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1.  Cortisol Responses to Mental Stress and the Progression of Coronary Artery Calcification in Healthy Men and Women 
PLoS ONE  2012;7(2):e31356.
Psychosocial stress is a risk factor for coronary heart disease (CHD). The mechanisms are incompletely understood, although dysfunction of the hypothalamic pituitary adrenal (HPA) axis might be involved. We examined the association between cortisol responses to laboratory-induced mental stress and the progression of coronary artery calcification (CAC).
Methods and Results
Participants were 466 healthy men and women (mean age = 62.7±5.6 yrs), without history or objective signs of CHD, drawn from the Whitehall II epidemiological cohort. At the baseline assessment salivary cortisol was measured in response to mental stressors, consisting of a 5-min Stroop task and a 5-min mirror tracing task. CAC was measured at baseline and at 3 years follow up using electron beam computed tomography. CAC progression was defined as an increase >10 Agatston units between baseline and follow up. 38.2% of the sample demonstrated CAC progression over the 3 years follow up. There was considerable variation in the cortisol stress response, with approximately 40% of the sample responding to the stress tasks with an increase in cortisol of at least 1 mmol/l. There was an association between cortisol stress reactivity (per SD) and CAC progression (odds ratio = 1.27, 95% CI, 1.02–1.60) after adjustments for age, sex, pre-stress cortisol, employment grade, smoking, resting systolic BP, fibrinogen, body mass index, and use of statins. There was no association between systolic blood pressure reactivity and CAC progression (odds ratio per SD increase = 1.03, 95% CI, 0.85–1.24). Other independent predictors of CAC progression included age, male sex, smoking, resting systolic blood pressure, and fibrinogen.
Results demonstrate an association between heightened cortisol reactivity to stress and CAC progression. These data support the notion that cortisol reactivity, an index of HPA function, is one of the possible mechanisms through which psychosocial stress may influence the risk of CHD.
PMCID: PMC3273460  PMID: 22328931
2.  Do Neighborhood Socioeconomic Deprivation and Low Social Cohesion Predict Coronary Calcification? 
American Journal of Epidemiology  2010;172(3):288-298.
Growing evidence suggests that neighborhood characteristics may influence the risk of coronary heart disease. No studies have yet explored associations of neighborhood attributes with subclinical atherosclerosis in younger adult populations. Using data on 2,974 adults (1,699 women, 1,275 men) aged 32–50 years in 2000 from the Coronary Artery Disease Risk Development in Young Adults (CARDIA) Study and 2000 US Census block-group-level data, the authors estimated multivariable-adjusted associations of neighborhood socioeconomic deprivation and perceived neighborhood cohesion with odds of coronary artery calcification (CAC) 5 years later. Among women, the quartiles of highest neighborhood deprivation and lowest cohesion were associated with higher odds of CAC after adjustment for individual-level demographic and socioeconomic factors (for deprivation, odds ratio = 2.49, 95% confidence interval: 1.22, 5.08 (P for trend = 0.03); for cohesion, odds ratio = 1.87, 95% confidence interval: 1.10, 3.16 (P for trend = 0.02)). Associations changed only slightly after adjustment for behavioral, psychosocial, and biologic factors. Among men, neither neighborhood deprivation nor cohesion was related to CAC. However, among men in deprived neighborhoods, low cohesion predicted higher CAC odds (for interaction between neighborhood deprivation and cohesion, P = 0.03). This study provides evidence on associations of neighborhood deprivation and cohesion with CAC in younger, asymptomatic adults. Neighborhood attributes may contribute to subclinical atherosclerosis.
PMCID: PMC2917055  PMID: 20610467
atherosclerosis; coronary disease; residence characteristics; risk factors; social environment
3.  Association Between Duration of Overall and Abdominal Obesity Beginning in Young Adulthood and Coronary Artery Calcification in Middle Age 
JAMA  2013;310(3):280-288.
Younger individuals are experiencing a greater cumulative exposure to excess adiposity over their lifetime. However, few studies have determined the consequences of long-term obesity.
To examine whether the duration of overall and abdominal obesity was associated with the presence and 10-year progression of coronary artery calcification (CAC), a subclinical predictor of coronary heart disease.
Prospective study of 3275 white and black adults aged 18 to 30 years at baseline in 1985–1986 who did not initially have overall obesity (body mass index [BMI] ≥30) or abdominal obesity (men: waist circumference [WC] >102 cm; women: >88 cm) in the multicenter, community-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants completed computed tomography scanning for the presence of CAC during the 15-, 20-, or 25-year follow-up examinations. Duration of overall and abdominal obesity was calculated using repeat measurements of BMI and WC, respectively, performed 2, 5, 7, 10, 15, 20, and 25 years after baseline.
Presence of CAC was measured by computed tomography at the year 15 (2000–2001), year 20 (2005–2006), or year 25 (2010–2011) follow-up examinations. Ten-year progression of CAC (2000–2001 to 2010–2011) was defined as incident CAC in 2010–2011 or an increase in CAC score of 20 Agatston units or greater.
During follow-up, 40.4% and 41.0% developed overall and abdominal obesity, respectively. Rates of CAC per 1000 person-years were higher for those who experienced more than 20 years vs 0 years of overall obesity (16.0 vs 11.0, respectively) and abdominal obesity (16.7 vs 11.0). Approximately 25.2% and 27.7% of those with more than 20 years of overall and abdominal obesity, respectively, experienced progression of CAC vs 20.2% and 19.5% of those with 0 years. After adjustment for BMI or WC and potential confounders, the hazard ratios for CAC for each additional year of overall or abdominal obesity were 1.02 (95% CI, 1.01–1.03) and 1.03 (95% CI, 1.02–1.05), respectively. The adjusted odds ratios for CAC progression were 1.04 (95% CI, 1.01–1.06) and 1.04 (95% CI, 1.01–1.07), respectively. Associations were attenuated but largely persisted following additional adjustment for potential intermediate metabolic factors during follow-up.
Longer duration of overall and abdominal obesity was associated with subclinical coronary heart disease and its progression through midlife independent of the degree of adiposity. Preventing or at least delaying the onset of obesity in young adulthood may lower the risk of developing atherosclerosis through middle age.
PMCID: PMC4226407  PMID: 23860986
4.  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.
PMCID: PMC3167681  PMID: 21685409
calcification, physiologic; continental population groups; coronary vessels; sex; social class
5.  The Association Between Physical Activity and Both Incident Coronary Artery Calcification and Ankle Brachial Index Progression: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2013;230(2):278-283.
Both coronary artery calcification (CAC) and the ankle brachial index (ABI) are measures of subclinical atherosclerotic disease. The influence of physical activity on the longitudinal change in these measures remains unclear. To assess this we examined the association between these measures and self-reported physical activity in the Multi-Ethnic Study of Atherosclerosis (MESA).
At baseline, the MESA participants were free of clinically evident cardiovascular disease. We included all participants with an ABI between 0.90 and 1.40 (n=5656). Predictor variables were based on self-reported measures with physical activity being assessed using the Typical Week Physical Activity Survey from which metabolic equivalent-minutes/week of activity were calculated. We focused on physical activity intensity, intentional exercise, sedentary behavior, and conditioning. Incident peripheral artery disease (PAD) was defined as the progression of ABI to values below 0.90 (given the baseline range of 0.90 to 1.40). Incident CAC was defined as a CAC score >0 Agatston units upon follow up with a baseline score of 0 Agatston units.
Mean age was 61 years, 53% were female, and mean body mass index was 28 kg/m2. After adjusting for traditional cardiovascular risk factors and socioeconomic factors, intentional exercise was protective for incident peripheral artery disease (Relative Risk (RR)= 0.85, 95% Confidence Interval (CI): 0.74 to 0.98). After adjusting for traditional cardiovascular risk factors and socioeconomic factors, there was a significant association between vigorous PA and incident CAC (RR=0.97, 95% CI: 0.94 to 1.00). There was also a significant association between sedentary behavior and increased amount of CAC among participants with CAC at baseline (Δlog(Agatston Units +25)=0.027, 95% CI 0.002, 0.052).
These data suggest that there is an association between physical activity/sedentary behavior and the progression of two different measures of subclinical atherosclerotic disease.
PMCID: PMC4085097  PMID: 24075757
Ankle Brachial Index; Coronary Artery Calcification; Physical Activity; Epidemiology; Prospective Cohort Study
6.  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
7.  The Associations of Fetuin-A with Subclinical Cardiovascular Disease in Community-Dwelling Persons: the Rancho Bernardo Study 
To determine the association of fetuin-A with subclinical CVD in community-living individuals.
Fetuin-A is a hepatic secretory protein that inhibits arterial calcium deposition in vitro. Lower fetuin-A levels are associated with arterial calcification and death in end-stage renal disease populations. The association of fetuin-A with subclinical cardiovascular disease (CVD) in the general population is unknown.
Among 1,375 community-living individuals without prevalent clinical CVD, we measured plasma fetuin-A concentrations measured by ELISA. Peripheral arterial disease (PAD) was defined by ankle brachial index (ABI) < 0.90, coronary artery calcification (CAC) was measured by computed tomography, and common and internal intima media thickness (cIMT) were measured by carotid ultrasound. PAD was measured concurrent with fetuin-A, and CAC and cIMT was measured 4.6 years (mean) later.
Mean age was 70 ± 11 years and 64% were female. Fetuin-A levels were inversely associated with CAC severity. When evaluated as CAC categories (0, 1–100, 101–300, > 300) using ordinal logistic regression, each standard deviation higher fetuin-A was associated with a 31% lower odds of CAC severity (proportional odds ratio [POR] 0.69; 95% confidence interval [CI] 0.46, 0.92; p=0.008) in models adjusted for demographics, lifestyle factors, traditional CVD risk factors and kidney function. In contrast, no association of fetuin-A was observed with PAD or high common or internal cIMT in adjusted models.
Lower fetuin-A levels are independently associated with greater CAC severity, but not PAD or cIMT. If confirmed, fetuin-A may mark calcium deposition within the vasculature, but not atherosclerosis per se.
PMCID: PMC3224791  PMID: 22115642
Fetuin-A; Cardiovascular Disease; Coronary Artery Calcification
8.  Walking speed and subclinical atherosclerosis in healthy older adults: the Whitehall II study 
Heart  2010;96(5):380-384.
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.
Epidemiological cohort.
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.
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.
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.
PMCID: PMC2921267  PMID: 19955091
Ageing; atherosclerosis; computed tomography scanning; epidemiology; exercise testing; gait speed; imaging; physical function; risk stratification
9.  Self-reported and accelerometer physical activity levels and coronary artery calcification progression in older women: Results from the Healthy Women Study 
Menopause (New York, N.Y.)  2013;20(2):152-161.
Regardless of the well-supported biological link between PA and atherosclerosis, most previous studies report a null association between PA and CAC. To examine the relation between physical activity (PA) and coronary artery calcification (CAC) progression in 148 Healthy Women Study (HWS) participants over 28 years of observation.
The HWS was designed to examine cardiovascular risk factor changes from pre- to post-menopause. Based on CAC scores collected at two follow-up visits (EBT1 and EBT4) scheduled 12 years apart, participants were classified into one of three groups: 1) no detectable CAC (n=37; 0 CAC at both visits), 2) incident CAC (n=46; 0 CAC at the first- and >0 CAC at the last- visit), or 3) prevalent CAC (n=65; >0 CAC at both visits). PA data were collected regularly throughout the study using self-report questionnaires and accelerometers at EBT4.
The percentage of HWS participants with no detectible CAC decreased from 56.1% at EBT1 to 25.0% at EBT4. Time spent per day in accumulated and bouts of moderate- to vigorous-intensity (MV)PA were each significantly higher in the no detectable CAC group when compared to the prevalent CAC group (both p≤.01). After covariate adjustment, these differences remained statistically significant (both p<.05). Although self-reported summary estimates collected throughout the study were significantly associated with accelerometer data at EBT4, there were no significant differences in self-reported physical activity levels by CAC groups after covariate adjustment.
Study findings suggest that low levels of accelerometer-derived MVPA may be indicative of subclinical disease in older women.
PMCID: PMC3897237  PMID: 22914209
coronary heart disease; motor activity; ambulatory monitoring; coronary calcification; women
10.  Association of sICAM-1 and MCP-1 with coronary artery calcification in families enriched for coronary heart disease or hypertension: the NHLBI Family Heart Study 
Data accumulated from mouse studies and in vitro studies of human arteries support the notion that soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play important roles in the inflammation process involved in atherosclerosis. However, at the population level, the utility of sICAM-1 and MCP-1 as biomarkers for subclinical atherosclerosis is less clear. In the follow-up exam of the NHLBI Family Heart Study, we evaluated whether plasma levels of sICAM-1 and MCP-1 were associated with coronary artery calcification (CAC), a measure of the burden of coronary atherosclerosis.
CAC was measured using the Agatston score with multidetector computed tomography. Information on CAC and MCP-1 was obtained in 2246 whites and 470 African Americans (mean age 55 years) without a history of coronary heart disease (CHD). Information on sICAM-1 was obtained for white participants only.
In whites, after adjustment for age and gender, the odds ratios (ORs) of CAC (CAC > 0) associated with the second, third, fourth, and fifth quintiles of sICAM-1 compared to the first quintile were 1.22 (95% confidence interval [CI]: 0.91–1.63), 1.15 (0.84–1.58), 1.49 (1.09–2.05), and 1.72 (1.26–2.36) (p = 0.0005 for trend test), respectively. The corresponding ORs for the second to fifth quintiles of MCP-1 were 1.26 (0.92–1.73), 0.99 (0.73–1.34), 1.42 (1.03–1.96), and 2.00 (1.43–2.79) (p < 0.0001 for trend test), respectively. In multivariable analysis that additionally adjusted for other CHD risk factors, the association of CAC with sICAM-1 and MCP-1 was attenuated and no longer statistically significant. In African Americans, the age and gender-adjusted ORs of CAC associated with the second and third tertiles of MCP-1 compared to the first tertile were 1.16 (0.64–2.08) and 1.25 (0.70–2.23) (p = 0.44 for trend test), respectively. This result did not change materially after additional adjustment for other CHD risk factors. Test of race interaction showed that the magnitude of association between MCP-1 and CAC did not differ significantly between African Americans and whites. Similar results were obtained when CAC ≥ 10 was analyzed as an outcome for both MCP-1 and sICAM-1.
This study suggests that sICAM-1 and MCP-1 are biomarkers of coronary atherosclerotic burden and their association with CAC was mainly driven by established CHD risk factors.
PMCID: PMC2204036  PMID: 17963506
11.  Self-reported racial discrimination, response to unfair treatment, and coronary calcification in asymptomatic adults - the North Texas Healthy Heart study 
BMC Public Health  2010;10:285.
Accruing evidence supports the hypothesis that psychosocial factors are related to cardiovascular disease. However, a limited number of studies have investigated the pathophysiologic pathways through which these associations occur. The purpose of this study was to assess whether experiences of self-reported racial discrimination and reactions to unfair treatment were associated with coronary artery calcification (CAC), an indicator of subclinical coronary heart disease (CHD).
This cross-sectional study recruited 571 subjects (45 years and older) who were asymptomatic of CHD from Fort Worth, Texas from 2006 to 2008. Subjects completed a questionnaire, a multi-slice computed tomography scan to assess for CAC presence (measured as Agatston score >0), and serum chemistries. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between self-reported discrimination and CAC. Results were stratified by response to unfair treatment as it was found to significantly modify the relationship between discrimination and CAC.
Among those who passively responded to unfair treatment, the odds of having CAC present were approximately 3 times higher for those experiencing discrimination (OR, 2.95; 95% CI, 1.19-7.32) after adjusting for age, gender, race/ethnicity, education, body mass index, hyperlipidemia, smoking status, hypertension, diabetes, and first degree relative with heart disease.
This is the first multi-racial/ethnic study to find racial discrimination associated with CAC, which differs based on how one responds to unfair treatment.
PMCID: PMC2887822  PMID: 20507602
12.  Carotid artery plaque and progression of coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis 
Carotid and coronary atherosclerosis are associated to each other in imaging and autopsy studies. We evaluated whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC).
Materials and Methods
We repeated Agatston calcium score measurements in 5445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 57.9 years; 62.9% female). Internal carotid artery lesions were graded as 0%, 1-24%, >25% diameter narrowing and intima-media thickness (IMT) was measured. Plaque was present for any stenosis > 0%. CAC progression was evaluated with multivariable relative risk regression in cases with CAC = 0 at baseline and with multivariable linear regression for CAC > 0 adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT.
CAC was positive at baseline in 2708/5445 (49.7%) participants and became positive in 458/2837 (16.1%) at mean interval of 2.4 years between repeat examinations. Plaque and ICA IMT were both strongly associated with presence of CAC. After statistical adjustment, presence of carotid artery plaque significantly predicted incident CAC with a relative risk(RR) of 1.37 (95% Confidence Intervals: 1.12, 1.67). Incident CAC was associated with ICA IMT with an RR of 1.13 (95% Confidence Intervals: 1.03, 1.25) for each mm increase. Progression of CAC was also significantly associated (p < 0.001) with plaque and ICA IMT.
In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.
PMCID: PMC4084492  PMID: 23522805
13.  Differences in Prevalence and Severity of Coronary Artery Calcification between Two Non-Hispanic White Populations with Diverse Lifestyles 
Atherosclerosis  2007;196(2):888-895.
Comparison of atherosclerosis and its risk factors among diverse populations may provide insights into the pathogenesis of the disease. We investigated differences in traditional coronary artery disease (CAD) risk factors and presence and quantity of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis, between two diverse non-Hispanic white populations living in the US.
Methods and Results
Members of the Old Order Amish (OOA), a unique culture with a physically active rural lifestyle who rarely use prescription medications, were compared to another non-Hispanic white population with a more typical US lifestyle, Epidemiology of Coronary Artery Calcification (ECAC) Study participants from Rochester, Minnesota. Although age- and sex-adjusted presence and quantity of CAC in those with detectable CAC were similar between study groups, there were significant differences in the distribution of many traditional CAD risk factors. OOA had significantly less abdominal adiposity and history of cigarette smoking but a less advantageous lipid profile than ECAC participants. Importantly, after adjusting for CAD risk factors, presence of CAC and quantity of CAC among those with detectable CAC were significantly higher among OOA than ECAC participants.
Identification of factors contributing to differences in subclinical disease across groups could increase our understanding of mechanisms for coronary atherosclerosis.
PMCID: PMC2277512  PMID: 17368463
Coronary Artery Calcification; Atherosclerosis; Epidemiology; Risk Factors; Imaging; Lifestyle
14.  Coronary Artery Calcification in Obese Youth: What Are the Phenotypic and Metabolic Determinants? 
Diabetes Care  2014;37(9):2632-2639.
Obesity in adolescence has been associated with increased risk for coronary heart disease in adulthood. This study evaluated subclinical atherosclerosis in obese youth and the underlying risk factors.
Ninety obese adolescents (37 normal glucose tolerant, 27 prediabetes, and 26 type 2 diabetes) underwent evaluation of coronary artery calcifications (CACs) by electron beam computed tomography, aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT), lipids, leptin, inflammatory markers, and body composition (DEXA). A total of 68 underwent evaluation of insulin sensitivity (IS) (hyperinsulinemic-euglycemic clamp) and abdominal adiposity (computed tomography).
A total of 50% had CACs (CAC+: Agatston CAC score ≥1). CAC+ youth had higher BMI, fat mass, and abdominal fat, with no difference in sex, race, IS per fat-free mass (ISFFM), glucose tolerance, PWV, or IMT compared with the CAC− group. PWV was inversely related to IS. In multiple regression analyses with age, race, sex, HbA1c, BMI (or waist circumference), ISFFM, diastolic blood pressure, non–HDL cholesterol, and leptin as independent variables, BMI (or waist) (R2 = 0.41; P = 0.001) was the significant determinant of CAC; leptin (R2 = 0.37; P = 0.034) for PWV; and HbA1c, race, and age (R2 = 0.34; P = 0.02) for IMT.
Early in the course of obesity, there is evidence of CAC independent of glycemia. The different biomarkers of subclinical atherosclerosis appear to be differentially modulated, adiposity being the major determinant of CAC, hyperglycemia, age, and race for IMT, and leptin and IS for arterial stiffness. These findings highlight the increased cardiovascular disease risk in obese youth and the need for early interventions to reverse obesity and atherosclerosis.
PMCID: PMC4392940  PMID: 25147256
15.  Coronary Artery Calcification and Myocardial Perfusion in Asymptomatic Adults: The MESA (Multi-Ethnic Study of Atherosclerosis) 
This study assessed the cross-sectional association between coronary artery calcification (CAC) and myocardial perfusion in an asymptomatic population.
Clinical studies showed that the prevalence of stress-induced ischemia increased with CAC burden among patients with coronary heart disease (CHD). Whether an association between CAC and myocardial perfusion exists in subjects without a history of CHD remains largely unknown.
A total of 222 men and women, ages 45 to 84 years old and free of CHD diagnosis, in the Minnesota field center of the MESA (Multi-Ethnic Study of Atherosclerosis) were studied. Myocardial blood flow (MBF) was measured using magnetic resonance imaging during rest and adenosine-induced hyperemia. Perfusion reserve was calculated as the ratio of hyperemic to resting MBF. Agatston CAC score was determined from chest multidetector computed tomography.
Mean values of hyperemic MBF and perfusion reserve, but not resting MBF, were monotonically lower across increasing CAC levels. After adjusting for age and gender, odds ratios (95% confidence intervals) of reduced perfusion reserve (<2.5) for subjects with CAC scores of 0, 0.1 to 99.9, 100 to 399, and ≥400 were 1.00 (reference), 2.16 (0.96 to 4.84), 2.81 (1.04 to 7.58), and 4.99 (1.73 to 14.4), respectively. Further adjustment for other coronary risk factors did not substantially modify the association. However, the inverse association between perfusion reserve and CAC attenuated with advancing age (p for interaction < 0.05).
Coronary vasodilatory response was associated inversely with the presence and severity of CAC in asymptomatic adults. Myocardial perfusion could be impaired by or manifest the progression to subclinical coronary atherosclerosis in the absence of clinical CHD.
PMCID: PMC1853335  PMID: 16949496
16.  Independent Association Between Obstructive Sleep Apnea and Subclinical Coronary Artery Disease 
Chest  2008;133(4):927-933.
Obstructive sleep apnea (OSA) is associated with coronary risk factors, but it is unknown if OSA is associated with development of coronary disease. We evaluated the association between OSA and the presence of subclinical coronary disease assessed by coronary artery calcification (CAC).
Consecutive patients with no history of coronary disease, who underwent electron-beam computed tomography within 3 years of polysomnography between March 1991 and December 2003, were included. OSA was defined by an apnea-hypopnea index (AHI) ≥ 5, and patients were grouped by quartiles of AHI severity. Logistic regression modeled the association between OSA severity and presence of CAC.
There were 202 patients (70% male, median age 50, mean body mass index 32, 8% diabetic, 9% current smokers, 60% hypercholesterolemic, and 47% hypertensive). OSA was present in 76%. CAC was present in 67% of OSA patients and 31% of non-OSA patients (p<0.001). The median CAC score (Agatston Units) was 9 in OSA patients and 0 in non-OSA patients (p<0.001). The median CAC score was higher as OSA severity increased (p for trend by AHI quartile<0.001). With multivariate adjustment, the odds ratio for CAC increased with OSA severity. Using the first AHI quartile as reference, the adjusted odds ratio for the second, third, and fourth quartiles were 2.1 (p=0.12), 2.4 (p=0.06), and 3.3 (p=0.03) respectively.
In patients without clinical coronary disease, the presence and severity of OSA is independently associated with the presence and extent of CAC. OSA identifies patients at risk for coronary disease and may represent a highly prevalent modifiable risk factor.
PMCID: PMC2831406  PMID: 18263678
Calcium; Coronary artery disease; Obstructive sleep apnea; Risk factors
17.  Shared Genetic Architecture in the Relationship between Adult Stature and Subclinical Coronary Artery Atherosclerosis 
Atherosclerosis  2011;219(2):679-683.
Short stature is associated with increased risk of coronary heart disease (CHD); although the mechanisms for this relationship are unknown, shared genetic factors have been proposed. Subclinical atherosclerosis, measured by coronary artery calcification (CAC), is associated with CHD events and represents part of the biological continuum to overt CHD. Many molecular mechanisms of CAC development are shared with bone growth. Thus, we examined whether there was evidence of shared genes (pleiotropy) between adult stature and CAC.
877 asymptomatic white adults (46% men) from 625 families in a community-based sample had computed tomography measures of CAC. Pleiotropy between height and CAC was determined using maximum-likelihood estimation implemented in SOLAR.
Adult height was significantly and inversely associated with CAC score (P=0.01). After adjusting for age, sex, and CHD risk factors, the estimated genetic correlation between height and CAC score was -0.37 and was significantly different than 0 (P=0.001) and -1 (P<0.001). The environmental correlation between height and CAC score was 0.60 and was significantly different than 0 (P=0.024).
Further studies of shared genetic factors between height and CAC may provide important insight into the complex genetic architecture of CHD, in part through increased understanding of the molecular pathways underlying the process of both normal growth and disease development. Bivariate genetic linkage analysis may provide a powerful mechanism for identifying specific genomic regions associated with both height and CAC.
PMCID: PMC3226925  PMID: 21937044
Genetics; Atherosclerosis; Calcium; Imaging; Stature
18.  Progression of Coronary Artery Calcification in Black and White Women: Do the Stresses and Rewards of Multiple Roles Matter? 
Black women experience higher rates of cardiovascular disease (CVD) than white women, though evidence for racial differences in subclinical CVD is mixed. Few studies have examined multiple roles (number, perceived stress, and/or reward) in relation to subclinical CVD, or whether those effects differ by race.
To investigate the effects of multiple roles on 2-year progression of coronary artery calcification (CAC).
Subjects were 104 black and 232 white women (mean age 50.8 years). Stress and reward from four roles (spouse, parent, employee, caregiver) were assessed on 5-point scales. CAC progression was defined as an increase of ≥10 Agatston units.
White women reported higher rewards from their multiple roles than black women, yet black women showed cardiovascular benefits from role rewards. Among black women only, higher role rewards were related significantly to lower CAC progression, adjusting for BMI, blood pressure, and other known CVD risk factors. Blacks reported fewer roles but similar role stress as whites; role number and stress were unrelated to CAC progression.
Rewarding roles may be a novel protective psychosocial factor for progression of coronary calcium among black women.
PMCID: PMC3586734  PMID: 21901270
multiple roles; role stress; role reward; women; middle-aged; coronary artery calcium
19.  Coronary artery calcification by computed tomography in epidemiological research and cardiovascular disease prevention 
Journal of Epidemiology  2012;22(3):188-198.
Both American and European guidelines recommend coronary artery calcification (CAC) as a tool for screening asymptomatic individuals at intermediate risk. These recommendations are based on epidemiological studies mostly in the United States (U.S.). We review (1) the use of CAC in primary prevention of coronary heart disease (CHD) in the U.S., (2) epidemiological studies of CAC in asymptomatic adults outside of the U.S., and (3) international epidemiological studies of CAC. This review does not consider clinical studies of CAC among patients or symptomatic individuals. Studies in the U.S. have documented that CAC is a strong independent predictor of CHD for both sexes, middle- to old-age groups, various ethnic groups, and diabetics and non-diabetics and that CAC plays an important role in reclassifying individuals at intermediate into high risk. Studies in Europe support these conclusions. The Electron-Beam Tomography, Risk factor Assessment among Japanese and U.S. men in the post-World-War-II birth cohort (ERA JUMP) Study is the first international research comparing subclinical atherosclerosis including CAC in Japanese, Japanese Americans, Koreas, and Caucasians. The study has demonstrated that Japanese had lower levels of atherosclerosis compared to Caucasians whereas Japanese Americans compared to Caucasians had similar or higher levels. CAC is being established as a screening tool for asymptomatic individuals in Europe and the U.S. CAC is a powerful research tool, enabling us to describe the difference in atherosclerotic burden across populations. Such research could elucidate factors responsible for the population difference, which may lead to prevention of CHD.
PMCID: PMC3362675
20.  Coronary Artery Calcification by Computed Tomography in Epidemiologic Research and Cardiovascular Disease Prevention 
Journal of Epidemiology  2012;22(3):188-198.
Both American and European guidelines recommend coronary artery calcification (CAC) as a tool for screening asymptomatic individuals at intermediate risk for coronary heart disease (CHD). These recommendations are based on epidemiologic studies mostly in the United States. We review (1) the use of CAC in primary prevention of CHD in the United States, (2) epidemiologic studies of CAC in asymptomatic adults outside of the United States, and (3) international epidemiologic studies of CAC. This review will not consider clinical studies of CAC among patients or symptomatic individuals. US studies have shown that CAC is a strong independent predictor of CHD in both sexes among middle-aged and old age groups, various ethnic groups, and individuals with and without diabetes and that CAC plays an important role in reclassifying individuals from intermediate to high risk. Studies in Europe support these conclusions. The Electron-Beam Tomography, Risk Factor Assessment Among Japanese and US Men in the Post-World-War-II birth cohort (ERA JUMP) Study is the first international study to compare subclinical atherosclerosis, including CAC among Japanese, Japanese Americans, Koreans, and whites. It showed that as compared with whites, Japanese had lower levels of atherosclerosis, whereas Japanese Americans had similar or higher levels. CAC is being increasingly used as a screening tool for asymptomatic individuals in Europe and the United States. CAC is a powerful research tool, because it enables us to describe differences in atherosclerotic burden across populations. Such research could identify factors responsible for differences among populations, which may improve CHD prevention.
PMCID: PMC3798619  PMID: 22485011
coronary artery calcification; primary prevention; coronary calcium score; EBCT; MDCT
21.  Renal Function Is Related to Severity of Coronary Artery Calcification in Elderly Persons: The Rotterdam Study 
PLoS ONE  2011;6(2):e16738.
Coronary artery calcification (CAC) has been proposed to be the underlying mechanism of the increased risk of coronary heart disease with reductions in glomerular filtration rate (GFR). Since renal function diminishes with aging we examined the association between GFR and CAC in the Rotterdam Study, a population-based study of elderly individuals.
The study was performed in 1703 subjects without a history of coronary heart disease. GFR was estimated using the modification of diet in renal disease equation. We used analysis of covariance to test for mean differences in CAC between GFR tertiles.
The mean CAC scores in the middle and lowest GFR tertile did not significantly differ from the mean CAC score in the highest GFR tertile (geometric mean CAC score 4.1 and 4.3 vs 4.2). In a multivariable model the mean CAC score did also not differ between the GFR tertiles. As the interaction term between age and GFR was significant (P = 0.037), we divided the population in two age categories based on median age of 70 years. Below 70 years, the mean CAC scores did not differ between the GFR tertiles. Above median age, mean CAC score in the lowest GFR tertile was significantly higher than the mean CAC score in the highest tertile in a multivariable model (CAC 4.9 vs 4.5, p = 0.010).
In this population-based study we observed that the association between CAC and GFR is modified by age. In participants at least 70 years of age, a decrease in GFR was associated with increased CAC.
PMCID: PMC3032739  PMID: 21311747
22.  Skin Fluorescence Correlates Strongly with Coronary Artery Calcification Severity in Type 1 Diabetes 
Coronary artery calcification (CAC) is more severe and occurs at an earlier age in type 1 diabetes. Risk factors for this subclinical marker of atherosclerotic burden, like coronary artery disease (CAD) itself, are not fully identified. One postulated mechanism for the increased CAC observed in type 1 diabetes is the accumulation of advanced glycation end products (AGEs). As certain collagen AGEs fluoresce, skin intrinsic fluorescence (SIF) can act as a novel marker of levels of collagen AGEs. We thus sought to determine the relationship between skin intrinsic fluorescence and CAC in type 1 diabetes.
One hundred five participants in the Pittsburgh Epidemiology of Diabetes Complications study of childhood-onset (age <17 years) type 1 diabetes who had previously undergone electron beam tomography scanning for CAC (80 of whom had follow-up data) had SIF measurements taken using the SCOUT DM® (VeraLight, Inc., Albuquerque, NM). Mean age and diabetes' duration were 49 and 40 years, respectively, at the time of SIF measurement.
Seventy-one percent of the study participants had some measurable CAC that was univariately (but not after age adjustment) cross-sectionally associated with SIF (odds ratio = 2.51, 1.37–4.59). However, for CAC severity using natural logarithmically transformed scores, SIF was both univariately (P < 0.0001) and multivariably (P = 0.03) associated with CAC. This relationship was independent of age, a history of CAD, renal function, or renal damage. Receiver operator characteristic analyses revealed that the discriminative ability of SIF to detect CAC went from an area under the curve of 71% for the presence of any CAC to 85% for those with a CAC score >400.
The relationship between SIF and CAC appears stronger with more severe calcification. Given the strong relationship of CAC with CAD this finding has important implications and suggests that SIF maybe a useful marker of CAC/CAD risk and potentially a therapeutic target.
PMCID: PMC2883484  PMID: 20388043
23.  Associations between Nonalcoholic Fatty Liver Disease and Subclinical Atherosclerosis in Middle-Aged Adults: The Coronary Artery Risk Development in Young Adults Study 
Atherosclerosis  2014;235(2):599-605.
Non-alcoholic fatty liver disease (NAFLD) is an obesity-related condition associated with cardiovascular mortality. Yet, whether or not NAFLD is independently related to atherosclerosis is unclear. In a population-based cross-sectional sample of middle-aged adults free from liver or heart disease, we tested the hypothesis that NAFLD is associated with subclinical atherosclerosis (coronary artery (CAC) and abdominal aortic calcification (AAC)) independent of obesity.
Participants from the Coronary Artery Risk Development in Young Adults study with CT quantification of liver fat, CAC and AAC were included (n=2,424). NAFLD was defined as liver attenuation ≤ 40 Hounsfield Units after exclusion of other causes of liver fat. CAC and AAC presence was defined as Agatston score > 0.
Mean participant age was 50.1±3.6 years, (42.7% men, 50.0% black) and BMI was 30.6±7.2 kg/m2. The prevalence of NAFLD, CAC, and AAC was 9.6%, 27.1%, and 51.4%. NAFLD participants had increased prevalence of CAC (37.9% vs. 26.0%, p<0.001) and AAC (65.1% vs. 49.9%, p<0.001). NAFLD remained associated with CAC (OR, 1.33; 95% CI, 1.001–1.82) and AAC (OR, 1.74; 95% CI, 1.29–2.35) after adjustment for demographics and health behaviors. However, these associations were attenuated after additional adjustment for visceral adipose tissue (CAC OR, 1.05; 95% CI, 0.74–1.48, AAC OR=1.20; 95% CI, 0.86–1.67). There was no interaction by race or sex.
In contrast to prior research, these findings suggest that obesity attenuates the relationship between NAFLD and subclinical atherosclerosis. Further studies evaluating the role of NAFLD duration on atherosclerotic progression and cardiovascular events are needed.
PMCID: PMC4124046  PMID: 24956534
calcium; cardiovascular diseases; epidemiology; imaging; liver; obesity; risk factors
24.  Relationship of Estimated GFR and Coronary Artery Calcification in the (CRIC) Chronic Renal Insufficiency Cohort Study 
Coronary artery calcification (CAC) is associated with increased mortality risk in the general population. Although individuals with chronic kidney disease (CKD) are at markedly increased mortality risk, the incidence, prevalence, and prognosis of CAC in CKD is not well-understood.
Study Design
Cross-sectional observational study.
Setting and Participants
Analysis of 1,908 participants who underwent coronary calcium scanning as part of the multi-ethnic CRIC (Chronic Renal Insufficiency Cohort) Study.
Estimated glomerular filtration rate (eGFR) computed using the Modification of Diet in Renal Disease (MDRD) Study equation, stratified by race, sex and diabetic status. eGFR was treated as a continous variable and a categorical variable compared to the reference range of >60 ml/min/1.73 m2
CAC detected using CT scans using either an Imatron C-300 electron beam computed tomography scanner or multi-detector CT scanner. CAC was computed using the Agatston score, as a categorical variable. Analyses were performed using ordinal logistic regression.
We found a strong and graded relationship between lower eGFR and increasing CAC. In unadjusted models, ORs increased from 1.68 (95% CI, 1.23–2.31) for eGFR from 50–59 to 2.82 (95% CI, 2.06–3.85) for eGFR of <30. Multivariable adjustment only partially attenuated the results (OR, 1.53; 95% CI, 1.07–2.20) for eGFR<30.
Use of eGFR rather than measured GFR.
We demonstrated a graded relationship between severity of CKD and CAC, independent of traditional risk factors. These findings supports recent guidelines that state that if vascular calcification is present, it should be considered as a complementary component to be included in the decision making required for individualizing treatment of CKD.
PMCID: PMC3183168  PMID: 21783289
25.  Determinants of Coronary Artery and Aortic Calcification in the Old Order Amish 
Circulation  2007;115(6):717-724.
Coronary artery calcification (CAC) is associated with an increased risk of cardiovascular disease; little is known, however, about thoracic aortic calcification (AC). Our goal was to characterize risk factors for CAC and AC and to estimate the genetic contribution to their variation.
Methods and Results
The presence and quantity of CAC and AC were measured with electron beam computed tomography and fasting blood tests and cardiovascular risk factors were obtained in 614 asymptomatic Amish subjects. CAC prevalence was higher in men than women (55% versus 41%; P<0.0001), although there was no sex difference in AC prevalence (51% and 56% in men and women, respectively; P=0.95). Age was more strongly associated with AC presence (odds ratio [OR], 2.7 for 5 years) than CAC presence (OR, 1.9 for 5 years) (homogeneity P=0.001). Subjects with AC had a 3.3-fold higher odds of having CAC. Heritabilities of CAC and AC presence were 0.27±0.17 (P=0.04) and 0.55±0.18 (P=0.0008), respectively, whereas the heritabilities of quantity of CAC and AC were 0.30±0.10 (P=0.001) and 0.40±0.10 (P<0.0001), respectively. The genetic correlation between CAC and AC quantity was 0.34±0.19, whereas the environmental correlation between these 2 traits was 0.38±0.09.
CAC and AC have similar risk factors, except male gender is associated only with CAC and age is more strongly associated with AC. The patterns of correlations suggest that CAC and AC share some common sets of genes and environmental factors, although it is likely that separate genes and environmental factors also influence calcification at each site.
PMCID: PMC4039563  PMID: 17261661
aging; aorta; atherosclerosis; coronary disease; epidemiology; genetics; imaging

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