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1.  Differences in Subclinical Cardiovascular Disease between African American and Caucasian Women with Systemic Lupus Erythematosus 
Racial differences exist in disease rates and mortality in both cardiovascular disease (CVD) and Systemic Lupus Erythematosus (SLE). The objective of this cross-sectional study was to compare the frequency of and risk factors for subclinical CVD in African-American (AA) and Caucasian women with SLE and no prior CVD events.
Traditional CVD risk factors and SLE-related factors were assessed in 309 SLE women. Subclinical CVD was assessed by carotid ultrasound to measure intima-medial thickness (IMT) and plaque, and electron beam computed tomography (EBCT) to measure coronary artery calcium (CAC).
AA had less education, higher body mass index, blood pressure, lipoprotein(a), CRP, fibrinogen, and ESR, but lower albumin; more and longer duration of corticosteroid use; higher SLE disease activity and damage; and more had dsDNA antibodies compared to Caucasian women, after adjustment for age and study-site. More AA had carotid plaque (adjusted OR 1.94, 95%CI 1.03, 3.65) and higher carotid IMT (0.620 vs. 0.605mm, p=0.07) compared with Caucasians, but similar CAC. Multivariate analysis included risk factor variables significantly different between the racial groups and associated with plaque: blood pressure, current corticosteroid use, SLE disease activity and damage. All factors contributed, but no individual risk factor fully accounted for the association between race and plaque.
In conclusion, the presence of carotid plaque was higher in AA compared with Caucasian women with SLE, in contrast to studies of non-SLE subjects, where AA have similar or less plaque than Caucasians. A combination of SLE-related and traditional CVD risk factors explained the racial difference in plaque burden.
doi:10.1016/j.trsl.2008.11.006
PMCID: PMC2674850  PMID: 19138649
Systemic Lupus Erythematosus; Race; Cardiovascular Disease
2.  Serum 25-hydroxyvitamin D levels are not associated with subclinical vascular disease or C-reactive protein in the Old Order Amish 
Calcified tissue international  2009;84(3):195-202.
Background
The relationship between vitamin D metabolites and subclinical vascular disease is controversial. Because low serum levels of 25-hydroxyvitamin D [25(OH)D] have been associated with many cardiovascular disease (CVD) risk factors, we hypothesized that serum 25(OH)D levels would be inversely associated with inflammation as measured by C-reactive protein (CRP) and with subclinical vascular disease as measured by carotid intimal medial thickness (cIMT) and coronary artery calcification (CAC).
Methods
We measured 25(OH)D levels in 650 Amish participants. CAC was measured by computed tomography, and cIMT by ultrasound. The associations of 25(OH)D levels with natural log(CAC+1), cIMT, and natural log(CRP) levels were estimated following adjustment for age, sex, family structure, and season of examination. Additional analyses were carried out adjusting for body mass index (BMI) and other CVD risk factors.
Results
25(OH)D deficiency (<20 ng/ml) and insufficiency (21-30 ng/ml) were common among the Amish (38.2% and 47.7%, respectively). 25(OH)D levels were associated with season, age, BMI, and parathyroid hormone levels. In neither the minimally or fully adjusted analyses were significant correlations observed between 25(OH)D levels and CAC, cIMT, or CRP (R2 < 0.01 for all).
Conclusion
Contrary to our hypothesis, this study failed to detect a cross-sectional association between serum 25(OH)D levels and CAC, cIMT, or CRP. Either there is no causal relationship between 25(OH)D and CVD risk, or, if there is, it may be mediated through mechanisms other than subclinical vascular disease severity.
doi:10.1007/s00223-008-9209-3
PMCID: PMC2908302  PMID: 19148561
3.  Coronary Calcification is More Predictive of Carotid Intimal Medial Thickness in Black Compared to White Middle Aged Men 
Atherosclerosis  2007;196(2):913-918.
Background
Race-specific data for the association between coronary artery calcification (CAC) and carotid intimal medial thickness (IMT) are limited. We sought to compare black-white specific associations of these two measures.
Methods
We conducted a population-based study of 379 randomly-selected men aged 40–49 years (84 black and 295 white) from Allegheny County, US (2004–2006). Agatston CAC score was evaluated by electron-beam tomography and carotid IMT was evaluated by ultrasonography.
Results
Compared to white men, black men had similar prevalence of CAC (p=0.56) and higher total carotid IMT (p<0.001). In black and white men, CAC score had significant positive correlations with total carotid IMT (r=0.47 & r=0.24 respectively, p<0.001 for both) as well as the IMT for the common carotid artery (CCA), internal carotid artery and carotid bulb. The associations of CAC with total and CCA IMT were significantly stronger in black (beta=0.07 & beta=0.05 respectively) than white men (beta=0.03 & beta=0.01 respectively) after adjustment for traditional coronary risk factors (p=0.046 & p=0.036 respectively).
Conclusions
In black and white middle-aged men, CAC score had significant positive correlations with total and segmental carotid IMT. CAC was more predictive of total and CCA IMT in black than white men independent of coronary risk factors.
doi:10.1016/j.atherosclerosis.2007.02.009
PMCID: PMC3089019  PMID: 17350026
Epidemiology; atherosclerosis; coronary calcification; carotid intimal medial thickness; Caucasian; black
4.  Predictors of progression in atherosclerosis over 2 years in systemic lupus erythematosus 
Rheumatology (Oxford, England)  2011;50(11):2071-2079.
Objectives. Cardiovascular disease remains the major cause of death in SLE. We assessed the degree to which cardiovascular risk factors (CVRFs) and disease activity were associated with 2-year changes in measures of subclinical atherosclerosis.
Methods. One hundred and eighty-seven SLE patients participating in a placebo-controlled trial of atorvastatin underwent multi-detector CT [for coronary artery calcium (CAC)] and carotid duplex [for carotid intima–media thickness (IMT) and carotid plaque] twice, 2 years apart. During the 2 years, patients were assessed every 3 months for CVRF. Both groups were combined for analysis, as atorvastatin did not differ from placebo in preventing progression of coronary calcium. We examined the correlation between these clinical measures and progression of CAC, IMT and plaque during the follow-up period.
Results. In an analysis adjusting for age, gender and ethnicity, CAC progression was positively associated with total serum cholesterol measured over the 2-year period (P = 0.04) and smoking (P = 0.003). Carotid IMT progression was associated with systolic BP (P = 0.003), high-sensitivity CRP (hsCRP) (P = 0.013) and white blood cell (WBC) count (P = 0.029). Carotid plaque progression, defined as patients without carotid plaque at baseline with subsequent development of plaque at follow-up, was associated with systolic BP (P = 0.003), WBC count (P = 0.02), physician's global assessment (P = 0.05), blood lymphocyte count (P = 0.048), urine protein (P = 0.017) and duration of SLE (P = 0.019).
Conclusion. Our data did not provide evidence of an association between measures of SLE disease activity (SLEDAI, anti-dsDNA, anti-phospholipid and treatment) and progression of subclinical atherosclerosis. Age and hypertension were associated with the progression of carotid IMT and plaque. Age, smoking and cholesterol were associated with progression of CAC.
doi:10.1093/rheumatology/ker285
PMCID: PMC3247795  PMID: 21875880
Systemic lupus erythematosus; Helical computed tomography; Coronary artery calcium; Carotid intima–media thickness; Carotid plaque; Inflammation; Atherosclerosis; Carotid duplex; Coronary artery disease; Statins
5.  Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2003;62(11):1071-1077.
Objective: To evaluate traditional and non-traditional risk factors for subclinical atherosclerosis in systemic lupus erythematosus (SLE).
Methods: A prospective cohort of 78 patients with SLE without overt atherosclerotic disease was studied. SLE clinical and laboratory parameters, disease activity and damage, treatment and traditional risk factors for atherosclerosis were evaluated. At baseline (T1) and after five years' follow up (T2), the serum levels of anti-oxidised palmitoyl arachidonoyl phosphocholine (oxPAPC), anti-heat shock protein 65, and anti-ß2-glycoprotein I antibodies and C reactive protein were tested. At T2, intima-media thickness (IMT) was measured using duplex carotid sonography. Thickened intima, plaque, mean IMT (m-IMT), and maximum IMT (M-IMT) were assessed.
Results: A thickened intima was seen in 22/78 (28%) patients and plaque in 13/78 (17%). M-IMT and m-IMT were (mean (SD)) 0.77 (0.34) mm and 0.55 (0.15) mm, respectively. Patients with carotid abnormalities were significantly older, had higher blood pressure and total serum cholesterol levels, and had taken a higher prednisone cumulative dosage than those without any lesions. The carotid abnormalities were associated with renal disease and ECLAM >2 at T1, and with azathioprine treatment. In multivariate analysis, age and cumulative prednisone dose were associated with carotid abnormalities; age, hypertension, and anti-oxPAPC at T2 were correlated with higher M-IMT and m-IMT.
Conclusions: In patients with SLE some non-traditional risk factors for atherosclerosis were identified, the most important of which was the cumulative prednisone dose. The role of some traditional risk factors, such as age and hypertension, was also confirmed. The predictive value of the new immunological and inflammatory markers of atherosclerosis seems to be masked by some disease related features.
doi:10.1136/ard.62.11.1071
PMCID: PMC1754370  PMID: 14583570
6.  Genetic ancestry is associated with subclinical cardiovascular disease in African Americans and Hispanics from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Differences in cardiovascular disease (CVD) burden exist among racial/ethnic groups in the United States, with African Americans having the highest prevalence. Subclinical CVD measures have also been shown to differ by race/ethnicity. In the United States, there has been significant intermixing among racial/ethnic groups creating admixed populations. Very little research exists on the relationship of genetic ancestry and subclinical CVD measures.
Methods and Results
These associations were investigated in 712 African-American and 705 Hispanic participants from the MESA candidate gene sub-study. Individual ancestry was estimated from 199 genetic markers using STRUCTURE. Associations of ancestry and coronary artery calcium (CAC) and common and internal carotid intima media thickness (cIMT) were evaluated using log-binomial and linear regression models. Splines indicated linear associations of ancestry with subclinical CVD measures in African-Americans, but presence of threshold effects in Hispanics. Among African Americans, each standard deviation (SD) increase in European ancestry was associated with an 8% (95% CI (1.02, 1.15), p=0.01) greater CAC prevalence. Each SD increase in European ancestry was also associated with a 2% (95% CI (−3.4%, −0.5%), p=0.008) lower common cIMT in African Americans. Among Hispanics, the highest tertile of European ancestry was associated with a 34% greater CAC prevalence, p=0.02 as compared to lowest tertile.
Conclusions
The linear association of ancestry and subclinical CVD suggests that genetic effects may be important in determining CAC and cIMT among African-Americans. Our results also suggest that CAC and common cIMT may be important phenotypes for further study with admixture mapping.
doi:10.1161/CIRCGENETICS.109.876243
PMCID: PMC2795643  PMID: 20031644
atherosclerosis; calcium; ancestry; epidemiology; genetics
7.  Low Physical Activity is Associated with Proinflammatory High Density Lipoprotein and Increased Subclinical Atherosclerosis in Women with Systemic Lupus Erythematosus 
Arthritis care & research  2010;62(2):258-265.
Objective
To investigate the association between physical activity, functional activity of HDL, and subclinical cardiovascular disease in patients with Systemic Lupus Erythematosus (SLE).
Methods
242 SLE patients (all women) participated in this cross-sectional study from February 2004 to February 2008. Carotid plaque and intima-media thickness (IMT), antioxidant function of HDL, and traditional cardiac risk factors were measured. Physical activity was assessed from self-reports by calculating the metabolic equivalent-minutes (METs) per week and by the physical function domain of the Medical Outcomes Study Short Form-36 (SF-36). Data were analyzed using bivariate and multivariate regression analyses.
Results
Number of METs per week spent performing strenuous exercise was negatively correlated with IMT (r = −.30, P = 0.002) and number of plaques (r = −.30, P = 0.0001). Physical function as assessed by the SF-36 was also negatively correlated with IMT (r = .14, P = 0.03) and number of plaques (r = −.14, P = 0.04). In multivariate analyses, number of strenuous exercise METs was significantly associated with IMT (t = −2.2, P = 0.028) and number of plaques (t = −2.5, P = 0.014) when controlling for markers of SLE disease activity and damage, but not after controlling for traditional cardiac risk factors. Low physical activity, defined as < 225 total METs per week, was associated with presence of piHDL (P = 0.03).
Conclusion
Low physical activity is associated with increased subclinical atherosclerosis and with piHDL in patients with SLE. Increased strenuous exercise may reduce the risk of atherosclerosis in SLE.
doi:10.1002/acr.20076
PMCID: PMC2853476  PMID: 20191526
8.  Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Obesity (Silver Spring, Md.)  2010;19(4):840-847.
Circulating adiponectin has been associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were Caucasian (n=712), African-American (n=712), Chinese (n=718), and Hispanic (n=705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African-Americans with genotypes AG/GG of rs2241767 had 36% greater (95% CI (16%, 59%), p=0.0001) CAC prevalence; they also had a larger common cIMT (p=0.0043). Also in African-Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), p=0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), p=0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or Caucasian participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African-American and Hispanics. Replication as well as assessment of other ADIPOQ SNPs appears warranted.
doi:10.1038/oby.2010.229
PMCID: PMC3510267  PMID: 20930713
9.  Sex Differences in Subclinical Atherosclerosis by Race/Ethnicity in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2011;174(2):165-172.
Sex differences in cardiovascular disease mortality are more pronounced among non-Hispanic whites than other racial/ethnic groups, but it is unknown whether this variation is present in the earlier subclinical stages of disease. The authors examined racial/ethnic variation in sex differences in coronary artery calcification (CAC) and carotid intimal media thickness at baseline in 2000–2002 among participants (n = 6,726) in the Multi-Ethnic Study of Atherosclerosis using binomial and linear regression. Models adjusted for risk factors in several stages: age, traditional cardiovascular disease risk factors, behavioral risk factors, psychosocial factors, and adult socioeconomic position. Women had a lower prevalence of any CAC and smaller amounts of CAC when present than men in all racial/ethnic groups. Sex differences in the prevalence of CAC were more pronounced in non-Hispanic whites than in African Americans and Chinese Americans after adjustment for traditional cardiovascular disease risk factors, and further adjustment for behavioral factors, psychosocial factors, and socioeconomic position did not modify these results (for race/sex, Pinteraction = 0.047). Similar patterns were observed for amount of CAC among adults with CAC. Racial/ethnic variation in sex differences for carotid intimal media thickness was less pronounced. In conclusion, coronary artery calcification is differentially patterned by sex across racial/ethnic groups.
doi:10.1093/aje/kwr088
PMCID: PMC3167681  PMID: 21685409
calcification, physiologic; continental population groups; coronary vessels; sex; social class
10.  Atherosclerotic plaques occur in absence of intima-media thickening in both systemic sclerosis and systemic lupus erythematosus: a duplexsonography study of carotid and femoral arteries and follow-up for cardiovascular events 
Introduction
The objective of this cross-sectional and retrospective cohort study was (1) to determine the usefulness of intima-media thickness (IMT) in contrast to plaque assessment, (2) to examine the value of additive femoral artery sonography and (3) to identify potential risk factors for atherosclerosis and incident cardiovascular events in systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) patients.
Methods
In this study, 90 SSc and 100 SLE patients were examined by duplexsonography. IMT was measured in common carotid and common femoral arteries, plaques were assessed in common, internal and external carotid and common, proximal superficial and deep femoral arteries. Different definitions of pathological IMT (pIMT) were compared with the presence of plaque. Results were evaluated in relation to traditional and non-traditional risk factors for baseline atherosclerosis (logistic regression) and their predictive value for cardiovascular events during follow-up (cox regression).
Results
Definite atherosclerosis occurred frequently without signs of subclinical atherosclerosis in both diseases: pIMT >0.9 mm was present in only 17/59 (28.9%) SSc and 13/49 (26.5%) SLE patients with already present atherosclerotic plaques. Using age-adjusted pIMT definitions, this rate was even lower (5.1-10.3% in SSc, 14.3-26.5% in SLE). Plaques were located only at the carotid or only at the femoral arteries in 26 (13.7%) and 24 (12.6%) patients, respectively. Age and nicotine pack-years were independently associated with atherosclerotic plaques in SLE and SSc patients, as well as the cumulative prednisolone dose in SSc subgroup, and ssDNA positive SLE patients had a lower risk for atherosclerotic plaque. During follow-up (available for 129/190 (67.9%) patients, 650 person-years), cardiovascular events occurred more often in patients with coronary heart disease (adjusted-hazards ratio (HR) 10.19, 95% confidence interval (CI) 3.04 to 34.17, P <0.001), male patients (adjusted-HR 8.78, 95% CI 2.73 to 28.19, P <0.001) and in patients with coexistent carotid and femoral plaques (adjusted-HR 5.92, 95% CI 1.55 to 22.67, P = 0.009). Patients with solely carotid or femoral plaque were not at higher risk.
Conclusion
Atherosclerotic plaque lesions can be found frequently in absence of intima-media thickening in both SSc and SLE patients. As well as routine sonography of carotid arteries, the sonography of femoral arteries is recommended to identify additional atherosclerotic lesions and to detect patients at a high risk for cardiovascular events.
doi:10.1186/ar4489
PMCID: PMC3978872  PMID: 24548804
11.  Coronary Artery Calcium, Carotid Artery Wall Thickness and Cardiovascular Disease Outcomes in Adults 70 to 99 Years Old 
The American journal of cardiology  2008;101(2):186-192.
Few population studies have evaluated the associations of both coronary artery calcium (CAC) and carotid ultrasound with cardiovascular events, especially in adults > 70 years of age. At the Pittsburgh Field Center of the Cardiovascular Health Study, 559 men and women, mean age 80.2 (SD 4.1) years had CAC score assessed by electron beam computerized tomography scan and common and internal carotid intimal-medial wall thickness (CCA-IMT and ICA-IMT) by carotid ultrasound between 1998−2000 and were followed for total and incident cardiovascular disease events through June 2003. Crude rates and hazard ratios for total and incident events were examined with and without adjustment for cardiovascular risk factors. After 5 years, there were 127 cardiovascular disease events, 48 myocardial infarctions or cardiovascular disease deaths and 28 strokes or stroke deaths. Total and incident cardiovascular disease event rates were higher in each quartile of CAC and CCA-IMT, but not ICA-IMT. For total cardiovascular disease, the adjusted hazard ratio for the 4th vs. 1st quartile of CAC was 2.1 (95% CI = 1.2−3.9) and for CCA-IMT was 2.3 (95% CI = 1.3−4.1). The CCA-IMT was more strongly related to stroke risk than was CAC, though CAC was also an important predictor of stroke. No significant sex differences were found, though relative risks appeared to be stronger in women, especially for stroke. In conclusion, in these adults > 70 years of age, CAC and CCA-IMT had similar hazard ratios for total cardiovascular disease and coronary heart disease. The CCA-IMT was more strongly related to stroke than was CAC, but CAC was also a predictor of stroke.
doi:10.1016/j.amjcard.2007.07.075
PMCID: PMC2213559  PMID: 18178404
calcium; cardiovascular diseases; coronary disease; prognosis
12.  Understanding Premature Atherosclerosis in Pediatric SLE: Risk Factors of Increased Carotid Intima Medial Thickness (CIMT) in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Cohort 
Arthritis and rheumatism  2009;60(5):1496-1507.
Objective
To evaluate risk factors of sub-clinical atherosclerosis in a pediatric SLE population.
Methods
A prospective multicenter cohort of 221 patients underwent baseline measurements of carotid intima medial thickening (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess thickness of the bilateral common carotids and mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT that were examined in multivariable linear regression modeling.
Results
Based on mean-mean common or mean-max CIMT as the dependent variable, univariable analysis showed significant associations with increased CIMT: increasing age, longer SLE duration, minority status, higher BMI, male sex, increased creatinine clearance, higher Lp(a), proteinuria, azathioprine use, and prednisone dose. Azathioprine use (P=0.005 for mean-mean common; P=0.102 for mean-max model) and male sex (P< 0.001) were both associated with increases in mean-max CIMT. Moderate dose prednisone (0.15–0.4 mg/kg/day) was associated with decreases in mean-max CIMT (P=0.024) while high or low dose prednisone was associated with mean-mean common CIMT (P=0.021) or mean-max CIMT (P=0.064), respectively. BMI (P<0.001) and creatinine clearance (P=0.031), remained associated with increased mean-mean common CIMT, while increasing age (P<0.001) and increasing Lp(a) (P=0.005) were associated with increased mean-max CIMT.
Conclusion
Traditional as well as non-traditional risk factors are associated with increased CIMT in pediatric SLE patients in this cohort. Azathioprine treatment was associated with increased CIMT. The relationship of CIMT with prednisone dose may not be linear.
doi:10.1002/art.24469
PMCID: PMC2770725  PMID: 19404953
13.  Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus 
Arthritis Research & Therapy  2010;12(6):R214.
Introduction
The risk of cardiovascular disease (CVD) and atherosclerosis is reported to be increased in systemic lupus erythematosus (SLE). We recently reported a negative association between natural IgM-antibodies against phosphorylcholine (anti-PC) in the general population, high anti-PC levels leading to decreased atherosclerosis development and low levels to increased risk of CVD. Potential mechanisms include anti-inflammatory properties and inhibition of uptake of oxidized low density lipoprotein (LDL) in macrophages. The objective herein was to study atherosclerosis in SLE in detail and in relation to traditional and non-traditional risk factors.
Methods
A total of 114 patients with SLE were compared with 122 age- and sex-matched population-based controls. Common carotid intima-media thickness (IMT), calculated intima-media area (cIMa) and plaque occurrence were determined by B-mode ultrasound as a surrogate measure of atherosclerosis. Plaques were graded according to echogenicity and grouped as 1 to 4, with 1 being echoluscent, and considered most vulnerable. Anti-PC was studied by ELISA.
Results
Hypertension, triglycerides and insulin resistance (determined by homeostasis model assessment of insulin resistance) and C-reactive protein (CRP) were increased in SLE (P < 0.01) while smoking, LDL, high density lipoprotein (HDL) did not differ between groups. Low levels of anti-PC IgM (lowest tertile) were more common in SLE patients than in controls (P = 0.0022). IMT and cIMa did not differ significantly between groups. However, plaques were more often found in SLE patients (P = 0.029). Age, LDL and IgM anti-PC (lowest tertile) were independently associated with plaque occurrence in SLE. Further, in the left carotid arteries echoluscent plaques (grade 1) were more prevalent in SLE as compared to controls (P < 0.016).
Conclusions
Plaque occurrence in the carotid arteries is increased in SLE and is independently associated with age, LDL and low anti-PC levels. Vulnerable plaques were more common in SLE. Anti-PC could be a novel risk marker also with a therapeutic potential in SLE.
doi:10.1186/ar3193
PMCID: PMC3046524  PMID: 21092251
14.  Walking speed and subclinical atherosclerosis in healthy older adults: the Whitehall II study 
Heart  2010;96(5):380-384.
Objective
Extended walking speed is a predictor of incident cardiovascular disease (CVD) in older individuals, but the ability of an objective short-distance walking speed test to stratify the severity of preclinical conditions remains unclear. This study examined whether performance in an 8-ft walking speed test is associated with metabolic risk factors and subclinical atherosclerosis.
Design
Cross-sectional.
Setting
Epidemiological cohort.
Participants
530 adults (aged 63±6 years, 50.3% male) from the Whitehall II cohort study with no known history or objective signs of CVD.
Main outcome
Electron beam computed tomography and ultrasound was used to assess the presence and extent of coronary artery calcification (CAC) and carotid intima-media thickness (IMT), respectively.
Results
High levels of CAC (Agatston score >100) were detected in 24% of the sample; the mean IMT was 0.75 mm (SD 0.15). Participants with no detectable CAC completed the walking course 0.16 s (95% CI 0.04 to 0.28) faster than those with CAC ≥400. Objectively assessed, but not self-reported, faster walking speed was associated with a lower risk of high CAC (odds ratio 0.62, 95% CI 0.40 to 0.96) and lower IMT (β=−0.04, 95% CI −0.01 to −0.07 mm) in comparison with the slowest walkers (bottom third), after adjusting for conventional risk factors. Faster walking speed was also associated with lower adiposity, C-reactive protein and low-density lipoprotein cholesterol.
Conclusions
Short-distance walking speed is associated with metabolic risk and subclinical atherosclerosis in older adults without overt CVD. These data suggest that a non-aerobically challenging walking test reflects the presence of underlying vascular disease.
doi:10.1136/hrt.2009.183350
PMCID: PMC2921267  PMID: 19955091
Ageing; atherosclerosis; computed tomography scanning; epidemiology; exercise testing; gait speed; imaging; physical function; risk stratification
15.  Elevated Fibrinogen Levels and Subsequent Subclinical Atherosclerosis: The CARDIA Study 
Atherosclerosis  2008;202(2):623-631.
Objective
To determine whether elevated levels of hemostatic factors are associated with the subsequent development of subclinical cardiovascular disease.
Methods
Fibrinogen, factors VII (FVII) and VIII (FVIII), and von Willebrand factor (vWF) were measured in 1396 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Coronary artery calcification (CAC) and carotid intimal/medial thickness (CIMT) were determined 13 years later. The adjusted prevalence of CAC and mean CIMT across the quartiles of each hemostatic factor was computed for the total sample and for each race and gender group.
Results
The age, race, and gender-adjusted prevalences of CAC with increasing quartiles of fibrinogen were 14.4%, 15.2%, 20.0%, and 29.1% (p<0.001 for trend). This trend persisted after further adjustment for body mass index (BMI), smoking, educational level, center, systolic blood pressure (BP), diabetes, antihypertensive medication use, total and high density lipoprotein (HDL) cholesterol, and CRP. A similar trend was observed for CIMT (age, race and gender-adjusted, p<0.001; multivariable-adjusted, p=0.014). Further analyses of race and gender subgroups showed that increasing quartiles of fibrinogen were associated with CAC and CIMT in all subgroups except black men. The prevalence of CAC was not associated with increasing quartiles of FVII, FVIII or vWF, suggesting they may be less involved in plaque progression.
Conclusion
An elevated fibrinogen concentration in persons aged 25 to 37 is independently associated with subclinical cardiovascular disease in the subsequent decade.
doi:10.1016/j.atherosclerosis.2008.05.039
PMCID: PMC2662501  PMID: 18602107
hemostatic factors; coronary calcium; carotid thickness; fibrinogen; atherosclerosis
16.  Inflammation induces fibrinogen nitration in experimental human endotoxemia 
Free radical biology & medicine  2009;47(8):1140-1146.
Elevated plasma fibrinogen is a prothrombotic risk factor for cardiovascular disease (CVD). Recent small studies report that fibrinogen oxidative modifications, specifically tyrosine residue nitration, can occur in inflammatory states and may modify fibrinogen function. HDL cholesterol is inversely related to CVD and suggested to reduce the oxidation of LDL cholesterol, but whether these antioxidant functions extend to fibrinogen modifications is unknown. We used a recently validated ELISA to quantify nitrated fibrinogen during experimental human endotoxemia (N=23) and in a cohort of healthy adults (N=361) who were characterized for inflammatory and HDL parameters as well as subclinical atherosclerosis measures, carotid artery intima-medial thickness (IMT) and coronary artery calcification (CAC). Fibrinogen nitration increased following endotoxemia and directly correlated with accelerated ex vivo plasma clotting velocity. In the observational cohort, nitrated fibrinogen was associated with levels of CRP and serum amyloid A. Nitrated fibrinogen levels were not lower with increasing HDL cholesterol and did not associate with IMT and CAC. In humans, fibrinogen nitration was induced during inflammation and was correlated with markers of inflammation and clotting function but not HDL cholesterol or subclinical atherosclerosis in our modest sample. Inflammation-induced fibrinogen nitration may be a risk factor for promoting CVD events.
doi:10.1016/j.freeradbiomed.2009.07.025
PMCID: PMC3651370  PMID: 19631267
Fibrinogen; Nitration; Intima-medial thickness; Coronary artery calcification; High-density lipoprotein (HDL)
17.  Association between depression and coronary artery calcification in women with systemic lupus erythematosus 
Rheumatology (Oxford, England)  2009;48(5):576-581.
Objectives. To determine the associations between depression, cardiovascular risk factors and coronary artery calcification (CAC) in women with SLE and controls.
Methods. CAC was measured using electron-beam CT (EBCT). Traditional, inflammatory and lupus-related risk factors as well as depressive symptoms (Center for Epidemiologic Studies Depression Scale—CES-D) were measured at a single study visit in 161 women with SLE and 161 age- and race frequency-matched female healthy controls.
Results. Women with SLE reported more depressive symptoms than controls, with 27% of SLE and 15% of controls having CES-D scores suggestive of clinical depression. SLE women were more likely to have CAC, as well as more severe CAC compared with controls. Among the SLE women, depression was associated with greater than 2-fold odds of having any CAC [odds ratio (OR) 2.48; 95% CI 1.05, 5.87; P = 0.04], independent of traditional risk factors (age, hypertension and triglycerides) and inflammatory markers. However, when BMI was included among the covariates, the association between depression and CAC was attenuated, indicating the potential mediating role of BMI. Depression was not a risk factor for CAC in controls.
Conclusions. In women with SLE, depression was associated with CAC. This association was mediated by BMI. Depression and adiposity may add to the inflammatory burden of SLE, thus contributing to cardiovascular disease risk.
doi:10.1093/rheumatology/kep020
PMCID: PMC2669765  PMID: 19286698
Systemic lupus erythematosus; Calcified tissue; Cardiovascular; Depression; CT scanning; Adipose tissue; Psychosocial factors; Risk factors; Inflammation
18.  Carotid Plaque, Carotid Intima-Media Thickness, and Coronary Calcification Equally Discriminate Prevalent Cardiovascular Disease in Kidney Disease 
American journal of nephrology  2012;36(4):342-347.
Background
Despite the significant morbidity and mortality attributable to cardiovascular disease (CVD), risk stratification remains an important challenge in the chronic kidney disease(CKD) population. We examined the discriminative ability of non-invasive measures of atherosclerosis, including carotid intima-media thickness(cIMT), carotid plaque, coronary artery calcification(CAC) and ascending and descending thoracic aorta calcification(TCAC), and Framingham Risk Score (FRS) to predict self-reported prevalent CVD.
Methods and Results
Participants were enrolled in the cIMT ancillary study of the Chronic Renal Insufficiency Cohort(CRIC) Study and also had all of the above measures within an 18 month period. CVD was present in 21% of study participants. C-statistics were used to ascertain the discriminatory power of each measure of atherosclerosis. The study population (n=220) was 64% male; 51% black and 45% white. The proportion of individuals with estimated glomerular filtration rate ≥60, 45–59, 30–44, and <30ml/min/1.73m2 was 21%, 41%, 28%, and 11%, respectively. In multivariable analyses adjusting for demographic factors, we failed to find a difference between CAC, carotid plaque, and cIMT as predictors of self-reported prevalent CVD (c-statistic 0.70, 95% confidence interval [CI]: 0.62–0.78; c-statistic 0.68, 95% CI: 0.60–0.75, and c-statistic 0.64, CI: 0.56–0.72, respectively). CAC was statistically better than FRS. FRS was the weakest discriminator of self-reported prevalent CVD (c-statistic 0.58).
Conclusions
There was a significant burden of atherosclerosis among individuals with CKD, ascertained by several different imaging modalities. We were unable to find a difference in the ability of CAC, carotid plaque, and cIMT to predict self-reported prevalent CVD.
doi:10.1159/000342794
PMCID: PMC3538165  PMID: 23107930
carotid intima media thickness; coronary artery calcification; kidney; plaque
19.  Coronary Artery Calcification Compared with Carotid Intima-Media Thickness in Prediction of Cardiovascular Disease Incidence: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Archives of internal medicine  2008;168(12):1333-1339.
Context
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence.
Objective
To assess whether maximum carotid IMT or CAC (Agatston Score) is the better predictor of incident CVD.
Design, Setting, Patients
Prospective cohort study of 45–84 year-olds initially free of CVD (n = 6,698) in four ethnic groups, with standardized carotid IMT and CAC measures at baseline, in six field centers of the Multi-Ethnic Study of Atherosclerosis (MESA).
Main Outcome Measure(s)
Incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up.
Results
There were 222 CVD events during follow-up. CAC was associated more strongly than carotid IMT with risk of incident CVD. After adjustment for each other and traditional CVD risk factors, the hazard of CVD increased 2.1-fold (95% CI 1.8–2.5) for each standard deviation greater level of log-transformed CAC, versus 1.3-fold (95% CI 1.1–1.4) for each standard deviation greater maximum IMT. For coronary heart disease, the hazard ratios per standard deviation increment were 2.5-fold (95% CI 2.1–3.1) for CAC and 1.2-fold (95% CI 1.0–1.4) for IMT. An ROC analysis also suggested that CAC predicted incident CVD better than IMT did.
Conclusions
Although whether and how to clinically use bio-imaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC predicts subsequent CVD events better than does carotid IMT.
doi:10.1001/archinte.168.12.1333
PMCID: PMC2555989  PMID: 18574091
20.  Factors Associated With Low Levels of Subclinical Vascular Disease in Older Adults: Multi-Ethnic Study of Atherosclerosis 
Preventive cardiology  2009;12(2):72-79.
Coronary artery calcium (CAC), carotid intimal medial thickness (cIMT), and reduced ankle brachial indices (ABI) are markers of subclinical vascular disease strongly associated with aging. We identified factors associated with low levels of subclinical vascular disease in 1824 participants ≥70 years in the Multi-Ethnic Study of Atherosclerosis. 452 had low CAC (<25th percentile), 441 had low cIMT (<25th percentile), 1636 had normal ABI (>0.9), and 165 had a combination index indicating favorable values for all three parameters. This combination index was independently associated with younger age [OR=2.5 per 1 SD (95%CI 1.8–3.6)], female gender [OR=3.0(1.9–4.8)], lower BMI [OR=1.6 per 1 SD (1.2–2.0)], absence of hypertension [OR=1.8(1.2–2.6)], absence of dyslipidemia [OR=1.6 (1.04–2.4)], and never smoking [OR=1.7(1.1–2.6)]. No significant associations were observed for C-reactive protein, education, diet, or physical activity. Favorable levels of multiple traditional risk factors, but not several novel risk factors, were associated with subclinical markers of successful cardiovascular aging.
doi:10.1111/j.1751-7141.2008.00023.x
PMCID: PMC2932469  PMID: 19476580
21.  Circulating CD34+ Cell Count is Associated with Extent of Subclinical Atherosclerosis in Asymptomatic Amish Men, Independent of 10-Year Framingham Risk 
Background
Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis.
Methods and Results
CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity (p = 0.03) and CIMT (p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: −77.8% to −9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: −20.1% to −8.1%) in CIMT.
Conclusions
Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process.
PMCID: PMC2856343  PMID: 20407620
atherosclerosis; carotid arteries; coronary artery calcification; epidemiology; risk factors
22.  Circulating CD34+ Cell Count is Associated with Extent of Subclinical Atherosclerosis in Asymptomatic Amish Men, Independent of 10-Year Framingham Risk 
Background:
Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis.
Methods and Results:
CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity (p = 0.03) and CIMT (p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: −77.8% to −9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: −20.1% to −8.1%) in CIMT.
Conclusions:
Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process.
PMCID: PMC2856343  PMID: 20407620
atherosclerosis; carotid arteries; coronary artery calcification; epidemiology; risk factors
23.  Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;200(2):359-367.
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
doi:10.1016/j.atherosclerosis.2007.12.038
PMCID: PMC3612981  PMID: 18243217
CETP; CVD; HDL; MESA
24.  The Epidemiology of Subclavian Stenosis and its Association with Markers of Subclinical Atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;211(1):266-270.
Background
Recent studies indicate that subclavian stenosis (SS), diagnosed by a large systolic blood pressure difference (SBPD) between the right and left brachial arteries, is associated with cardiovascular disease (CVD) risk factors and outcomes. We sought to describe the epidemiology of SS and determine its association with markers of subclinical CVD in the baseline cohort of the Multi-Ethnic Study of Atherosclerosis.
Methods
We defined SS by an absolute SBPD ≥15 mmHg. Peripheral artery disease (PAD) was defined by an ankle-brachial index ≤0.90. The coronary artery calcium score (CAC) and the common-carotid artery intima-media thickness (CCA-IMT) were measured by computed tomography and B-mode ultrasound, respectively. Odds ratios for the associations of SS with risk factors and subclinical disease were estimated using logistic regression.
Results
Of 6,743 subjects studied, 307 participants (4.6%) had SS, with a higher prevalence in women (5.1%) than men (3.9%), and in African-Americans (7.4%) and non-Hispanic whites (5.1%) than Hispanic (1.9%) or Chinese (1.0%) participants (p<0.01). In a model including age, gender, ethnicity, traditional and novel CVD risk factors, significant associations with SS were observed for C-reactive protein (highest vs. three lower quartiles: OR=1.41; 95%CI: 1.06-1.87) and brachial artery pulse pressure (OR=1.12 /10 mmHg; 95%CI: 1.03-1.21). Adjusted for age, gender, ethnicity, traditional and novel CVD risk factors, SS was significantly associated with PAD (OR=2.35; 1.55-3.56), with CCA-IMT (highest vs. the lower three quartiles: OR=1.32; 1.00-1.75), and high CAC (score >100 vs. score=0; OR=1.43; 1.03-2.01).
Conclusions
The subclavian stenosis is positively associated with other markers of subclinical atherosclerosis.
doi:10.1016/j.atherosclerosis.2010.01.013
PMCID: PMC2925848  PMID: 20138280
subclavian artery; blood pressure; atherosclerosis; epidemiology
25.  Risk Factors Associated with Aortic and Carotid Intimal-Medial Thickness in Adolescents and Young Adults: the Muscatine Offspring Study 
Objectives
To determine whether cardiovascular risk factors are associated with aortic and carotid intimal-medial thickness (aIMT and cIMT) in adolescents and young adults.
Background
Atherosclerotic lesions begin developing in youth, first in the distal abdominal aorta and later in the carotid arteries. Knowledge of how risk factors relate to aIMT and cIMT may help in the design of early interventions to prevent cardiovascular disease.
Methods
Participants were 635 members of the Muscatine Offspring cohort. The mean aIMT and cIMT were measured using an automated reading program.
Results
The means (SDs) of aIMT and cIMT were 0.63 (0.14) mm and 0.49 (0.04) mm, respectively. In adolescents (ages 11 to 17), aIMT was associated with triglycerides, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist/hip ratio, after adjusting for age, gender, and height. In young adults (ages 18 to 34), aIMT was associated with those same five risk factors, plus HDL-cholesterol and pulse pressure. In adolescents, cIMT was associated with SBP, pulse pressure, heart rate, BMI, and waist/hip ratio. In young adults, cIMT was associated total cholesterol, LDL-cholesterol, triglycerides, SBP, .DBP, BMI, waist/hip ratio, and HbA1C. In both age groups, aIMT and cIMT were significantly correlated with the PDAY coronary artery risk score.
Conclusions
Both aIMT and cIMT are associated with cardiovascular risk factors. Using aIMT in adolescents gives information beyond that obtained from cIMT alone. Measurement of aIMT and cIMT may help identify those at risk for premature cardiovascular disease.
doi:10.1016/j.jacc.2009.03.026
PMCID: PMC2747309  PMID: 19520251
Atherosclerosis; Ultrasound; Preclinical disease; Abdominal aorta; IMT

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