjects, aged 45-84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium (CAC) scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and non-fatal strokes, resuscitated cardiac arrest and cardiovascular death, while a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers and subclinical coronary atherosclerosis.
Over a median follow up of 5.8 [IQR 5.6, 5.9] years, adjusting for demographics and cardiovascular risk factors, subjects with AVC (n=894, 13.4%) had higher risks of cardiovascular (HR, 1.50; 95% CI, 1.10-2.03) and coronary (HR, 1.72; 95% CI, 1.19-2.49) events compared to those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for CAC substantially attenuated both cardiovascular (HR, 1.32; 95% CI: 0.98-1.78) and coronary (HR, 1.41; 95% CI, 0.98-2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR, 2.51; 95% CI, 1.22-5.21).
In this multiethnic MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation.
PMCID: PMC3376353  PMID: 22698532
6.  Relationships of Mitral Annular Calcification to Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;213(2):558-562.
Mitral annular calcification (MAC) is a fibrous, degenerative calcification of the mitral valve. The relationship between MAC and cardiovascular disease (CVD) risk factors is not well defined. Thus, we performed a cross-sectional study to determine which CVD risk factors are independently associated with MAC in the Multi-Ethnic Study of Atherosclerosis (MESA).
MESA includes 6,814 women and men ages 45–84 years old without apparent CVD in 4 ethnic groups (12% Chinese, 38% Caucasian, 22% Hispanic, and 28% African-American). MAC was defined by presence of calcium in the mitral annulus by cardiac computed tomography at enrollment. Multivariable logistic regression was used to evaluate relationships between MAC and CVD risk factors.
The overall prevalence of MAC was 9%. The prevalence of MAC was highest in Caucasians (12%), followed by Hispanics (10%), African Americans (7%) and was lowest in Chinese (5%). Characteristics associated with MAC included age (p<0.01), female gender (p<0.01), increased body mass index (BMI) (p=0.03), and former smoking status (p<0.008). The MAC group had a higher prevalence of hypertension, diabetes mellitus (DM), and family history of heart attack (all p<0.001). After adjusting for all variables, age, female gender, diabetes mellitus, and increased BMI remained strongly associated with MAC.
Age, female gender, DM, and increased BMI were significantly associated with MAC. Prevalence of MAC was strongly associated with female gender and increasing age in all ethnicities.
PMCID: PMC2997868  PMID: 20926076
Mitral annular calcification; MESA; Cardiac CT; risk factors
7.  Thoracic Aortic Calcification and Coronary Heart Disease Events: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;215(1):196-202.
The presence and extent of coronary artery calcium (CAC) is an independent predictor of coronary heart disease (CHD) morbidity and mortality. Few studies have evaluated interactions or independent incremental risk for coronary and thoracic aortic calcification (TAC). The independent predictive value of TAC for CHD events is not well-established.
This study used risk factor and computed tomography scan data from 6,807 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Using the same images for each participant, TAC and CAC were each computed using the Agatston method. The study subjects were free of incident CHD at entry into the study.
The mean age of the study population (n=6807) was 62±10 years (47% males). At baseline, the prevalence of TAC and CAC was 28 % (1,904/6,809) and 50% (3393/6809), respectively. Over 4.5±0.9 years, a total of 232 participants (3.41%) had CHD events, of which 132 (1.94%) had a hard event (myocardial infarction, resuscitated cardiac arrest, or CHD death). There was a significant interaction between gender and TAC for CHD events (p<0.05). Specifically, in women, the risk of all CHD event was nearly 3-fold greater among those with any TAC (hazard ratio: 3.04, 95% CI; 1.60–5.76). After further adjustment for increasing CAC score, this risk was attenuated but remained robust (HR: 2.15, 95% CI: 1.10–4.17). Conversely, there was no significant association between TAC and incident CHD in men. In women, the likelihood ratio chi square statistics indicate that the addition of TAC contributed significantly to predicting incident CHD event above that provided by traditional risk factors alone (chi square= 12.44, p=0.0004) as well as risk factors + CAC scores (chi square= 5.33, p=0.02) . On the other hand, addition of TAC only contributed in the prediction of hard CHD events to traditional risk factors (chi-square=4.33, p=0.04) in women, without contributing to the model containing both risk factors and CAC scores (chi square=1.55, p=0.21).
Our study indicates that TAC is a significant predictor of future coronary events only in women, independent of CAC. On studies obtained for either cardiac or lung applications, determination of TAC may provide modest supplementary prognostic information in women with no extra cost or radiation.
PMCID: PMC4110678  PMID: 21227418
atherosclerosis; cardiac CT; coronary calcium; multi-detector CT; prognosis; thoracic atherosclerosis
8.  Relationship of Metabolic Syndrome With Incident Aortic Valve Calcium and Aortic Valve Calcium Progression 
Diabetes  2009;58(4):813-819.
Metabolic syndrome (MetS) has been associated with increased prevalence of aortic valve calcium (AVC) and with increased progression of aortic stenosis. The purpose of this study was to determine whether MetS is associated with increased risks for the development of new (“incident”) AVC or for progression of established AVC as assessed by CT.
The relationships of MetS or its components as well as of diabetes to risks for incident AVC or AVC progression were studied among participants with CT scans performed at baseline and at either year 2 or year 3 examinations in the Multi-Ethnic Study of Atherosclerosis (MESA).
Of 5,723 MESA participants meeting criteria for inclusion, 1,674 had MetS by Adult Treatment Panel III criteria, whereas 761 had diabetes. Among the 5,123 participants without baseline AVC, risks for incident AVC, adjusted for time between scans, age, sex, race/ethnicity, LDL cholesterol, lipid-lowering medications, and smoking, were increased significantly for MetS (odds ratio [OR] 1.67 [95% CI 1.21–2.31]) or diabetes (2.06 [1.39–3.06]). In addition, there was an increase in incident AVC risk with increasing number of MetS components. Similar results were found using the International Diabetes Federation MetS criteria. Among the 600 participants (10.5%) with baseline AVC, neither MetS nor diabetes was associated with AVC progression.
In the MESA cohort, MetS was associated with a significant increase in incident (“new”) AVC, raising the possibility that MetS may be a potential therapeutic target to prevent AVC development.
PMCID: PMC2661576  PMID: 19136658
9.  Association of Aortic Valve Calcification to the Presence, Extent, and Composition of Coronary Artery Plaque Burden: ROMICAT Study 
American heart journal  2009;158(4):562-568.
Aortic valve calcification (AVC) is associated with cardiovascular risk factors and coronary artery calcification. We sought to determine whether AVC is associated with the presence and extent of overall plaque burden, as well as to plaque composition (calcified, mixed, and non-calcified).
We examined 357 subjects (mean age: 53 ± 12 years, 61% male) who underwent contrast-enhanced ECG-gated 64-slice multi-detector computed tomography from the ROMICAT trial for the assessment of presence and extent of coronary plaque burden according to the 17-coronary segment model and presence of AVC.
Patients with AVC (n=37, 10%) were more likely than those without AVC (n=320, 90%) to have coexisting presence of any coronary plaque (89% vs. 46%, p<0.001) and had a greater extent of coronary plaque burden (6.4 segments vs. 1.8 segments, p<0.001). Those with AVC had over 3-fold increase odds of having any plaque (adjusted odds ratio [OR] 3.6, p=0.047) and an increase of 2.5 segments of plaque (p<0.001) as compared to those without AVC. When stratified by plaque composition, AVC was associated most with calcified plaque (OR 5.2, p=0.004), then mixed plaque (OR 3.2, p=0.02), but not with non-calcified plaque (p=0.96).
AVC is associated with the presence and greater extent of coronary artery plaque burden and may be part of the later stages of the atherosclerosis process, as its relation is strongest with calcified plaque, less with mixed plaque, and nonsignificant with non-calcified plaque. If AVC is present, consideration for aggressive medical therapy may be warranted.
PMCID: PMC2764241  PMID: 19781415
Aortic valve calcification; coronary artery disease; multi-detector computed tomography; calcified plaque; non-calcified plaque; mixed plaque
10.  Relationship between Coronary Artery and Descending Thoracic Aortic Calcification as Detected by Computed Tomography: the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;204(2):440-446.
Cardiac computed tomography (CT) is a well-established tool for the detection of cardiovascular calcium. Coronary artery calcification (CAC) is highly sensitive for the detection of coronary artery disease (CAD) as well as predictive of future cardiovascular (CV) events. Descending thoracic aortic calcification (DTAC) is common in the elderly and its presence is also associated with increased risk of CV events. Previous studies demonstrate that DTAC is associated with obstructive CAD and coronary risk factors. However, no prior studies have examined the association of CAC and DTAC as detected by cardiac CT in a large population-based cohort.
In the Multi-Ethnic Study of Atherosclerosis, the study population included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45−84 years old. Participants underwent non-enhanced cardiac CT and both CAC and DTAC were quantified. DTAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. Multivariable relative risk regression was used to evaluate relationships between CAC, DTAC and measured cardiovascular risk factors.
Overall 3030 (44%) did not demonstrate any detectable CAC or DTAC. A total of 1930 (28%) had only CAC, 386 (6%) had isolated DTAC, and 1464 (22%) participants were found to have both CAC and DTAC. CAC had a higher prevalence than DTAC in men (58% vs. 45%). Participants with DTAC were older than those with CAC (mean age was 71 and 66 years old, respectively). Participants with DTAC had increased risk for the presence of CAC independent of cardiovascular risk factors (prevalence ratio [PR]; 1.17 95% CI 1.07−1.28). Severity of DTAC was a stronger predictor of the presence of CAC in women as compared to men (PR; 1.04 95% CI 1.02 −1.06, and PR; 0.99 95% CI 0.98− 1.01, respectively).
DTAC was found to be a strong predictor of CAC independent of CV risk factors. Ongoing follow-up of this cohort will evaluate whether DTAC is an independent marker of risk for CV events.
PMCID: PMC2732017  PMID: 19027115
11.  Relationship between Common Carotid Intima-Media Thickness and Thoracic Aortic Calcification: the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;209(1):142-146.
Mean maximum carotid intima-media thickness (CIMT) is associated with both coronary artery disease and cerebral thromboembolism. Thoracic aortic calcification (TAC) detected by computed tomography (CT) is also highly associated with vascular disease and cardiovascular risk. No previous study has examined the relationship between CIMT and TAC in a large patient cohort. We performed a cross-sectional study to determine whether, at baseline, there is a relationship between CIMT and CT-determined TAC score.
In the Multi-Ethnic Study of Atherosclerosis, the study cohort included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45-84 years. After exclusion of 198 persons due to incomplete information, we compared results of 6616 participants with both CIMT and TAC. TAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. CIMT at the common carotid artery site was represented as the mean maximal CIMT of the right and left near and far walls, respectively. Multivariable relative risk regression analysis was used to evaluate relationships between TAC and CIMT.
The prevalence of TAC was 28% (n=1846) and the mean maximum (±SD) CIMT was 0.87±0.19 mm. A higher prevalence of TAC was noted across increasing CIMT quartiles (1st: 12%, 2nd: 21%, 3rd: 30%, 4th: 49%, P<0.0001). One standard deviation increase in CIMT was associated with a 16% higher likelihood for presence of TAC after adjusting for demographics and cardiovascular disease (CVD) risk factors (95% CI: 1.12-1.26). In addition, individuals with CIMT in the highest quartile, as compared to those with CIMT in the first quartile, had a 76% higher likelihood for presence of TAC (prevalence ratio [PR]: 1.76, 95% CI: 1.37-2.26). In race-ethnic stratified analyses, similar associations were seen in all groups. Among those with TAC>0, a higher CIMT was significantly associated with continuous TAC scores (log transformed) in the overall population as well as among all ethnic-racial groups.
Our study demonstrates that TAC is associated with increasing severity of carotid atherosclerotic burden as measured by CIMT. The combined utility of these two noninvasive measures of subclinical atherosclerosis for CVD risk assessment needs to be determined in future studies.
PMCID: PMC2830343  PMID: 19782983
Atherosclerosis; carotid IMT; aortic calcification; ethnic; cardiac CT
12.  Association of renal function with cardiac calcifications in older adults: the cardiovascular health study 
Background. Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are highly prevalent in patients with end-stage renal disease. It is less well established whether milder kidney disease is associated with cardiac calcifications. We evaluated the relationships between renal function and MAC, aortic annular calcification (AAC) and AVS in the elderly.
Methods. From the Cardiovascular Health Study, a community-based cohort of ambulatory adults ≥ age 65, a total of 3929 individuals (mean ± SD age 74 ± 5 years, 60% women) were evaluated with two-dimensional echocardiography. Renal function was assessed by means of creatinine-based estimated glomerular filtration rate (eGFR) and cystatin C.
Results. The prevalences of MAC and AAC were significantly higher in individuals with an eGFR < 45 mL/ min/1.73 m2 (P < 0.01 for each), and cystatin C levels were significantly higher in individuals with MAC or AAC compared to individuals without these cardiac calcifications (P < 0.001 for each). After multivariate-adjustment, an eGFR <45 mL/min/1.73 m2 was significantly associated with MAC [odds ratio 1.54 (95% CI 1.16–2.06), P = 0.003] and not associated with AAC [1.30 (0.97–1.74), P = 0.085] and AVS [1.15 (0.86–1.53), P = 0.355]. In addition, cystatin C levels were independently associated with MAC [odds ratio per SD 1.12 (1.05–1.21), P = 0.001] and not associated with AAC [1.07 (1.00–1.15), P = 0.054] and AVS [0.99 (0.93–1.06), P = 0.82]. Furthermore, the prevalence of multiple cardiac calcifications was higher in subjects with an eGFR < 45 mL/ min/1.73 m2 and increased per quartile of cystatin C (P-values < 0.001). In addition, a significant trend was observed between an eGFR < 45 mL/min/1.73 m2, increasing levels of cystatin C and the number of cardiac calcifications (P < 0.05).
Conclusions. In a community-based cohort of the elderly, moderate kidney disease as defined by an eGFR <45 mL/min/1.73m2 and elevated levels of cystatin C was associated with prevalent MAC. In addition, a significant trend was observed between an eGFR <45 mL/min/1.73m2, increasing levels of cystatin C and the number of cardiac calcifications. No associations were found between renal function and AAC or AVS.
PMCID: PMC2721419  PMID: 18840892
chronic kidney disease; cohort; creatinine; cystatin C; elderly
13.  Risk Factors Associated with the Incidence and Progression of Mitral Annulus Calcification: The Multi-Ethnic Study of Atherosclerosis 
American heart journal  2013;166(5):904-912.
Significant cardiovascular morbidity has been associated with mitral annulus calcification (MAC), but limited data exist regarding its progression. The purpose of this study was to examine the natural history of and risk factors for MAC progression.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal cohort study of participants aged 45–84 years without clinical cardiovascular disease who underwent serial cardiac computed tomography studies with quantification of MAC. Regression models were used to identify risk factors associated with MAC incidence and progression.
Prevalent MAC was observed in 534 of 5,895 (9%) participants. Over a median 2.3 years, 280 (5%) developed incident MAC. After adjustment, age was the strongest predictor of incident MAC (adjusted OR, 2.25 per 10 yrs; 95% CI, 1.97 to 2.58; P<0.0001). Female gender, white ethnicity, body mass index, diabetes, hypertension, hyperlipidemia, serum cholesterol, smoking, and interleukin-6 were also significant predictors of incident MAC. In participants with prevalent MAC, the median rate of change was 10.1 [IQR, −6.7, 60.7] Agatston units (AU)/year. Baseline MAC severity was the predominant predictor of rate of MAC progression (β-coefficient per 10 AU, 0.88; 95% CI, 0.85 to 0.91; P<0.0001), although ethnicity and smoking status possessed modest influence.
Several cardiovascular risk factors predicted incident MAC, as did female gender. Severity of baseline MAC was the primary predictor of MAC progression, suggesting that, while atherosclerotic processes may initiate MAC, they are only modestly associated with its progression over these time frames.
PMCID: PMC3978772  PMID: 24176447
calcification; mitral valve; progression; risk factors; gender
14.  Relationships of thoracic aortic wall calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis 
American heart journal  2008;155(4):765-771.
The aim of this paper is to determine the relationships between aortic wall calcification (AWC) including ascending and descending thoracic aortic calcification and gender, race/ethnicity, age, and traditional risk factors. Allison et al and Post et al previously described the relationship of noted risk factors and AWC as detected by computed tomography (CT) in smaller cohorts. We performed a cross-sectional study to determine which of these variables are independently associated with thoracic calcium.
The Multi-Ethnic Study of Atherosclerosis (MESA) study population included a population based sample of four ethnic groups (12% Chinese, 38% White, 22% Hispanic and 28% black) of 6814 women and men ages 45–84 years old. CT scans were performed for all participants. We quantified AWC, which ranged from the lower edge of the pulmonary artery bifurcation to the cardiac apex. Multivariable logistic regression was used to evaluate relationships between AWC and measured cardiovascular risk factors.
Overall prevalence of AWC was 28.0%. In the ethnic groups, prevalence of AWC was 32.4% Chinese, 32.4% White, 24.9% Hispanic and 22.4% Black. All age categories of females had a higher prevalence of thoracic calcification than males (total age prevalence: 29.1% and 26.8%, respectively). AWC were most strongly associated with hypertension and current smoking. In addition, diabetes, hypercholesterolemia, high LDL, low HDL, family history of heart attack and high CRP were all associated with increased AWC. Overall p-value for difference between genders for prevalence of AWC = 0.037. Overall p-value for difference between race for prevalence of AWC <0.001. The only significant gender differences distributed by race were for Chinese (p=0.035) and Hispanic (p=0.042) participants.
Risk factors for aortic calcification were similar to cardiovascular risk factors in a large population based cohort. Suprisingly, AWC was similar for the Chinese and white populations despite the fact that MESA demonstrated that coronary caclium was more prevalent in the white population. Further studies are needed to investigate whether aortic calcification is a risk factor for coronary disease, independent of coronary calcification.
PMCID: PMC2323597  PMID: 18371491
15.  Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study 
BMC Nephrology  2013;14:219.
Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. Here, we assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients.
We conducted a cross-sectional multi-slice computed tomography (MS-CT) scanning study in 67 chronic HD patients (59.4 ± 14.8 yrs) for measurement of CAC and AVC. We tested established biomarkers as well as serum sclerostin (ELISA) regarding their association to the presence of calcification. Fifty-four adults without relevant renal disease served as controls for serum sclerostin levels. Additionally, sclerostin expression in explanted aortic valves from 15 dialysis patients was analysed ex vivo by immunohistochemistry and mRNA quantification (Qt-RT-PCR).
CAC (Agatston score > 100) and any AVC were present in 65% and in 40% of the MS-CT patient group, respectively. Serum sclerostin levels (1.53 ± 0.81 vs 0.76 ± 0.31 ng/mL, p < 0.001) were significantly elevated in HD compared to controls and more so in HD patients with AVC versus those without AVC (1.78 ± 0.84 vs 1.35 ± 0.73 ng/mL, p = 0.02). Multivariable regression analysis for AVC revealed significant associations with higher serum sclerostin. Ex vivo analysis of uraemic calcified aortic valves (n = 10) revealed a strong sclerostin expression very close to calcified regions (no sclerostin staining in non-calcified valves). Correspondingly, we observed a highly significant upregulation of sclerostin mRNA in calcified valves compared to non-calcified control valves.
We found a strong association of sclerostin with calcifying aortic heart valve disease in haemodialysis patients. Sclerostin is locally produced in aortic valve tissue adjacent to areas of calcification.
PMCID: PMC3851854  PMID: 24112318
Aortic valve disease; Cardiovascular disease; Coronary calcification; Hemodialysis; Mineral metabolism; Vascular calcification; Renal osteodystrophy; Sclerostin
16.  Incidence and Progression of Aortic Valve Calcium in the Multi-Ethnic Study of Atherosclerosis (MESA) 
The American journal of cardiology  2010;105(5):701-708.
Aortic valve calcium (AVC) is common among older adults and shares epidemiologic and histopathologic similarities to atherosclerosis. However, prospective studies have failed to identify meaningful risk-associations with incident (“new”) AVC or its progression. In this study, AVC was quantified from serial computed tomography (CT) images in 5,880 participants (aged 45–84 years) of the Multi-Ethnic Study of Atherosclerosis, using Agatston methodology. Multivariate backwards selection modeling was used to identify risk factors for incident AVC and AVC progression. During a mean follow up of 2.4±0.9 years, 210 subjects (4.0%) developed incident AVC. The incidence rate (mean 1.7 %/year) increased significantly with age (p<0.001). Risk factors for incident AVC included age, male gender, BMI, current smoking, and the use of lipid lowering and antihypertensive medications. Among those with AVC at baseline, the median rate of AVC progression was 2 Agatston units/year [IQR −21, 37]. Baseline Agatston score was a strong, independent predictor of progression, especially among those with high calcium scores at baseline. In conclusion, in this ethnically diverse, pre-clinical cohort, the rate of incident AVC a significantly with age. Incident AVC risk was associated with several traditional cardiovascular risk factors, specifically age, male gender, BMI, current smoking, and the use of both antihypertensive and lipid lowering medications. AVC progression risk was associated with male gender and the baseline Agatston score. Additional research is needed to determine if age- and stage-specific mechanisms underlie risk for AVC progression.
PMCID: PMC2829478  PMID: 20185020
valves; calcium; risk factors; epidemiology; imaging
17.  The Association of Bone Density and Calcified Atherosclerosis is Stronger in Women Without Dyslipidemia: The Multi-Ethnic Study of Atherosclerosis 
We tested whether the association between bone mineral density (BMD) and coronary artery calcification (CAC) varies according to dyslipidemia in community-living individuals. Between 2002 and 2005, 305 women and 631 men (mean age of 64 years) and naïve to lipid-modifying medications and estrogen use were assessed for spine BMD, CAC, and total (TC), HDL- and LDL-cholesterol and triglycerides.
Random sample of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) without clinical cardiovascular disease.
Predictor variable
Spine BMD at the L3 vertebrate by computer tomography (CT).
Main outcome
CAC prevalence by CT.
Effect Modifier
Total cholesterol to HDL ratio (TC:HDL) ≥ 5.0.
The association of BMD with CAC differed in women with TC:HDL < 5.0 vs. higher (p-interaction =0.01). In age and race adjusted models, among women with TC:HDL < 5.0, each SD (43.4 mg/cc) greater BMD was associated with a 25% lower prevalence of CAC (Prevalence Ratio [PR] 0.75, 95% confidence interval [CI] 0.63–0.89), whereas among women with higher TC:HDL, higher BMD was not significantly associated with CAC (PR 1.22, 95% CI 0.82–1.82). Results were similar using other definitions of hyperlipidemia. In contrast, no consistent association was observed between BMD and CAC in men irrespective of the TC:HDL ratio (p interaction 0.54).
The inverse association of BMD with CAC is stronger in women without dyslipidemia. These data argue against the hypothesis that dyslipidemia is the key factor responsible for the inverse association of BMD with atherosclerosis.
PMCID: PMC4100475  PMID: 21834088
18.  Ten-Year Trends in Coronary Calcification in Individuals without Clinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2014;9(4):e94916.
Coronary heart disease (CHD) incidence has declined significantly in the US, as have levels of major coronary risk factors, including LDL-cholesterol, hypertension and smoking, but whether trends in subclinical atherosclerosis mirror these trends is not known.
Methods and Findings
To describe recent secular trends in subclinical atherosclerosis as measured by serial evaluations of coronary artery calcification (CAC) prevalence in a population over 10 years, we measured CAC using computed tomography (CT) and CHD risk factors in five serial cross-sectional samples of men and women from four race/ethnic groups, aged 55–84 and without clinical cardiovascular disease, who were members of Multi-Ethnic Study of Atherosclerosis (MESA) cohort from 2000 to 2012. Sample sizes ranged from 1062 to 4837. After adjusting for age, gender, and CT scanner, the prevalence of CAC increased across exams among African Americans, whose prevalence of CAC was 52.4% in 2000–02, 50.4% in 2003–04, 60.0% is 2005–06, 57.4% in 2007–08, and 61.3% in 2010–12 (p for trend <0.001). The trend was strongest among African Americans aged 55–64 [prevalence ratio for 2010–12 vs. 2000–02, 1.59 (95% confidence interval 1.06, 2.39); p = 0.005 for trend across exams]. There were no consistent trends in any other ethnic group. Risk factors generally improved in the cohort, and adjustment for risk factors did not change trends in CAC prevalence.
There was a significant secular trend towards increased prevalence of CAC over 10 years among African Americans and no change in three other ethnic groups. Trends did not reflect concurrent general improvement in risk factors. The trend towards a higher prevalence of CAC in African Americans suggests that CHD risk in this population is not improving relative to other groups.
PMCID: PMC3990562  PMID: 24743658
19.  Calcifications of the Thoracic Aorta on Extended Non-Contrast-Enhanced Cardiac CT 
PLoS ONE  2014;9(10):e109584.
The presence of calcified atherosclerosis in different vascular beds has been associated with a higher risk of mortality. Thoracic aorta calcium (TAC) can be assessed from computed tomography (CT) scans, originally aimed at coronary artery calcium (CAC) assessment. CAC screening improves cardiovascular risk prediction, beyond standard risk assessment, whereas TAC performance remains controversial. However, the curvilinear portion of the thoracic aorta (TA), that includes the aortic arch, is systematically excluded from TAC analysis. We investigated the prevalence and spatial distribution of TAC all along the TA, to see how those segments that remain invisible in standard TA evaluation were affected.
Methods and Results
A total of 970 patients (77% men) underwent extended non-contrast cardiac CT scans including the aortic arch. An automated algorithm was designed to extract the vessel centerline and to estimate the vessel diameter in perpendicular planes. Then, calcifications were quantified using the Agatston score and associated with the corresponding thoracic aorta segment. The aortic arch and the proximal descending aorta, “invisible” in routine CAC screening, appeared as two vulnerable sites concentrating 60% of almost 11000 calcifications. The aortic arch was the most affected segment per cm length. Using the extended measurement method, TAC prevalence doubled from 31% to 64%, meaning that 52% of patients would escape detection with a standard scan. In a stratified analysis for CAC and/or TAC assessment, 111 subjects (46% women) were exclusively identified with the enlarged scan.
Calcium screening in the TA revealed that the aortic arch and the proximal descending aorta, hidden in standard TA evaluations, concentrated most of the calcifications. Middle-aged women were more prone to have calcifications in those hidden portions and became candidates for reclassification.
PMCID: PMC4193816  PMID: 25302677
20.  Stages of Systemic Hypertension and Blood Pressure as Correlates of Computed Tomography-Assessed Aortic Valve Calcium (From the Multi-Ethnic Study of Atherosclerosis) 
Hypertension has been identified as a risk factor for aortic valve calcium (AVC) but the magnitude of the risk relation with hypertension severity or whether age affects the strength of this risk association has not been studied. The relationship of hypertension severity, as defined by JNC-7 hypertension stages or blood pressure (BP), to CT-assessed AVC prevalence and severity was examined in 4,274 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) without treated hypertension. Analyses were stratified by age < or ≥ 65 years, were adjusted for common cardiovascular risk factors, and excluded those on antihypertensive medications. In age-stratified, adjusted analyses, Stage I/II hypertension was associated with prevalent AVC in those <65 but not in those ≥65 years of age [OR (95% CI): 2.31 (1.35, 3.94) vs. 1.33 (0.96, 1.85), P-interaction = 0.041]. Similarly, systolic BP and pulse pressure (PP) were more strongly associated with prevalent AVC in those <65 than those ≥65 years of age [OR (95% CI): 1.21 (1.08, 1.35) vs. 1.07 (1.01, 1.14) per 10 mmHg increase in systolic BP, Pinteraction = 0.006] and [OR (95% CI): 1.41 (1.21, 1.64) vs. 1.14 (1.05, 1.23) per 10 mmHg increase in PP]. No associations were found between either hypertension stage or BP and AVC severity. In conclusion, stage I/II hypertension, as well as higher systolic pressure and pulse pressure were associated with prevalent AVC. These risk associations were strongest in participants younger than age 65 years.
PMCID: PMC3032359  PMID: 21146685
Blood Pressure; Aortic Valve; Calcification
21.  Association Between Coronary Artery Calcification Progression and Microalbuminuria 
JACC. Cardiovascular imaging  2010;3(6):595-604.
This study sought to evaluate the relationship between microalbuminuria (MA) and the development and progression of atherosclerosis, as assessed by incident and progression of coronary artery calcification (CAC).
MA is associated with an increased risk of cardiovascular disease, but the mechanism by which MA imparts this increased risk is not known.
The MESA (Multi-Ethnic Study of Atherosclerosis) study is a prospective cohort study of 6,814 self-identified White, African-American, Hispanic, or Chinese participants free of clinical cardiovascular disease at entry. Of the 6,775 individuals with available urine albumin data, we excluded 97 subjects with macroalbuminuria and 1,023 with missing follow-up CAC data. The final study population consists of 5,666 subjects.
At baseline, individuals with MA were more likely to have CAC >0 compared with those without MA (62% vs. 48%, p < 0.0001). During a mean follow-up of 2.4 ± 0.8 years, those with MA and no CAC at baseline were more likely to develop CAC (relative risk [RR]: 2.05, 95% confidence interval [CI]: 1.41 to 3.02, p < 0.0001) as compared with those without MA in demographic-adjusted analyses. After multivariant adjustment, the relationship was attenuated but remained statistically significant (RR: 1.76, 95% CI: 1.19 to 2.61, p = 0.005). Among those with CAC at baseline, those with versus those without MA had a 15 (95% CI: 8 to 22, p < 0.0001) volume units higher median increase in CAC in demographic-adjusted analyses. After multivariant adjustment, MA remained associated with incident CAC (RR: 1.76, 95% CI: 1.19 to 2.61, p = 0.005) and with progression of CAC (median increase in CAC volume score of 9 [95% CI: 2 to 16, p = 0.009]), relative to those without MA.
This large multiethnic, population-based study of asymptomatic individuals demonstrates an increased risk of incident CAC as well as greater CAC progression among those with MA. Further study is needed to determine the degree to which MA precedes and predicts progression of atherosclerosis and how this information can be used to reduce cardiovascular events.
PMCID: PMC4083743  PMID: 20541715
coronary artery calcium; microalbuminuria; risk prediction; coronary heart disease; Multi-Ethnic Study of Atherosclerosis
22.  Relationship of Carotid Distensibility and Thoracic Aorta Calcification: Multi-Ethnic Study of Atherosclerosis (MESA) 
Hypertension  2009;54(6):1408-1415.
Stiffening of the central elastic arteries is one of the earliest detectable manifestations of adverse change within the vessel wall. While an association between carotid artery stiffness and adverse events has been demonstrated, little is known about the relationship between stiffness and atherosclerosis. Even less is known about the impact of age, gender, and race on this association. To elucidate this question, we used baseline data from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000-2002). Carotid artery distensibility coefficient (DC) was calculated after visualization of the instantaneous waveform of common carotid diameter using high resolution B-mode ultrasound. Thoracic aorta calcification (TAC) was identified using non-contrast cardiac CT. We found a strong association between decreasing DC (increasing carotid stiffness) and increasing TAC as well as a graded increase in TAC score (p<0.001). After controlling for age, gender, race, and traditional and emerging cardiovascular risk factors, individuals in the stiffest quartile had a prevalence ratio of 1.52 (95% CI 1.15-2.00) for TAC compared to the least stiff quartile. In exploratory analysis, carotid stiffness was more highly correlated with calcification of the aorta than calcification of the coronary arteries (ρ=0.32 vs. 0.22, p<0.001 for comparison). In conclusion, there is a strong independent association between carotid stiffness and thoracic aorta calcification. Carotid stiffness is more highly correlated with calcification of the aorta, a central elastic artery, than calcification of the coronary arteries. The prognostic significance of these findings requires longitudinal follow-up of the MESA cohort.
PMCID: PMC4118641  PMID: 19805639
Carotid stiffness; carotid compliance; subclinical atherosclerosis; thoracic aorta calcification; coronary calcification
23.  Signs of subclinical coronary atherosclerosis in relation to risk factor distribution in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) 
European Heart Journal  2008;29(22):2782-2791.
Modern imaging technology allows us the visualization of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis. The prevalence, quantity, and risk factors for CAC were compared between two studies with similar imaging protocols but different source populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR).
Methods and results
The measured CAC in 2220 MESA participants were compared with those in 3126 HNR participants with the inclusion criteria such as age 45–75 years, Caucasian race, and free of baseline cardiovascular disease. Despite similar mean levels of CAC of 244.6 among participants in MESA and of 240.3 in HNR (P = 0.91), the prevalence of CAC > 0 was lower in MESA (52.6%) compared with HNR (67.0%) with a prevalence rate ratio of CAC > 0 of 0.78 [95% confidence interval (CI): 0.72–0.85] after adjustment for known risk factors. Consequently, among participants with CAC > 0, the participants in MESA tended to have higher levels of CAC than those in HNR (ratio of CAC levels: 1.39; 95% CI: 1.19–1.63), since many HNR participants have small (near zero) CAC values.
The CAC prevalence was lower in the United States (MESA) cohort than in the German (HNR) cohort, which may be explained by more favourable risk factor levels among the MESA participants. The predictors for increased levels of CAC were, however, similar in both cohorts with the exception that male gender, blood pressure, and body mass index were more strongly associated in the HNR cohort.
PMCID: PMC2582985  PMID: 18845666
Epidemiology; Atherosclerosis; Coronary artery calcium; Risk factors; Screening
24.  Null Association between Abdominal Muscle and Calcified Atherosclerosis in Community-Living Persons Without Clinical Cardiovascular Disease: the Multi-Ethnic Study of Atherosclerosis 
Metabolism: clinical and experimental  2013;62(11):10.1016/j.metabol.2013.06.001.
Detrimental effects of lean muscle loss have been hypothesized to explain J-shaped relationships of body mass index (BMI) with cardiovascular disease (CVD), yet associations of muscle mass with CVD are largely unknown. We hypothesized that low abdominal lean muscle area would be associated with greater calcified atherosclerosis, independent of other CVD risk factors.
We investigated 1020 participants from the Multi-Ethnic Study of Atherosclerosis who were free of clinical CVD. Computed tomography (CT) scans at the 4th and 5th lumbar disk space were used to estimate abdominal lean muscle area. Chest and abdominal CT scans were used to assess coronary artery calcification(CAC), thoracic aortic calcification (TAC), and abdominal aortic calcification (AAC).
The mean age was 64±10 years, 48% were female, and mean BMI was 28±5 kg/m2. In models adjusted for demographics, physical activity, caloric intake, and traditional CVD risk factors, there was no inverse association of abdominal muscle mass with CAC(Prevalence Ratio [PR] 1.02 [95% CI 0.95,1.10]), TAC (PR 1.13 [95%CI 0.92, 1.39]) or AAC (PR 0.99 [95%CI 0.94, 1.04]) prevalence. Similarly, there was no significant inverse relationship between abdominal lean muscle area and CAC, TAC, and AAC severity.
In community-living individuals without clinical CVD, greater abdominal lean muscle area is not associated with less calcified atherosclerosis.
PMCID: PMC3740763  PMID: 23916063
Cardiovascular Disease; atherosclerosis; lean muscle
25.  Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Obesity (Silver Spring, Md.)  2010;19(4):840-847.
Circulating adiponectin has been associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were Caucasian (n=712), African-American (n=712), Chinese (n=718), and Hispanic (n=705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African-Americans with genotypes AG/GG of rs2241767 had 36% greater (95% CI (16%, 59%), p=0.0001) CAC prevalence; they also had a larger common cIMT (p=0.0043). Also in African-Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), p=0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), p=0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or Caucasian participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African-American and Hispanics. Replication as well as assessment of other ADIPOQ SNPs appears warranted.
PMCID: PMC3510267  PMID: 20930713

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