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1.  Coronary Artery Calcium Score and Association with Recurrent Nephrolithiasis: The Multi-Ethnic Study of Atherosclerosis 
The Journal of urology  2015;195(4 Pt 1):971-976.
Subclinical coronary artery calcification is an established predictor of cardiovascular events. While a history of kidney stones has been linked to subclinical carotid atherosclerosis, to our knowledge no study has examined its relationship with coronary artery calcification. We studied the association between kidney stone history and prevalent coronary artery calcification in MESA (Multi-Ethnic Study of Atherosclerosis).
Materials and Methods
MESA is a multisite cohort study of participants 45 to 84 years old without known cardiovascular disease at baseline from 2000 to 2002. Computerized tomography was done in 3,282 participants at followup in 2010 to 2012 to determine coronary artery calcification and kidney stone history was assessed by self-report. Coronary artery calcification scores were categorized as none—0, mild—1 to 99, moderate—100 to 399 or severe—400 or greater. Cross-sectional analysis was performed adjusting for demographic and dietary factors related to kidney stones.
The prevalence of kidney stone disease history was approximately 9%, mean ± SD participant age was 69.5 ± 9.3 years, 39% of participants were Caucasian, 47% were men and 69% had detectable coronary artery calcification (score greater than 0). No difference in the score was seen between single stone formers and nonstone formers. Recurrent kidney stone formation was associated with moderate or severe calcification on multivariable logistic regression vs none or mild calcification (OR 1.80, 95% CI 1.22–2.67). When coronary artery calcification scores were separated into none, mild, moderate and severe calcification, recurrent stone formation was associated with a higher score category on multivariable ordinal logistic regression (OR 1.44 per category, 95% CI 1.04–2.01).
Recurrent kidney stone formation is associated with subclinical coronary atherosclerosis. This association appeared stronger with coronary artery calcification severity than with coronary artery calcification presence.
PMCID: PMC4966606  PMID: 26454103
kidney; urolithiasis; coronary artery disease; arteriosclerosis; recurrence
2.  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
3.  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
4.  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
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.  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
7.  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
8.  Rheumatoid Arthritis and Incidence of Twelve Initial Presentations of Cardiovascular Disease: A Population Record-Linkage Cohort Study in England 
PLoS ONE  2016;11(3):e0151245.
While rheumatoid arthritis is an established risk factor for cardiovascular disease (CVD), our knowledge of how the pattern of risk varies for different cardiovascular phenotypes is incomplete. The association between rheumatoid arthritis and the initial presentation of 12 types of CVDs were examined in a contemporary population of men and women of a wide age range.
CALIBER data, which links primary care, hospital and mortality data in England, was analysed. A cohort of people aged ≥18 years and without history of CVD was assembled and included all patients with prospectively recorded rheumatoid arthritis from January 1997, until March 2010, matched with up to ten people without rheumatoid arthritis by age, sex and general practice. The associations between rheumatoid arthritis and the initial presentation of 12 types of CVDs were estimated using multivariable random effects Poisson regression models.
The analysis included 12,120 individuals with rheumatoid arthritis and 121,191 comparators. Of these, 2,525 patients with and 18,146 without rheumatoid arthritis developed CVDs during a median of 4.2 years of follow-up. Patients with rheumatoid arthritis had higher rates of myocardial infarction (adjusted incidence ratio [IRR] = 1.43, 95%CI 1.21–1.70), unheralded coronary death (IRR = 1.60, 95%CI 1.18–2.18), heart failure (IRR = 1.61, 95%CI 1.43–1.83), cardiac arrest (HR = 2.26, 95%CI 1.69–3.02) and peripheral arterial disease (HR = 1.36, 95%CI 1.14–1.62); and lower rates of stable angina (HR = 0.83, 95%CI 0.73–0.95). There was no evidence of association with cerebrovascular diseases, abdominal aortic aneurysm or unstable angina, or of interactions with sex or age.
The observed associations with some but not all types of CVDs inform both clinical practice and the selection of cardiovascular endpoints for trials and for the development of prognostic models for patients with rheumatoid arthritis.
PMCID: PMC4792375  PMID: 26978266
9.  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
10.  Implications of Gender Difference in Coronary Calcification as Assessed by CT Coronary Angiography 
Clinical Medicine Insights. Cardiology  2015;8(Suppl 4):51-55.
Arterial calcium as measured by 64-slice computed tomography coronary angiography (64-CT) is a reliable predictor of cardiovascular disease risk. Lipid-rich plaques with lower degrees of calcification may pose greater risk for adverse coronary events than more stabilized calcified plaques as a result of the increased risk of plaque rupture, migration, and subsequent acute coronary syndrome. We sought to examine coronary artery calcium scores as measured via 64-CT to assess the extent of calcification and plaque distribution in women compared to men.
A total of 138 patients referred for 64-CT were evaluated. Computerized tomographic angiography was performed using the GE LightSpeed VCT. Subgroup analysis comparing male and female data (including demographic data) was performed. All major coronary arteries were analyzed for coronary stenosis/plaque characterization as well as total vessel calcium (Agatston) score quantification. Patient demographics and coronary risk factors were recorded.
A total of 552 coronary arteries were evaluated in 138 patients (85 men, 53 women). The average age for females was 64.4 ± 10.8 years and for males 60.0 ± 12.8 years. The only demographic/cardiovascular risk factor in which the difference between men and women was significant was smoking history, where 23.5% of men had a history of smoking while only 9.6% of females endorsed having a smoking history (P < 0.044). On comparison of all total vessel calcium scores, males had a higher total mean calcium score than females in each individual vessel. The results were as follows for males versus females, respectively: left main total vessel calcium score 46.49 versus 16.71 (P = 0.167); left anterior descending 265.21 versus 109.6 (P < 0.003); left circumflex 130.5 versus 39.7 (P < 0.004); and right coronary 213.5 versus 73.8 (P < 0.01). The odds of having a total calcium score >100 (versus not) was 3.62 times greater in males relative to females, given that all the other cardiovascular risk factors are adjusted for (95% confidence interval: 1.37–9.54). On average, men had an average of 2.1 ± 1.5 epicardial vessels with a calcium score ≥11 compared to 1.3 ± 1.4 for women (P < 0.005).
There are clear differences between males and females regarding total vessel calcium scores and therefore risk of future adverse coronary events. Males tended to have higher average calcium scores in each coronary artery than females with a greater tendency to have multiple vessel involvement. Using this information, more large-scale, randomized controlled studies should be performed to correlate differences in the extent of coronary calcification with the observed variance in clinical presentation during coronary events between males and females as a means to potentially establish gender-specific therapeutic regimens.
PMCID: PMC4412426  PMID: 25983560
coronary artery disease; coronary computed tomography; gender
11.  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
12.  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
13.  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
14.  QCT Volumetric Bone Mineral Density and Vascular and Valvular Calcification: The Framingham Study 
There is increasing evidence that bone and vascular calcification share common pathogenesis. Little is known about potential links between bone and valvular calcification. The purpose of this study was to determine the association between spine bone mineral density (BMD) and vascular and valvular calcification. Participants included 1317 participants (689 women, 628 men) in the Framingham Offspring Study (mean age 60 years). Integral, trabecular, and cortical volumetric bone density (vBMD) and arterial and valvular calcification were measured from computed tomography (CT) scans and categorized by sex-specific quartiles (Q4 = high vBMD). Calcification of the coronary arteries (CAC), abdominal aorta (AAC), aortic valve (AVC), and mitral valve (MVC) were quantified using the Agatston Score (AS). Prevalence of any calcium (AS >0) was 69% for CAC, 81% for AAC, 39% for AVC, and 20% for MVC. In women, CAC increased with decreasing quartile of trabecular vBMD: adjusted mean CAC = 2.1 (Q4), 2.2 (Q3), 2.5 (Q2), 2.6 (Q1); trend p = 0.04. However, there was no inverse trend between CAC and trabecular vBMD in men: CAC = 4.3 (Q4), 4.3 (Q3), 4.2 (Q2), 4.3 (Q1); trend p = 0.92. AAC increased with decreasing quartile of trabecular vBMD in both women (AAC = 4.5 [Q4], 4.8 [Q3], 5.4 [Q2], 5.1 [Q1]; trend p = 0.01) and men (AAC = 5.5 [Q4], 5.8 [Q3], 5.9 [Q2], 6.2 [Q1]; trend p = 0.01). We observed no association between trabecular vBMD and AVC or MVC in women or men. Finally, cortical vBMD was unrelated to vascular calcification and valvular calcification in women and men. Women and men with low spine vBMD have greater severity of vascular calcification, particularly at the abdominal aorta. The inverse relation between AAC and spine vBMD in women and men may be attributable to shared etiology and may be an important link on which to focus treatment efforts that can target individuals at high risk of both fracture and cardiovascular events.
PMCID: PMC4809363  PMID: 25871790
15.  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
16.  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
17.  Complement Proteins and Arterial Calcification in Middle Aged Women: Cross-sectional Effect of Cardiovascular Fat. The SWAN Cardiovascular Fat Ancillary Study 
Atherosclerosis  2015;243(2):533-539.
CVD risk increases in women after menopause. Recent data suggest higher levels of complement protein C3 and cardiovascular fat (CF) in postmenopausal women. Whether complement proteins are associated with early markers of atherosclerosis in healthy midlife women has never been evaluated. Additionally, the potential impact of the local CF on these associations has never been assessed.
Participants (n=100, age (mean(SD)):50.48(2.63), 50% premenopausal) were from the Study of Women's Health Across the Nation (SWAN). Arterial calcification (aortic-AC and coronary-CAC) and CF volumes around the heart and aorta (total heart-TAT and aortic perivascular adipose tissue-PVAT) were quantified using EBCT scans. AC and CAC were each evaluated as presence (Agatston scores>0) and extent of calcification (log (Agatston scores +1)). Logistic and linear regression models were used for statistical analysis.
Adjusting for age, race, menopausal status and lipids, C3 was significantly associated with both presence and extent of AC and CAC, all P values <0.05. Associations between C3 and presence and extent of AC and CAC were explained by additional adjustment for logTAT and logPVAT, respectively. Association between C3 and log(AC+1) was more pronounced at higher volumes of logTAT (interaction-P=0.013) adjusting for study variables. No associations were found with C4.
Higher C3 was significantly associated with presence and greater extent of arterial calcification in midlife women. These associations were explained by higher volumes of CF, suggesting CF as a potential source of C3. C3 could be a potential non-invasive biomarker of early diagnosis of atherosclerosis. These findings need to be replicated in larger studies.
PMCID: PMC4817718  PMID: 26523990
Subclinical atherosclerosis; complement proteins; cardiovascular fat; women; midlife
18.  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
19.  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
20.  Lack of Association of Oral Calcium Supplementation with Coronary Artery Calcification in Rheumatoid Arthritis 
To investigate the association between oral calcium supplementation and coronary arterial calcification among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD).
This study was nested in a prospective cohort study of RA patients without known CVD. Daily supplemental calcium dose was ascertained from prescription and over-the-counter medications at baseline and visit 2 (median 20 months post-baseline). Coronary artery calcium (CAC), a measure of coronary atherosclerosis, was assessed by cardiac multi-detector row computed tomography at baseline and visit 3 (median 39 months post-baseline). The association of calcium supplementation with CAC was explored.
Among the 145 RA patients studied, 42 (28%) took ≥1000mg/day of supplemental calcium at baseline. Forty-four (30%) and 50 (34%) had a CAC score >100 units at baseline and follow-up, respectively. Baseline CAC scores >100 units were significantly less frequent in the higher (≥1000mg/day) supplemental calcium group than in the lower dosed group (<1000mg/day) [OR 0.28 (95% CI 0.11-0.74)]; this remained significant after adjusting for relevant confounders [OR 0.30 (95% CI 0.09-0.93)]. Similarly, at the third study visit, CAC scores >100 units were less frequent in the higher vs. the lower supplemental calcium group [OR 0.41 (95% CI 0.18-0.95)].
When adjusted for relevant confounders, statistical significance was lost [OR 0.39 (95% CI 0.14-1.12)]. No gender interaction and no change in CAC score over time were appreciated.
Higher levels of oral calcium supplementation were not associated with an increased risk of coronary atherosclerosis as measured by CAC score in this RA cohort.
PMCID: PMC4446236  PMID: 25808397
21.  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
22.  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
23.  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
24.  Coronary artery calcifications predict long term cardiovascular events in non diabetic Caucasian hemodialysis patients 
Aging (Albany NY)  2015;7(4):269-279.
Vascular calcifications are frequent in chronic renal disease and are associated to significant cardiovascular morbidity and mortality. The long term predictive value of coronary artery calcifications detected by multi-layer spiral computed tomography for major cardiovascular events was evaluated in non-diabetic Caucasian patients on maintenance hemodialysis free of clinical cardiovascular disease. Two-hundred and five patients on maintenance hemodialysis were enrolled into this observational, prospective cohort study. Patients underwent a single cardiac multi-layer spiral computed tomography. Calcium load was quantified and patients grouped according to the Agatston score: group 1 (Agatston score: 0), group 2 (Agatston score 1-400), group 3 (Agatston score 401-1000) and group 4 (Agatston score >1000). Follow-up was longer than seven years. Primary endpoint was death from a major cardiovascular event. Actuarial survival was calculated separately in the four groups with Kaplan-Meier method. Patients who died from causes other than cardiovascular disease and transplanted patients were censored. The “log rank” test was employed to compare survival curves. One-hundred two patients (49.7%) died for a major cardiovascular event during the follow-up period. Seven-year actuarial survival was more than 90% for groups 1 and 2, but failed to about 50% for group 3 and to <10% for group 4. Hence, Agatston score >400 predicts a significantly higher cardiovascular mortality compared with Agatston score <400 (p<0.0001); furthermore, serum Parathyroid hormone levels > 300 pg/l were associated to a lower survival (p < 0.05). Extended coronary artery calcifications detected by cardiac multi-layer spiral computed tomography, strongly predicted long term cardiovascular mortality in non-diabetic Caucasian patients on maintenance hemodialysis. Moreover, it was not related to conventional indices of atherosclerosis, but to other non-traditional risk factors, as serum Parathyroid hormone levels. A full cost-benefit analysis is however necessary to justify a widespread use of cardiac multi-layer spiral computed tomography in clinical practice.
PMCID: PMC4429091  PMID: 26131456
aging; cardiac calcifications; spiral computed tomography; mortality; morbidity; cardiovascular events; vascular pathology; endothelial cells; hemodialysis
25.  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

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