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1.  Relationship between Baseline Coronary Calcium Score and Demonstration of Coronary Artery Stenoses During Follow up in the Multi-Ethnic Study of Atherosclerosis (MESA) 
JACC. Cardiovascular imaging  2009;2(10):1175-1183.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of 6,814 men and women. We sought to analyze the relationship between the extent of coronary calcium (CC) at baseline and the severity of coronary stenoses in clinically indicated coronary angiography studies during follow-up.
CC is an established predictor of major cardiovascular events. Yet, the relationship between CC and the distribution and severity of coronary artery stenoses has not been widely explored.
All MESA participants underwent non-contrast enhanced cardiac CT during enrollment to determine baseline CC. We analyzed 175 consecutive angiography reports from participants who underwent coronary catheterization for clinical indications during a median follow-up period of 18 months. The association between baseline CC and the severity of coronary stenosis detected in coronary angiographies was determined.
Baseline Agatston score was zero in only 7/175 (4%) MESA participants who underwent invasive angiography during follow-up. When coronary arteries were studied separately, 13–18% of coronary arteries with ≥75% stenosis had zero calcium mass scores at baseline. There was close association between baseline calcium mass score and the severity of stenosis in each of the coronary arteries (test for trend, p<0.001). As an example, mean calcium mass scores for <50, 50–74 and ≥75% stenosis in the left anterior descending coronary artery were 105.1 mg, 157.2 mg and 302.2 mg, respectively (p<0.001). Finally, there was a direct relationship between the total Agatston Score at baseline and the number of diseased vessels (test for trend, p<0.001)
The majority of patients with clinically indicated coronary angiography during follow up had detectable coronary calcification at baseline. While there is a significant relationship between the extent of calcification and mean degree of stenosis in individual coronary vessels, 16% of the coronary arteries with significant stenoses had no calcification at baseline.
PMCID: PMC2803053  PMID: 19833306
2.  Utility of the Framingham risk score to predict the presence of coronary atherosclerosis in patients with rheumatoid arthritis 
The prevalence of ischemic heart disease and atherosclerosis is increased in patients with rheumatoid arthritis (RA). In the general population, but not in patients with systemic lupus erythematosus, the Framingham risk score identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. We examined the hypothesis that the Framingham score is increased and associated with coronary-artery atherosclerosis in patients with RA. The Framingham score and the 10-year cardiovascular risk were compared among 155 patients with RA (89 with early disease, 66 with long-standing disease) and 85 control subjects. The presence of coronary-artery calcification was determined by electron-beam computed tomography. The Framingham score was compared in patients with RA and control subjects, and the association between the risk score and coronary-artery calcification was examined in patients. Patients with long-standing RA had a higher Framingham score (14 [11 to 18]) (median [interquartile range]) compared to patients with early RA (11 [8 to 14]) or control subjects (12 [7 to 14], P < 0.001). This remained significant after adjustment for age and gender (P = 0.015). Seventy-six patients with RA had coronary calcification; their Framingham risk score was higher (14 [12 to 17]) than that of 79 patients without calcification (10 [5 to 14]) (P < 0.001). Furthermore, a higher Framingham score was associated with a higher calcium score (odds ratio [OR] = 1.20, 95% confidence interval [CI] 1.12 to 1.29, P < 0.001), and the association remained significant after adjustment for age and gender (OR = 1.15, 95% CI 1.02 to 1.29, P = 0.03). In conclusion, a higher Framingham risk score is independently associated with the presence of coronary calcification in patients with RA.
PMCID: PMC1794532  PMID: 17169159
3.  Left Ventricular Structure and Function by Cardiac Magnetic Resonance Imaging in Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(4):940-951.
Heart failure is a major contributor to cardiovascular morbidity and mortality in rheumatoid arthritis. However, little is known about myocardial structure and function in this population.
Using cardiac magnetic resonance imaging, measures of myocardial structure and function were assessed in men and women with rheumatoid arthritis enrolled in ESCAPE RA, a cohort study of subclinical cardiovascular disease in rheumatoid arthritis, and compared with controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis.
Myocardial measures were compared between 75 rheumatoid arthritis patients and 225 matched controls. After adjustment, mean left-ventricular mass was 26 grams lower for the RA group compared to controls (p<0.001), an 18% difference. After similar adjustment, mean left-ventricular ejection fraction, cardiac output, and stroke volume were modestly lower in the rheumatoid arthritis group vs. controls. Mean left-ventricular end-systolic and end-diastolic volumes did not differ by rheumatoid arthritis status. Within the rheumatoid arthritis group, higher levels of anti-CCP antibodies and current use of biologics, but not other disease activity or severity measures, were associated with significantly lower adjusted mean left-ventricular mass, end-diastolic volume, and stroke volume, but not ejection fraction. The combined associations of anti-CCP antibody level and biologic use on myocardial measures were additive, without evidence of interaction.
These findings suggest that the progression to heart failure in RA may occur through reduced myocardial mass rather than hypertrophy. Both modifiable and non-modifiable factors may contribute to lower levels of left-ventricular mass and volume.
PMCID: PMC3008503  PMID: 20131277
myocardial dysfunction; heart failure; inflammation; cardiac imaging
4.  Incidence and progression of coronary calcification in chronic kidney disease: the Multi-Ethnic Study of Atherosclerosis 
Kidney international  2009;76(9):991-998.
We studied the incidence and progression of coronary artery calcification in people with early chronic kidney disease. We used a cohort of 562 adult patients with chronic kidney disease who had an estimated glomerular filtration rate of <60 ml/min/1.73 m2, in a community-based study of people without clinical cardiovascular disease, the Multi-Ethnic Study of Atherosclerosis. The majority had stage 3 disease. Coronary artery calcification was measured at baseline and again approximately 1.6 or 3.2 years later. The prevalence of coronary artery calcification at baseline was 66%, and its adjusted prevalence was 24% lower in African Americans as compared to Caucasians. The incidence of coronary artery calcification was 6.1% per year in women and 14.8% in men. Coronary artery calcification progressed in approximately 17% of subjects per year across all subgroups, and diabetes was associated with a 65% greater adjusted risk of progression. Male gender and diabetes were the only factors associated with adjusted coronary artery calcification incidence and progression, respectively. Our study shows that coronary artery calcification is common in people with stage 3 disease, progresses rapidly, and may contribute to cardiovascular risk.
PMCID: PMC3039603  PMID: 19692998
chronic kidney disease; coronary calcification; vascular calcification
5.  Metabolic syndrome is common among middle‐to‐older aged Mediterranean patients with rheumatoid arthritis and correlates with disease activity: a retrospective, cross‐sectional, controlled, study 
Patients with rheumatoid arthritis have an increased risk for cardiovascular disease (CVD). The prevalence of metabolic syndrome (MetS)—a major contributor to CVD—in a cohort of patients with rheumatoid arthritis and its relationship with rheumatoid arthritis related factors is investigated here.
200 outpatients with rheumatoid arthritis (147 women and 53 men), with a mean (standard deviation (SD)) age of 63 (11) years, and 400 age and sex‐matched controls were studied. MetS was assessed according to the adult treatment panel III criteria and rheumatoid arthritis disease activity by the disease activity score of 28 joints (DAS28). A standard clinical evaluation was carried out, and a health and lifestyle questionnaire was completed.
The overall prevalence of MetS was 44% in patients with rheumatoid arthritis and 41% in controls (p = 0.5). Patients with rheumatoid arthritis were more likely to have low high‐density lipoprotein cholesterol compared with controls (p = 0.02), whereas controls were more likely to have increased waist circumference or raised blood pressure (p = 0.001 and 0.003, respectively). In multivariate logistic regression analysis adjusting for demographics and rheumatoid arthritis treatment modalities, the risk of having moderate‐to‐high disease activity (DAS28>3.2) was significantly higher in patients with MetS compared with those with no MetS components (OR 9.24, 95% CI 1.49 to 57.2, p = 0.016).
A high, albeit comparable to the control population, prevalence of MetS was found in middle‐to‐older aged patients with rheumatoid arthritis. The correlation of rheumatoid arthritis disease activity with MetS suggests that the increased prevalence of coronary heart disease in patients with rheumatoid arthritis may, at least in part, be attributed to the inflammatory burden of the disease.
PMCID: PMC1798406  PMID: 16793841
6.  Total calcium-sensing receptor expression in circulating monocytes is increased in rheumatoid arthritis patients with severe coronary artery calcification 
Human circulating monocytes express the calcium-sensing receptor (CaSR) and are involved in atherosclerosis. This study investigated the potential association between vascular calcification in rheumatoid arthritis (RA) and CaSR expression in circulating monocytes.
In this cross-sectional study, 50 RA patients were compared to 25 control subjects matched for age and gender. Isolation of peripheral blood mononuclear cells and flow cytometry analysis were performed to study the surface and total CaSR expression in circulating monocytes. Coronary artery calcium (CAC) and abdominal aortic calcification (AAC) scores were evaluated by computed tomography and an association between these scores and the surface and/or total CaSR expression in circulating monocytes in RA patients was investigated.
The two groups were similar in terms of age (RA: 60.9 ± 8.3 years, versus controls: 59.6 ± 5.3 years) and gender (RA: 74.0% females versus 72.0% females). We did not find a higher prevalence and greater burden of CAC or AAC in RA patients versus age- and gender-matched controls. When compared with control subjects, RA patients did not exhibit greater total CaSR (101.6% ± 28.8 vs. 99.9% ± 22.0) or surface CaSR (104.6% ± 20.4 vs. 99.9% ± 13.7) expression, but total CaSR expression in circulating monocytes was significantly higher in RA patients with severe CAC (Agatston score ≥200, n = 11) than in patients with mild-to-moderate CAC (1 to 199, n = 21) (P = 0.01).
This study demonstrates for the first time that total CaSR expression in human circulating monocytes is increased in RA patients with severe coronary artery calcification.
PMCID: PMC4149257  PMID: 25134967
7.  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
8.  Pericardial adipose tissue and coronary artery calcification in The Multi-Ethnic Study of Atherosclerosis (MESA) 
Obesity (Silver Spring, Md.)  2013;21(5):1056-1063.
We examined the relationship of pericardial adipose tissue (PAT) with coronary artery calcification in MESA, a large cohort in which associations by race/ethnicity can be compared. The baseline cohort comprised 6,814 Caucasian (38%), African American (28%), Chinese American (12%) and Hispanic (22%) adults aged 45–84, without known clinical cardiovascular disease. Cardiac CT was used to measure PAT (cm3) and calcification (Agatston score). We examined cross-sectional associations of PAT with the presence (score>0) and severity (continuous score if >0) of calcification using prevalence ratio (PR) (n=6,672) and linear regression (n=3,362), respectively. Main models were adjusted for age, age2, gender, race/ethnicity, field site, smoking, physical activity, alcohol and education. PAT volume (adjusted for age, height, weight and site) was greatest in Chinese males, while Black males had less PAT than all but Black females. PAT was associated with presence [PR per standard deviation (SD): 1.06 (95% CI: 1.04, 1.08)] and severity [difference in log Agatston score per SD: 0.15 (0.09, 0.21)] of calcification, but neither association varied by race/ethnicity. Adjustment for generalized adiposity attenuated but did not eliminate the associations. With further adjustment for traditional risk factors and inflammatory markers, only the association with severity remained statistically significant [PR: 1.02 (1.00, 1.04), difference: 0.10 (0.03, 0.17)]. Heterogeneity by sex was observed for presence of calcification (PR in men: 1.04; in women: 1.08; p for interaction<0.0001). Pericardial adipose tissue was associated with the presence and severity of coronary artery calcification in this cohort, but despite differences in PAT volumes and calcification across race/ethnic groups, neither association varied by race/ethnicity.
PMCID: PMC4042681  PMID: 23784910
Coronary artery calcification; pericardial fat; subclinical atherosclerosis risk factors; obesity; epidemiology
9.  Comparison of Subclinical Coronary Atherosclerosis and Risk Factors in Unselected Populations in Germany and US-America 
Atherosclerosis  2007;195(1):e207-e216.
On the basis of the Framingham risk algorithm, overestimation of clinical events has been reported in some European populations. Electron-beam computed tomography-derived quantification of coronary artery calcification (CAC) allows for noninvasive assessment of coronary atherosclerosis in the general population and may thus add important in vivo information on the path from risk factor exposure to formation of clinical events. The current study was undertaken to compare the relationship between risk factors and subclinical coronary atherosclerosis between non-Hispanic white cohorts in Germany and US-America, the hypothesis being that subclinical coronary atherosclerosis might be less prevalent in Europe at the same level of classical risk factor exposure.
The Heinz Nixdorf Recall (HNR) study, conducted in the German Ruhr area and the Epidemiology of Coronary Calcification (ECAC) study, conducted in Olmsted County, Minnesota, both recruited large unselected cohorts, men and women aged 45 – 74 years, from the general population. All subjects with no history of coronary artery disease (CAD) or stroke were included (n = 3,120 in HNR, n = 703 in ECAC). Coronary risk factors were assessed by personal and computer-assisted interviews and direct laboratory measurements. Cardiovascular medication use (antihypertensive, lipid-lowering, and anti-diabetic) was noted. CAC scores were determined using the Agatston method in an identical fashion in both studies.
Adverse levels of risk factors were more prevalent, and the Framingham risk score was higher (10.6 ± 7.6 vs. 9.3 ± 7.1, p < 0.001) in HNR than ECAC, respectively. There was no difference in body mass index (BMI). CAC scores were greater in HNR than in ECAC (mean values, 155.7 ± 423.0 versus 107.2 ± 280.0; median values, 11.9 versus 2.4; p < 0.001, respectively). When subjects were matched on CAD risk factors, presence and quantity of CAC were similar in the 2 cohorts. Risk factors significantly associated with CAC score in both studies included: age, male sex, current and former smoking, systolic blood pressure, and non HDL-cholesterol. Inferences were similar after excluding subjects using lipid- or blood pressure-lowering medications. Using the same risk factor variables for modelling, the predicted CAC scores were comparable in both cohorts.
In the higher-risk German cohort, presence and quantity of CAC were greater than in the lower-risk US-American cohort. Risk factor associations, however, with CAC were very similar in both unselected populations. As opposed to studies concerning clinical endpoints, we could not demonstrate a relative increase in subclinical coronary atherosclerosis in the US-American cohort.
PMCID: PMC2293130  PMID: 17532322
10.  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
11.  Serum Osteoprotegerin is Increased and Independently Associated with Coronary-Artery Atherosclerosis in Patients with Rheumatoid Arthritis 
Atherosclerosis  2007;195(2):e135-e141.
Osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor B ligand, is implicated in the pathogenesis of atherosclerosis. Patients with rheumatoid arthritis (RA) have inflammation and increased atherosclerosis. We examined the hypothesis that OPG concentrations are increased in patients with RA and are associated with coronary-artery atherosclerosis. Serum OPG concentrations were measured by ELISA and coronary-artery calcification by electron beam computer tomography in 157 patients with RA and 87 control subjects. OPG concentrations were higher in patients with long-standing RA (n=67) [median (interquartile range)]: [1895 (1337–2847) pg/mL, and early RA (n=90): [1340 (1021–1652) pg/mL, than controls 1068 (692–1434) pg/ml; (P<0.001)]. In patients with RA, OPG concentrations were associated with erythrocyte sedimentation rate (p<0.001), homocysteine (p=0.001), disease duration (p=0.02), coronary calcium score (p=0.03), and cumulative dose of corticosteroids (p=0.04) after adjustment for age and sex. In patients with long-standing RA, OPG was associated with coronary artery calcification independently of cardiovascular risk factors and disease activity [OR for every increase in 500 pg/mL of OPG = 2.22 (1.43–3.34), p<0.001]. In conclusion, OPG concentrations are increased in patients with RA and are associated with inflammation. In patients with long-standing disease, OPG is independently associated with coronary-artery calcification.
PMCID: PMC2174431  PMID: 17570371
rheumatoid arthritis; osteoprotegerin; atherosclerosis; coronary calcification; cardiovascular disease
12.  Predictive value of coronary calcifications for future cardiac events in asymptomatic patients with diabetes mellitus: A prospective study in 716 patients over 8 years 
To establish an efficient prophylaxis of coronary artery disease reliable risk stratification is crucial, especially in the high risk population of patients suffering from diabetes mellitus. This prospective study determined the predictive value of coronary calcifications for future cardiovascular events in asymptomatic patients with diabetes mellitus.
We included 716 patients suffering from diabetes mellitus (430 men, 286 women, age 55.2 ± 15.2 years) in this study. On study entry all patients were asymptomatic and had no history of coronary artery disease. In addition, all patients showed no signs of coronary artery disease in ECG, stress ECG or echocardiography. Coronary calcifications were determined with the Imatron C 150 XP electron beam computed tomograph. For quantification of coronary calcifications we calculated the Agatston score. After a mean observation period of 8.1 ± 1.1 years patients were contacted and the event rate of cardiac death (CD) and myocardial infarction (MI) was determined.
During the observation period 40 patients suffered from MI, 36 patients died from acute CD. The initial Agatston score in patients that suffered from MI or died from CD (475 ± 208) was significantly higher compared to those without cardiac events (236 ± 199, p < 0.01). An Agatston score above 400 was associated with a significantly higher annualised event rate for cardiovascular events (5.6% versus 0.7%, p < 0.01). No cardiac events were observed in patients with exclusion of coronary calcifications. Compared to the Framingham risk score and the UKPDS score the Agatston score showed a significantly higher diagnostic accuracy in the prediction of MI with an area under the ROC curve of 0.77 versus 0.68, and 0.71, respectively, p < 0.01.
By determination of coronary calcifications patients at risk for future MI and CD could be identified within an asymptomatic high risk group of patients suffering from diabetes mellitus. On the other hand future events could be excluded in patients without coronary calcifications.
PMCID: PMC2569906  PMID: 18847481
13.  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
14.  Adipocytokines, Insulin Resistance and Coronary Atherosclerosis in Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(5):1259-1264.
Subclinical coronary atherosclerosis is increased in patients with rheumatoid arthritis (RA) and is associated with insulin resistance. Adipocytokines are associated with obesity, insulin resistance, inflammation and coronary heart disease in the general population. We examined the hypothesis that adipocytokines affect insulin resistance and coronary atherosclerosis among patients with RA.
Coronary calcium, insulin resistance (HOMA) and serum adipocytokine concentrations (leptin, adiponectin, resistin and visfatin) were measured in 169 patients with RA. The independent effect of each adipocytokine on HOMA and coronary artery calcification determined by electron beam CT was assessed adjusting for age, race, sex, BMI, traditional cardiovascular risk factors and inflammatory mediators. We also examined whether the effect of HOMA on coronary calcium is moderated by adipocytokines throughan interaction analysis.
Leptin was associated with higher HOMA, even after adjusting for age, race, sex, BMI, traditional cardiovascular risk factors and inflammatory mediators (p<0.001), but visfatin (p=0.06), adiponectin (p=0.55) and resistin (p=0.98) were not. None of the adipocytokines were independently associated with coronary calcium (all p>0.05). Serum leptin concentrations interacted with HOMA (multivariate p interaction=0.02). Increasing leptin concentrations attenuated the increased risk of coronary calcification related to HOMA. The other adipocytokines and HOMA did not interact significantly (p>0.05).
Leptin is associated with insulin resistance in patients with RA but paradoxically attenuated the effects of insulin resistance on coronary calcification.
PMCID: PMC2910412  PMID: 20213808
Rheumatoid Arthritis; Adipocytokines; Atherosclerosis; Insulin Resistance; Leptin; Adiponectin; Resistin; Visfatin
15.  Inflammatory Mediators and Premature Coronary Atherosclerosis in Rheumatoid Arthritis 
Arthritis and rheumatism  2009;61(11):1580-1585.
Rheumatoid arthritis (RA) is an inflammatory disease associated with premature atherosclerosis. We examined the hypothesis that mediators of inflammation associated with atherosclerosis in other populations IL-6, TNF-α, SAA, VEGF, neutrophil count, IL-1α, E-selectin, ICAM-1, MPO, MMP-9, and VCAM-1 were increased and associated with the severity of coronary atherosclerosis in patients with RA.
Clinical variables, concentrations of inflammatory mediators and coronary artery calcification were measured in 169 patients with RA and 92 control subjects. Differences in concentrations of inflammatory mediators were compared using median quantile regression. The relationship of inflammatory mediators with the severity of coronary calcification in RA and control subjects was examined using proportional odds logistic regression allowing for interaction with disease status. Models were adjusted for traditional cardiovascular risk factors.
Median serum concentrations of IL-6, SAA, ICAM-1, E-selectin, TNF-α, and MPO and peripheral blood neutrophil count were higher in patients with RA than controls (all p<0.05) independent of Framingham risk score and diabetes. IL-6 (main effect OR 1.72, 95%CI 1.12–2.66) and TNF-α concentrations (main effect OR 1.49, 95%CI 1.16–1.90) were significantly associated with higher amounts of coronary calcium independent of Framingham risk score and diabetes, and such main effects significantly differed from controls (p-value for interaction=0.001 and 0.03, respectively).
TNF-α and IL-6 are significantly associated with the severity of subclinical atherosclerosis independent of Framingham risk score in RA.
PMCID: PMC2828265  PMID: 19877084
Rheumatoid arthritis; Atherosclerosis; Cytokine; Inflammation; TNF-α; IL-6; Coronary Calcium
16.  Blood Pressure Trajectories in Early Adulthood and Subclinical Atherosclerosis in Middle Age 
Single measures of blood pressure (BP) levels are associated with the development of atherosclerosis; however, long-term patterns in BP and their impact on CVD risk are poorly characterized.
To identify common BP trajectories throughout early adulthood and to determine their association with presence of coronary artery calcification (CAC) during middle age.
We used data from the CARDIA study from baseline in 1985-1986 through 25 years of follow-up (2010-2011).
Prospective cohort study
CARDIA participants were Black and White men and women aged 18-30 years at baseline.
We examined systolic BP, diastolic BP, and mid-BP [calculated as (SBP+DBP)/2 and an important marker of CHD risk among younger populations] at baseline and years 2, 5, 7, 10, 15, 20, and 25. Latent mixture modeling was used to identify trajectories in SBP, DBP and mid-BP over time.
Main Outcome Measure
Coronary artery calcification greater than or equal to Agatston score of 100 Agatston units at year 25.
Among 4,681 participants, we identified 5 distinct mid-BP trajectories: Low-Stable (22% [95% CI 19.9-23.7], n=987), Moderate-Stable (42% [40.3-44.3], n=2,085), Moderate-Increasing (12% [10.4-14.0], n=489), Elevated-Stable (19% [17.1-20.0], n=903) and Elevated-Increasing (5% [4.0-5.5], n=217). As compared to the Low-Stable group, trajectories with elevated BP levels had greater odds of having CAC >100. Adjusted odds ratios (95% CI) were 1.44 (0.83-2.49) for Moderate-Stable, 1.86 (0.91-3.82) for Moderate-Increasing, 2.28 (1.24-3.70) for Elevated-Stable, and 3.70 (1.66-8.20) for Elevated-Increasing groups. The adjusted prevalence of CAC ≥ 100 was 5.8% in the Low-Stable group. These ORs represent an absolute increase of 2.7%, 5%, 6.3% and 12.9% for the prevalence of CAC ≥100 for the Moderate-Stable, Moderate-Increasing, Elevated Stable and Elevated Increasing groups respectively as compared to the Low-Stable Group. Associations were not altered after adjustment for baseline and year 25 BP. Findings were similar for trajectories of isolated systolic BP trajectories, but were attenuated for diastolic BP trajectories.
Conclusions and Relevance
BP trajectories throughout young adulthood vary and higher BP trajectories were associated with an increased risk of CAC in middle age. Long-term trajectories in BP may assist in more accurate identification of individuals with subclinical atherosclerosis.
PMCID: PMC4122296  PMID: 24496536
blood pressure; calcium; epidemiology; risk factors
17.  Reduced endothelial progenitor cells in European and South Asian men with atherosclerosis 
Circulating endothelial progenitor cells (EPCs) play a role in the repair and regeneration of the endothelium and may represent a novel cardiovascular risk factor. South Asian subjects have an increased risk of cardiovascular disease which is not fully explained by known risk factors. This study examined associations of EPCs with atherosclerosis and possible ethnic differences in EPCs.
Materials and methods
A population sample of 58 European and South Asian adult men was enriched with the recruitment of an additional 59 European and South Asian men with known coronary disease. The coronary artery calcification score was measured by multi-slice computerized tomography (CT), carotid and femoral intima-media thickness (IMT), and femoral plaques were measured by ultrasound. The subjects were further subdivided into three categories of coronary artery disease on the basis of coronary artery calcification score and clinical history. Total EPCs and non-senescent EPCs (ns-EPCs) were quantified after 5 days cell culture and the number of late outgrowth colonies was measured over a 6-week test period. Circulating CD34+ haematopoietic precursor cells were measured by flow cytometry.
Individuals with femoral plaques had reduced total and ns-EPCs. The number of ns-EPCs were reduced in individuals with the most coronary atheroma and were inversely related to the coronary calcification score and femoral IMT. These relationships persisted after multivariate adjustment for other risk factors. The numbers of late outgrowth colonies or circulating CD34+ cells were unrelated to the presence of atherosclerosis. There were no differences in the number of EPCs between European and South Asian subjects.
The number of EPCs are reduced in subjects with atherosclerosis independent of other risk factors. Reduction in EPC numbers may be an independent risk factor for atherosclerosis but does not explain ethnic differences in cardiovascular risk.
PMCID: PMC1869046  PMID: 17181565
Atherosclerosis; coronary calcification; endothelial progenitor cells; ethnicity; intima-media thickness
18.  Bisphosphonate use and the Prevalence of Valvular and Vascular Calcification in Women: The Multi-Ethnic Study of Atherosclerosis 
To determine whether nitrogen-containing bisphosphonate (NCBP) therapy is associated with the prevalence of cardiovascular calcification.
Cardiovascular calcification correlates with atherosclerotic disease burden. Experimental data suggest that NCBP may limit cardiovascular calcification, which has implications for disease prevention.
The relationship of NCBP use to the prevalence of aortic valve, aortic valve ring, mitral annulus, thoracic aorta, and coronary artery calcification (AVC, AVRC, MAC, TAC, and CAC, respectively) detected by computed tomography was assessed in 3,636 women within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling.
Analyses were age-stratified because of a significant interaction between age and NCBP use (interaction p-values: AVC p<0.0001; AVRC p<0.0001; MAC p=0.002; TAC p<0.0001; CAC p=0.046). After adjusting for age, body mass index, demographics, diabetes, smoking, blood pressure, cholesterol levels, and statin, hormone replacement, and renin-angiotensin inhibitor therapy, NCBP use was associated with a lower prevalence of cardiovascular calcification in women ≥65 years old (prevalence ratio [95% confidence interval]: AVC 0.68 [0.41, 1.13]; AVRC 0.65 [0.51, 0.84]; MAC 0.54 [0.33, 0.93]; TAC 0.69 [0.54, 0.88]; CAC 0.89 [0.78, 1.02]), whereas calcification was more prevalent in NCBP users among the 2,181 women <65 years old (AVC 4.00 [2.33, 6.89]; AVRC 1.92 [1.42, 2.61]; MAC 2.35 [1.12, 4.84]; TAC 2.17 [1.49, 3.15]; CAC 1.23 [0.97, 1.57]).
Among women in the diverse MESA cohort, NCBPs were associated with decreased prevalence of cardiovascular calcification in older subjects, but more prevalent cardiovascular calcification in younger ones. Further study is warranted to clarify these age-dependent NCBP effects.
PMCID: PMC3004769  PMID: 21070928
bisphosphonate; calcification; coronary artery; valve; vascular
19.  Phosphorus Is Associated with Coronary Artery Disease in Patients with Preserved Renal Function 
PLoS ONE  2012;7(5):e36883.
High serum phosphorus levels have been associated with mortality and cardiovascular events in patients with chronic kidney disease and in the general population. In addition, high phosphorus levels have been shown to induce vascular calcification and endothelial dysfunction in vitro. The aim of this study was to evaluate the relation of phosphorus and coronary calcification and atherosclerosis in the setting of normal renal function. This was a cross-sectional study involving 290 patients with suspected coronary artery disease and undergoing elective coronary angiography, with a creatinine clearance >60 ml/min/1.73 m2. Coronary artery obstruction was assessed by the Friesinger score and coronary artery calcification by multislice computed tomography. Serum phosphorus was higher in patients with an Agatston score >10 than in those with an Agatston score ≤10 (3.63±0.55 versus 3.49±0.52 mg/dl; p = 0.02). In the patients with Friesinger scores >4, serum phosphorus was higher (3.6±0.5 versus 3.5±0.6 mg/dl, p = 0.04) and median intact fibroblast growth factor 23 was lower (40.3 pg/ml versus 45.7 pg/ml, p = 0.01). Each 0.1-mg/dl higher serum phosphate was associated with a 7.4% higher odds of having a Friesinger score >4 (p = 0.03) and a 6.1% greater risk of having an Agatston score >10 (p = 0.01). Fibroblast growth factor 23 was a negative predictor of Friesinger score (p = 0.002). In conclusion, phosphorus is positively associated with coronary artery calcification and obstruction in patients with suspected coronary artery disease and preserved renal function.
PMCID: PMC3349637  PMID: 22590632
20.  Coronary Artery Calcification and Myocardial Perfusion in Asymptomatic Adults: The MESA (Multi-Ethnic Study of Atherosclerosis) 
This study assessed the cross-sectional association between coronary artery calcification (CAC) and myocardial perfusion in an asymptomatic population.
Clinical studies showed that the prevalence of stress-induced ischemia increased with CAC burden among patients with coronary heart disease (CHD). Whether an association between CAC and myocardial perfusion exists in subjects without a history of CHD remains largely unknown.
A total of 222 men and women, ages 45 to 84 years old and free of CHD diagnosis, in the Minnesota field center of the MESA (Multi-Ethnic Study of Atherosclerosis) were studied. Myocardial blood flow (MBF) was measured using magnetic resonance imaging during rest and adenosine-induced hyperemia. Perfusion reserve was calculated as the ratio of hyperemic to resting MBF. Agatston CAC score was determined from chest multidetector computed tomography.
Mean values of hyperemic MBF and perfusion reserve, but not resting MBF, were monotonically lower across increasing CAC levels. After adjusting for age and gender, odds ratios (95% confidence intervals) of reduced perfusion reserve (<2.5) for subjects with CAC scores of 0, 0.1 to 99.9, 100 to 399, and ≥400 were 1.00 (reference), 2.16 (0.96 to 4.84), 2.81 (1.04 to 7.58), and 4.99 (1.73 to 14.4), respectively. Further adjustment for other coronary risk factors did not substantially modify the association. However, the inverse association between perfusion reserve and CAC attenuated with advancing age (p for interaction < 0.05).
Coronary vasodilatory response was associated inversely with the presence and severity of CAC in asymptomatic adults. Myocardial perfusion could be impaired by or manifest the progression to subclinical coronary atherosclerosis in the absence of clinical CHD.
PMCID: PMC1853335  PMID: 16949496
21.  Hyperuricemia and the risk for subclinical coronary atherosclerosis - data from a prospective observational cohort study 
Our purpose was to test the hypothesis that hyperuricemia is associated with coronary artery calcification (CAC) among a relatively healthy population, and that the extent of calcification is directly proportional to the serum uric acid (sUA) concentration.
Data from 2,498 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were analyzed using logistic regression models. Subjects were free of clinical heart disease, diabetes, and renal impairment. The main measure was the presence of any CAC by computerized tomography (Agatston score >0).
Forty-eight percent of the study participants were male and 45% were African-American. Mean (± SD) age was 40 ± 4 years, body mass index 28 ± 6 kg/m2, Framingham risk score -0.7 ± 5%, blood pressure 113 ± 14/75 ± 11 mmHg, alcohol consumption 12 ± 27 ml/day, and sUA 297 ± 89 μmol/L (5.0 ± 1.5 mg/dL). Prevalence of CAC increased with sUA concentration among both men and women. Adjusted for age, gender, race, lipoproteins, triglycerides, smoking, blood pressure, presence of metabolic syndrome, C-reactive protein, waist circumference, alcohol use, creatinine, and serum albumin, the highest quartile of sUA (>393 μmol/L [6.6 mg/dL] for men and >274 μmol/L [4.6 mg/dL] for women) was associated with an odds ratio of 1.87 (1.19-2.93) compared to the lowest quartile (<291 μmol/L [4.9 mg/dL] for men and <196 μmol/L [3.3 mg/dL] for women). Among those with any CAC, each unit increase in sUA was associated with a 22% increase in Agatston score (P = 0.008) after adjusting for the above covariates.
Hyperuricemia is an independent risk factor for subclinical atherosclerosis in young adults.
PMCID: PMC3132061  PMID: 21501486
22.  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
23.  Inflammation, Coronary Artery Calcification and Cardiovascular Events in Incident Renal Transplant Recipients 
Atherosclerosis  2010;212(2):589-594.
Coronary artery calcification (CAC) predicts cardiovascular events in the general population. We conducted a prospective study to determine if inflammatory markers were predictive of CAC and if CAC predicted cardiovascular events and mortality in incident renal transplant recipients.
A prospective cohort of 112 asymptomatic incident renal transplant recipients who had no prior history of coronary artery revascularization or myocardial infarction had coronary calcifications measured early post-transplant and at least 18 months later by Agatston score and volume method.
The mean CAC score was 367.7 (682.3). Inflammatory markers such as WBC and CRP were predictive of CAC severity. Recipients with cardiovascular events (n=11) or death (n=12) during the follow-up period had higher mean [675.1 (669.3) vs. 296.8(669.0), p=0.02] and median [434.8 vs. 28.9, p=0.01] CAC score compared to those without them. Recipients with CAC score less than 100 had a better cumulative survival rate compared to the recipients with CAC score greater than 100 [95.1 vs. 82.3%, p=0.03]. We found a significant unadjusted and adjusted association between CAC score and cardiovascular events and mortality. A quarter (25.9%) of recipients had CAC progression. Coronary calcification progression also predicted cardiovascular events and mortality after adjustment for diabetes, age, dialysis vintage and presence of CAC at time of transplant.
CAC is prevalent in renal recipients and is predictive of cardiovascular events and mortality. Changes in coronary calcification are common and predict clinical outcomes. Inflammatory markers are predictive of CAC severity at time of transplant, but are not predictive of future cardiovascular event or mortality.
PMCID: PMC2953547  PMID: 20934074
coronary calcification; EBCT; renal transplant; inflammation; C-reactive protein
24.  Quantification of Lower Leg Arterial Calcifications by High-Resolution Peripheral Quantitative Computed Tomography 
Bone  2013;58:42-47.
Vascular calcifications and bone health seem to be etiologically linked via common risk factors such as aging and subclinical chronic inflammation. Epidemiologic studies have shown significant associations between low bone mineral density (BMD), fragility fractures and calcifications of the coronary arteries and the abdominal aorta. In the last decade, high-resolution peripheral quantitative computed tomography (HR-pQCT) has emerged as in-vivo research tool for the assessment of peripheral bone geometry, density, and microarchitecture. Although vascular calcifications are frequently observed as incidental findings in HR-pQCT scans, they have not yet been incorporated into quantitative HR-pQCT analyses. We developed a semi-automated algorithm to quantify lower leg arterial calcifications (LLAC), captured by HR-pQCT. The objective of our study was to determine validity and reliability of the LLAC measure.
HR-pQCT scans were downscaled to a voxel size of 250 µm. After subtraction of bone volumes from the scans, LLAC were detected and contoured by a semi-automated, dual-threshold seed-point segmentation. LLAC mass (in mg hydroxyapatite; HA) was calculated as the product of voxel-based calcification volume (mm3) and mean calcification density (mgHA/cm3)/1000. To determine validity, we compared LLAC to coronary artery calcifications (CAC), as quantified by multi-detector computed tomography (MDCT) and Agatston scoring in forty-six patients on chronic hemodialysis. Moreover, we investigated associations of LLAC with age, time on dialysis, type-2 diabetes mellitus, history of stroke, and myocardial infarction. In a second step, we determined intra- and inter-reader reliability of the LLAC measure.
In the validity study, LLAC were present (>0 mgHA) in 76% of patients, 78% of patients had CAC (>0 mgHA). Median LLAC was 6.65 (0.08 – 24.40) mgHA and median CAC as expressed by Agatston score was 266.3 (15.88 – 1877.28). We found a significant positive correlation between LLAC and CAC (rho=0.6; p<0.01). Dialysis patients with type-2 diabetes mellitus (DM; 35%) and history of stroke (13%) had higher median LLAC than patients without those conditions (DM 20.0 fold greater, p=0.006; Stroke 5.1 fold greater, p=0.047;). LLAC was positively correlated with time on dialysis (rho=0.337, p=0.029), there was a trend towards a positive association of LLAC and age (rho=0.289, p=0.053). The reliability study yielded excellent intra- and inter-reader agreement of the LLAC measure (intra-reader ICC=0.999, 95% CI=0.998–1.000; inter-reader ICC=0.998, 95% CI=0.994–0.999).
Our study indicates that the LLAC measure has good validity and excellent reliability. The use of HR-pQCT for the simultaneous evaluation of arterial calcifications, peripheral bone geometry, bone density, and bone microarchitecture should facilitate future research on osteo-vascular interactions and potential associations with cardiovascular events.
PMCID: PMC4042679  PMID: 23954758
HR-pQCT; Lower Leg Arterial Calcifications; Quantification; Agatston-Score
25.  Magnesium Intake Is Inversely Associated With Coronary Artery Calcification 
JACC. Cardiovascular imaging  2013;7(1):59-69.
The aim of this study was to examine whether magnesium intake is associated with coronary artery calcification (CAC) and abdominal aortic calcification (AAC).
Animal and cell studies suggest that magnesium may prevent calcification within atherosclerotic plaques underlying cardiovascular disease. Little is known about the association of magnesium intake and atherosclerotic calcification in humans.
We examined cross-sectional associations of self-reported total (dietary and supplemental) magnesium intake estimated by food frequency questionnaire with CAC and AAC in participants of the Framingham Heart Study who were free of cardiovascular disease and underwent Multi-Detector Computed Tomography (MDCT) of the heart and abdomen (n = 2,695; age: 53 ± 11 years), using multivariate-adjusted Tobit regression. CAC and AAC were quantified using modified Agatston scores (AS). Models were adjusted for age, sex, body mass index, smoking status, systolic blood pressure, fasting insulin, total-to-high-density lipoprotein cholesterol ratio, use of hormone replacement therapy (women only), menopausal status (women only), treatment for hyperlipidemia, hypertension, cardiovascular disease prevention, or diabetes, as well as self-reported intake of calcium, vitamins D and K, saturated fat, fiber, alcohol, and energy. Secondary analyses included logistic regressions of CAC and AAC outcomes as cut-points (AS >0 and AS ≥90th percentile for age and sex), as well as sex-stratified analyses.
In fully adjusted models, a 50-mg/day increment in self-reported total magnesium intake was associated with 22% lower CAC (p < 0.001) and 12% lower AAC (p = 0.07). Consistent with these observations, the odds of having any CAC were 58% lower (p trend: <0.001) and any AAC were 34% lower (p trend: 0.01), in those with the highest compared to those with the lowest magnesium intake. Stronger inverse associations were observed in women than in men.
In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium's protective associations in stroke and fatal coronary heart disease.
PMCID: PMC3957229  PMID: 24290571
abdominal aortic calcification; computed tomography; coronary artery calcification; diet; Framingham Heart Study; magnesium

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