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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.
Objectives
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).
Background
Cardiac valve calcification has been associated with left ventricular hypertrophy (LVH), which portends cardiovascular events. However, this relationship and its mediators are poorly understood.
Methods
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.
Results
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.
Conclusions
Within the MESA cohort, LVH was associated with prevalence, severity, and incidence of valve calcification independent of hypertension and other identified confounders.
doi:10.1016/j.jcmg.2011.12.025
PMCID: PMC3426868  PMID: 22897991
aortic valve; calcification; left ventricular mass; mitral valve annulus
2.  Relationships of Mitral Annular Calcification to Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;213(2):558-562.
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.atherosclerosis.2010.08.072
PMCID: PMC2997868  PMID: 20926076
Mitral annular calcification; MESA; Cardiac CT; risk factors
3.  Association of mitral annulus calcification, aortic valve calcification with carotid intima media thickness 
Background
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.
Aim
To examine the relationship between the degree of calcification at mitral and/or aortic valve annulus and large artery structure (thickness).
Methods
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.
Results
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).
Conclusion
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.
doi:10.1186/1476-7120-2-19
PMCID: PMC526215  PMID: 15471552
carotid artery disease; heart disease; atherosclerosis; imaging
4.  The association of incidentally detected heart valve calcification with future cardiovascular events 
European Radiology  2010;21(5):963-973.
Objectives
This study aims to investigate the prognostic value of incidental aortic valve calcification (AVC), mitral valve calcification (MVC) and mitral annular calcification (MAC) for cardiovascular events and non-rheumatic valve disease in particular on routine diagnostic chest CT.
Methods
The study followed a case-cohort design. 10410 patients undergoing chest CT were followed for a median period of 17 months. Patients referred for cardiovascular disease were excluded. A random sample of 1285 subjects and the subjects who experienced an endpoint were graded for valve calcification by three reviewers. Cox-proportional hazard analysis was performed to evaluate the prognostic value.
Results
515 cardiovascular events were ascertained. Compared with patients with no valve calcification, patients with severe AVC, MVC or MAC had respectively 2.03 (1.48–2.78), 2.08 (1.04–4.19) and 1.53 (1.13–2.08) increased risks of experiencing an event during follow-up. For valve endpoints the hazard ratios were respectively 14.57 (5.19–40.53), 8.78 (2.33–33.13) and 2.43 (1.18–4.98).
Conclusion
Incidental heart valve calcification, detected on routine chest CT is an independent predictor of future cardiovascular events. The study emphasises how incidental imaging findings can contribute to clinical care. It is a step in the process of composing an evidence-based approach in the reporting of incidental subclinical findings.
doi:10.1007/s00330-010-1995-0
PMCID: PMC3072500  PMID: 21058039
Survival analysis; Heart valves; Thorax; Cardiovascular diseases; Computed tomography
5.  Relationship of Metabolic Syndrome With Incident Aortic Valve Calcium and Aortic Valve Calcium Progression 
Diabetes  2009;58(4):813-819.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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).
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/db08-1515
PMCID: PMC2661576  PMID: 19136658
6.  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.
Background
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).
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.ahj.2009.07.027
PMCID: PMC2764241  PMID: 19781415
Aortic valve calcification; coronary artery disease; multi-detector computed tomography; calcified plaque; non-calcified plaque; mixed plaque
7.  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.
doi:10.1016/j.amjcard.2010.08.042
PMCID: PMC3032359  PMID: 21146685
Blood Pressure; Aortic Valve; Calcification
8.  Patients with echocardiographic aortic valve calcium or mitral annular calcium have an increased prevalence of moderate or severe coronary artery calcium diagnosed by cardiac computed tomography 
The association between aortic valve calcium (AVC) and mitral annular calcium (MAC), as diagnosed by two-dimensional echocardiography, was investigated in 138 patients (76 women and 62 men, mean age 64±8 years) seen in a private cardiology practice at the New York Medical College. Coronary artery calcium (CAC) scores were diagnosed by 64-multislice computed tomography. AVC was present in 25 of 57 patients (44%) with moderate or severe CAC (a CAC score of more than 100) and in 15 of 81 patients (19%) with no or mild CAC (a CAC score of 0 to 100), P<0.001. Moderate or severe AVC was present in nine of 57 patients (16%) with moderate or severe CAC, and in two of 81 patients (2%) with no or mild CAC, P<0.005. MAC was present in 18 of 57 patients (32%) with moderate or severe CAC, and in seven of 81 patients (9%) with no or mild CAC, P<0.001. Moderate or severe MAC was present in eight of 57 patients (14%) with moderate or severe CAC, and in two of 81 patients (2%) with no or mild CAC, P<0.001.
PMCID: PMC2733013  PMID: 22477269
Aortic valve calcium; Cardiac computed tomography; Coronary artery calcium; Coronary artery disease; Echocardiography; Mitral annular calcium
9.  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.
doi:10.1093/ndt/gfn544
PMCID: PMC2721419  PMID: 18840892
chronic kidney disease; cohort; creatinine; cystatin C; elderly
10.  Calcific aortic valve damage as a risk factor for cardiovascular events 
Polish Journal of Radiology  2012;77(4):30-34.
Summary
Aortic valve calcification (AVC) is a common disease of the elderly. It is a progressive disease ranging from mild valve thickening to severe calcification with aortic valve stenosis. Risk factors for AVC are similar to those for atherosclerosis: age, gender, hypercholesterolemia, diabetes, hypertension, smoking and renal failure. AVC shares many similarities to atherosclerosis, including inflammatory cells and calcium deposits, and correlates with coronary plaque burden. Presence of AVC is associated with increased risk of adverse cardiovascular events. The objective for this review is to discuss the clinical features, natural history and prognostic significance of aortic valve calcifications, including mechanical and hemodynamic factors of flow distribution.
PMCID: PMC3529709  PMID: 23269934
aortic valve calcification; multi-slice computed tomography; coronary calcium score; atherosclerosis
11.  Aortic Valve Calcium Independently Predicts Coronary and Cardiovascular Events in a Primary Prevention Population 
Jacc. Cardiovascular Imaging  2012;5(6):619-625.
Objective
This study aimed to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.jcmg.2011.12.023
PMCID: PMC3376353  PMID: 22698532
12.  The Relationship of Insulin Resistance and Extracoronary Calcification in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2011;218(2):507-510.
OBJECTIVE
We hypothesized that insulin resistance, measured by the homeostatic model assessment of insulin resistance (HOMA), is independently associated with prevalent and incident extra-coronary calcification (ECC).
METHODS
We studied calcium scores of the aortic valve (AVC), mitral valve (MVC), thoracic aorta (TAC) and aortic valve root (AVR) in 6,104 MESA participants not on diabetes medication who had baseline cardiac CT scans; 5,312 had follow-up scans (mean 2.4y). Relative-risk regression modeled prevalent and incident ECC adjusted for baseline demographics (model 1), and additionally for CVD risk factors (model 2).
RESULTS
In model 1, prevalence and incidence risk-ratios for the highest versus lowest quartile of HOMA were 20–30% higher in all ECC locations (p-value for trend ≤0.05 for all but incident-AVC). In model 2, all associations were attenuated, primarily by adjustment for metabolic syndrome components.
CONCLUSIONS
HOMA has a positive and graded association with ECC, but not independently of cardiovascular risk factors—particularly metabolic syndrome components.
doi:10.1016/j.atherosclerosis.2011.06.047
PMCID: PMC3185155  PMID: 21798541
cardiovascular calcification; insulin resistance; atherosclerosis; metabolic syndrome; computed tomography; valvular calcification; thoracic aortic calcification
13.  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.
doi:10.1016/j.amjcard.2009.10.071
PMCID: PMC2829478  PMID: 20185020
valves; calcium; risk factors; epidemiology; imaging
14.  Association of Serum Phosphate Levels with Aortic Valve Sclerosis and Annular Calcification: the Cardiovascular Health Study 
Objectives
To evaluate mineral metabolism markers as potential risk factors for calcific aortic valve disease.
Background
Mineral metabolism disturbances are common among older people and may contribute to cardiac valvular calcification. Associations of serum mineral metabolism markers with cardiac valvular calcification have not been evaluated in a well-characterized general population of older adults.
Methods
We measured serum levels of phosphate, calcium, parathyroid hormone, and 25-hydroxyvitamin D in 1,938 Cardiovascular Health Study participants who were free of clinical cardiovascular disease and who underwent echocardiography measurements of aortic valve sclerosis (AVS), mitral annular calcification (MAC), and aortic annular calcification (AAC). We used logistic regression models to estimate associations of mineral metabolism markers with AVS, MAC, and AAC after adjustment for relevant confounding variables, including kidney function.
Results
The respective prevalences of AVS, MAC, and AAC were 54%, 39%, and 44%. Each 0.5 mg/dl higher serum phosphate concentration was associated with a greater adjusted odds of AVS (odds ratio 1.17, 95% confidence interval 1.04 to 1.31, p = 0.01), MAC (odds ratio 1.12, 95% confidence interval 1.00 to 1.26, p =0.05), and AAC (odds ratio 1.12, 95% confidence interval 0.99 to 1.25, p = 0.05). In contrast, serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations were not associated with aortic or mitral calcification.
Conclusions
Higher serum phosphate levels within the normal range are associated with valvular and annular calcification in a community-based cohort of older adults. Phosphate may be a novel risk factor for calcific aortic valve disease and warrants further study.
doi:10.1016/j.jacc.2010.11.073
PMCID: PMC3147295  PMID: 21737022
Phosphate; Aortic Valve; Mitral Valve; Calcification; Epidemiology
15.  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.
doi:10.1038/oby.2010.229
PMCID: PMC3510267  PMID: 20930713
16.  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.
Aims
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.
Conclusions
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.
doi:10.1093/eurheartj/ehn439
PMCID: PMC2582985  PMID: 18845666
Epidemiology; Atherosclerosis; Coronary artery calcium; Risk factors; Screening
17.  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.
Background
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.
Conclusions
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.
doi:10.1371/journal.pone.0094916
PMCID: PMC3990562  PMID: 24743658
18.  Determinants of Coronary Artery and Aortic Calcification in the Old Order Amish 
Circulation  2007;115(6):717-724.
Background
Coronary artery calcification (CAC) is associated with an increased risk of cardiovascular disease; little is known, however, about thoracic aortic calcification (AC). Our goal was to characterize risk factors for CAC and AC and to estimate the genetic contribution to their variation.
Methods and Results
The presence and quantity of CAC and AC were measured with electron beam computed tomography and fasting blood tests and cardiovascular risk factors were obtained in 614 asymptomatic Amish subjects. CAC prevalence was higher in men than women (55% versus 41%; P<0.0001), although there was no sex difference in AC prevalence (51% and 56% in men and women, respectively; P=0.95). Age was more strongly associated with AC presence (odds ratio [OR], 2.7 for 5 years) than CAC presence (OR, 1.9 for 5 years) (homogeneity P=0.001). Subjects with AC had a 3.3-fold higher odds of having CAC. Heritabilities of CAC and AC presence were 0.27±0.17 (P=0.04) and 0.55±0.18 (P=0.0008), respectively, whereas the heritabilities of quantity of CAC and AC were 0.30±0.10 (P=0.001) and 0.40±0.10 (P<0.0001), respectively. The genetic correlation between CAC and AC quantity was 0.34±0.19, whereas the environmental correlation between these 2 traits was 0.38±0.09.
Conclusions
CAC and AC have similar risk factors, except male gender is associated only with CAC and age is more strongly associated with AC. The patterns of correlations suggest that CAC and AC share some common sets of genes and environmental factors, although it is likely that separate genes and environmental factors also influence calcification at each site.
doi:10.1161/CIRCULATIONAHA.106.637512
PMCID: PMC4039563  PMID: 17261661
aging; aorta; atherosclerosis; coronary disease; epidemiology; genetics; imaging
19.  Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study 
BMC Nephrology  2013;14:219.
Background
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.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1186/1471-2369-14-219
PMCID: PMC3851854  PMID: 24112318
Aortic valve disease; Cardiovascular disease; Coronary calcification; Hemodialysis; Mineral metabolism; Vascular calcification; Renal osteodystrophy; Sclerostin
20.  Relationship between Common Carotid Intima-Media Thickness and Thoracic Aortic Calcification: the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;209(1):142-146.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.atherosclerosis.2009.09.013
PMCID: PMC2830343  PMID: 19782983
Atherosclerosis; carotid IMT; aortic calcification; ethnic; cardiac CT
21.  Fine Particulate Matter Air Pollution, Proximity to Traffic, and Aortic Atherosclerosis 
Epidemiology (Cambridge, Mass.)  2009;20(2):254-264.
Background
The initiation and acceleration of atherosclerosis is hypothesized as a physiologic mechanism underlying associations between air pollution and cardiovascular effects. Despite toxicologic evidence, epidemiologic data are limited.
Methods
In this cross-sectional analysis we investigated exposure to fine particulate matter (PM2.5) and residential proximity to major roads in relation to abdominal aortic calcification a sensitive indicator of systemic atherosclerosis. Aortic calcification was measured by computed tomography among 1147 persons, in 5 U.S. metropolitan areas, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). The presence and quantity of aortic calcification were modeled using relative risk regression and linear regression, respectively, with adjustment for potential confounders.
Results
We observed a slightly elevated risk of aortic calcification (RR = 1.06; 95% confidence interval = 0.96–1.16) with a 10-μg/m3 contrast in PM2.5. The PM2.5-associated risk of aortic calcification was stronger among participants with long-term residence near a PM2.5 monitor (RR = 1.11; 1.00–1.24) and among participants not recently employed outside the home (RR = 1.10; 1.00–1.22). PM2.5 was not associated with an increase in the quantity of aortic calcification (Agatston score) and no roadway proximity effects were noted. There was indication of PM2.5 effect modification by lipid-lowering medication use, with greater effects among users, and PM2.5 associations were observed most consistently among Hispanics.
Conclusions
Although we did not find persuasive associations across our full study population, associations were stronger among participants with less exposure misclassification. These findings support the hypothesis of a relationship between particulate air pollution and systemic atherosclerosis.
doi:10.1097/EDE.0b013e31819644cc
PMCID: PMC3292428  PMID: 19129730
22.  Associations of Long-term and Early Adult Atherosclerosis Risk Factors with Aortic and Mitral Valve Calcium 
Objective
To determine the association of long-term exposure to atherosclerosis risk factors with valvular calcification.
Background
Traditional atherosclerosis risk factors have been associated with aortic and mitral valve calcium in cross-sectional studies but long-term prospective data is lacking.
Methods
Prospective community-based cohort study with 27-year follow-up (median follow-up 26.9 years; range 23.1–29.6 years). Participants from the Framingham Offspring Study (n=1323, enrolled between 1971–1975, mean age at enrollment 34±9 years, 52% women) underwent cardiac multi-detector computed tomography testing between 2002–2005. Associations between the long-term average of each cardiovascular risk factor and valve calcium were estimated using logistic regression.
Results
Aortic valve calcium was present in 39% of participants and mitral valve calcium in 20%. In multivariable models, the odds ratio for aortic valve calcium associated with every standard deviation (SD) increment in long-term mean total cholesterol was 1.74 (P<0.0001), with every SD increment in high-density lipoprotein cholesterol, 0.77 (P=0.002), and with every 9 cigarettes smoked per day, 1.23 (P=0.002). Associations of similar magnitude were seen for mitral valve calcium. The mean of three serum C-reactive protein measurements was associated with mitral valve calcium (OR 1.29 per-SD increment in CRP levels, P=0.002). A higher Framingham risk score in early adulthood (≤40 years age) was associated with increased prevalence and severity of aortic valve calcium measured three decades later.
Conclusions
Exposure to multiple atherosclerotic risk factors starting in early to mid-adulthood is associated with aortic and mitral valve calcium. Studies evaluating early risk factor modification to reduce the burden of valve disease are warranted.
doi:10.1016/j.jacc.2010.03.019
PMCID: PMC3042249  PMID: 20510217
calcification; aortic valve; mitral valve; atherosclerosis; stenosis
23.  Cardiovascular Risk Factors and Mitral Annular Calcification in Type 2 Diabetes 
Atherosclerosis  2012;226(2):419-424.
Objective
Mitral annular calcification (MAC) is a degenerative process of the mitral fibrous annulus associated with cardiac disease and stroke. Although thought to be more prevalent in type 2 diabetes (T2DM), MAC remains poorly characterized in this population, due to confounding by renal and cardiac disease. Our goal was to study the risk factors for MAC in asample of T2DM subjects without renal and cardiac disease.
Methods
The Penn Diabetes Heart Study (PDHS) is a cross-sectional study of diabetic individuals without clinical cardiovascular or renal disease. We quantified and analyzed MAC Agatston scores in baseline cardiac CTs from 1753 individuals. Logistic and tobit regression were used to assess MAC’s relationship with risk factors and coronary artery calcification (CAC).
Results
MAC was present in 12.0% of -subjects, with a median Agatston score of 72.3 [Interquartile range (22.2 256.9)]. Older age, diabetes female gender, Caucasian race, and longer duration were independently associated with both the presence and extent MAC even after controlling for the CAC; hypertension, hyperlipidemia, comorbidities however, tobacco use, CRP levels, and other were not associated. CAC was strongly associated with MAC [OR of 4.0, (95% CI 2.4-6.6)] in multivariable models.
Conclusions
Age, AC female gender, Caucasian race, and diabetes duration were associated with the presence and extent of MAC in T2DM subjects, independent of CAC, which was also strongly associated with MAC. These data suggest that additional mechanisms for MAC formation in diabetics may exist which are distinct from those related to generalized atherosclerosis and deserve further investigation.
doi:10.1016/j.atherosclerosis.2012.11.011
PMCID: PMC3568504  PMID: 23273961
Diabetes; Mitral Annular Calcification; Coronary Heart Disease; Risk Factors
24.  The Association of Uncarboxylated Matrix Gla Protein with Mitral Annular Calcification Differs by Diabetes Status: The Heart and Soul Study 
Atherosclerosis  2009;210(1):320-325.
Objective
Mitral annular calcification (MAC) and aortic stenosis (AS) are associated with systemic calcification and cardiovascular disease (CVD) events. Matrix Gla protein (MGP) is an inhibitor of vascular calcification and lower levels of its precursor – uncarboxylated MGP (ucMGP) – are associated with vascular calcification in pilot studies.
Methods and Results
In this cross-sectional study of 839 outpatients with stable CVD, we measured serum ucMGP, and evaluated MAC and AS by echocardiography. The association of ucMGP with MAC differed by diabetes status (interaction P<0.001). Among participants without diabetes (n=615), higher ucMGP (per standard deviation [1,178 nM] increase) was associated with lower odds of MAC (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.55-0.97) in models adjusted for traditional CVD risk factors, C-reactive protein, and kidney function. Among persons with diabetes (n=221), higher ucMGP was associated with higher odds of MAC (OR 1.89; 95% CI 1.29-2.78). Results were qualitatively similar for the association of ucMGP with AS although not statistically significant.
Conclusions
Among outpatients with stable CVD, higher ucMGP is associated with lower odds of MAC in persons without diabetes, and higher odds of MAC in persons with diabetes. Future studies should determine whether ucMGP levels are associated with CVD events, and whether such associations differ by diabetes status.
doi:10.1016/j.atherosclerosis.2009.11.023
PMCID: PMC2862076  PMID: 20015492
aortic stenosis; calcification; diabetes mellitus; matrix Gla protein; mitral annular calcification
25.  Abdominal Aortic Calcium and Multi-Site Atherosclerosis: The Multiethnic Study of Atherosclerosis 
Atherosclerosis  2011;214(2):436-441.
Background
Abdominal aortic calcification (AAC) is a measure of subclinical cardiovascular disease (CVD). Data are limited regarding its relation to other measures of atherosclerosis.
Methods
Among 1,812 subjects (49% female, 21% black, 14% Chinese, and 25% Hispanic) within the population-based Multiethnic Study of Atherosclerosis, we examined the cross-sectional relation of AAC with coronary artery calcium (CAC), ankle brachial index (ABI), and carotid intimal medial thickness (CIMT), as well as multiple measures of subclinical CVD.
Results
AAC prevalence ranged from 34% in those aged 45–54 to 94% in those aged 75–84 (p<0.0001), was highest in Caucasians (79%) and lowest in blacks (62%) (p<0.0001). CAC prevalence, mean maximum CIMT ≥ 1 mm, and ABI<0.9 was greater in those with vs. without AAC: CAC 60% vs 16%, CIMT 38% vs 7%, and ABI 5% vs 1% for women and CAC 80% vs 37%, CIMT 43% vs 16%, and ABI 4% vs 2% for men (p<0.01 for all except p<0.05 for ABI in men). The presence of multi-site atherosclerosis (≥ 3 of the above) ranged from 20% in women and 30% in men (p<0.001), was highest in Caucasians (28%) and lowest in Chinese (16%) and ranged from 5% in those aged 45–54 to 53% in those aged 75–84 (p<0.01 to p<0.001). Finally, increased AAC was associated with 2 to 3-fold relative risks for the presence of increased CIMT, low ABI, or CAC.
Conclusions
AAC is associated with an increased likelihood of other vascular atherosclerosis. Its additive prognostic value to these other measures is of further interest.
doi:10.1016/j.atherosclerosis.2010.09.011
PMCID: PMC3040451  PMID: 21035803
atherosclerosis; calcification; cardiovascular disease; epidemiology

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