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1.  Left Ventricular Global Function Index By Magnetic Resonance Imaging- A Novel Marker for Assessment of Cardiac Performance for the Prediction Of Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(4):770-778.
LV function is generally assessed independent of structural remodeling and vice versa. The purpose of this study was to evaluate a novel LV global function index (LVGFI) that integrates LV structure with global function and to assess its predictive value for cardiovascular (CV) events throughout adult life in a multi-ethnic population of men and women without history of cardiovascular diseases at baseline. A total of 5004 participants in the Multi-Ethnic Study of Atherosclerosis underwent a cardiac magnetic resonance (CMR) study and were followed up for a median of 7.2 years. The LVGFI by CMR was defined by the ratio of stroke volume divided by LV total volume defined as the sum of mean LV cavity and myocardial volumes. Cox proportional hazard models were constructed to predict the end points of heart failure (HF), hard CV events and a combined endpoint of all CV events after adjustment for established risk factors, calcium score and biomarkers. A total of 579 (11.6%) incident events were observed during the follow-up period. In adjusted models, the end points of HF, hard CV events and all events were all significantly associated with LVGFI (HF, hazard ratio [HR]= 0.64, p<0.0001; hard CV events, HR=0.79, p=0.007; all events, HR=0.79, p<0.0001). LVGFI had a significant independent predictive value in the multivariable models for all CV event categories. The LVGFI was a powerful predictor of incident heart failure, hard CV events and a composite endpoint including all events in this multiethnic cohort.
doi:10.1161/HYPERTENSIONAHA.111.198028
PMCID: PMC3691067  PMID: 23424238
left ventricle; ejection fraction; heart failure; LV mass; LV global function index
2.  Reduction in Observation Unit Length of Stay with Coronary Computed Tomography Angiography Depends on Time of Emergency Department Presentation 
Objectives
Prior studies demonstrating shorter length of stay (LOS) from coronary computed tomography angiography (CCTA) relative to stress testing in emergency department (ED) patients have not considered time of patient presentation. The objectives of this study were to determine whether low-risk chest pain patients receiving stress testing or CCTA have differences in ED plus observation unit (OU) LOS, and if there are disparities in testing modality use, based upon the time of patient presentation to the ED.
Methods
The authors examined a cohort of low-risk chest pain patients evaluated in an ED-based OU using prospective and retrospective OU registry data. During the study period, stress testing and CCTA were both available from 08:00 to 17:00 hrs. CCTA was not available on weekends, and therefore only subjects presenting on weekdays were included. Cox regression analysis was used to model the effect of testing modality (stress testing vs. CCTA) on OU LOS. Separate models were fit based on time of patient presentation to the ED using four hour blocks beginning at midnight. The primary independent variable was testing modality: stress testing or CCTA. Age, sex, and race were included as covariates. Logistic regression was used to model testing modality choice by time period adjusted for age, sex, and race.
Results
Over the study period, 841 subjects presented Monday through Friday. Median LOS was 18.0 hours (IQR 11.7 to 22.9 hours). Objective cardiac testing was completed in 788 of 841 (94%) patients, with 496 (63%) receiving stress testing and 292 (37%) receiving CCTA. After adjusting for age, race, and sex, patients presenting between 08:00 and 11:59 hrs not only had a shorter LOS associated with CCTA (p < 0.0001), but also had a greater likelihood of being tested by CCTA (p = 0.001). None of the other time periods had significant differences in LOS or testing modality choice for CCTA relative to stress testing.
Conclusions
In an OU setting with weekday and standard business hours CCTA availability, CCTA testing was associated with shorter LOS among low-risk chest pain patients only in patients presenting to the ED between 08:00 and 11:59 hrs. That time period was also associated with a greater likelihood of being tested by CCTA, suggesting that ED providers may have intuited the inability of CCTA to shorten LOS during other times.
doi:10.1111/acem.12094
PMCID: PMC3607957  PMID: 23517254
3.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
doi:10.1093/aje/kws169
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
4.  Statins, Risk of Dementia and Cognitive Function: Secondary Analysis of the Ginkgo Evaluation of Memory Study (GEMS) 
Goal
To examine whether lipid lowering medications (LLMs) and especially statin drugs can delay cognitive decline and dementia onset in individuals with and without Mild Cognitive Impairment (MCI) at baseline.
Methods
Longitudinal, observational study of 3,069 cognitively healthy elderly, ages 75 years and older, who were enrolled in the Ginkgo Evaluation of Memory Study. Primary outcome measure was the time to adjudicated all-cause dementia and Alzheimer dementia (AD). Secondary outcome measure was the change in global cognitive function over time measured by 3MSE and ADAS-cog scores.
Findings
Among participants without MCI at baseline current use of statins was consistently associated with a reduced risk of all cause dementia (HR 0. 79, 95% confidence interval, 0.65–0.96, p=0.021) and AD (HR 0.57, 95% confidence interval, 0.39–0.85, p= 0.005). In participants who initiated statin therapy lipophilic statins tended to reduce dementia risk more than nonlipophilic agents. In contrast there was no significant association between LLM use (including statins), dementia onset or cognitive decline in individuals with baseline MCI. However, in individuals without MCI at baseline there was a trend for a neuroprotective effect of statins on cognitive decline.
Conclusions
Statins may slow the rate of cognitive decline and delay the onset of AD and all cause dementia in cognitively healthy elderly individuals whereas individuals with MCI may not have comparable cognitive protection from these agents. However, the results from this observational study need to be interpreted with caution and will require confirmation by randomized clinical trials stratifying treatment groups based on MCI status at baseline.
doi:10.1016/j.jstrokecerebrovasdis.2010.11.002
PMCID: PMC3140577  PMID: 21236699
Cognitive function; 3HMG-ACoA reductase inhibitors; Mild Cognitive Impairment; dementia
5.  Gender Differences Between the Minnesota Code and Novacode Electrocardiographic Prognostication of Coronary Heart Disease in the Cardiovascular Health Study 
The American journal of cardiology  2011;107(6):817-820.e1.
The Minnesota Code (MC) and Novacode (Nova) are the most widely used electrocardiographic (ECG) classification systems. The comparative strengths of their classifications for Q- and ST-T–wave abnormalities in predicting coronary heart disease (CHD) events and total mortality have not been evaluated separately by gender. We studied standard 12-lead electrocardiograms at rest from 4,988 participants in the Cardiovascular Health Study. Average age at baseline was 73 years, 60% of participants were women 85% were white, and 22% had a history of cardiovascular disease or presence of ECG myocardial infarction by MC or Nova. Starting in 1989 with an average 17-year follow-up, 65% of participants died and 33% had incident CHD in a cohort free of cardiovascular disease at baseline. Of these, electrocardiograms with major Q-wave or major ST-T abnormalities by MC or Nova predicted increased risk for CHD events and total mortality with no significant differences in predictability between men and women. The study also found that women had fewer major Q-wave changes but more major ST-T abnormalities than men. However, there were no gender differences in predicting CHD events and total mortality. In conclusion, ECG classification systems for myocardial infarction/ischemia abnormalities by MC or Nova are valuable and useful for men and women in clinical trials and epidemiologic studies.
doi:10.1016/j.amjcard.2010.11.004
PMCID: PMC3673724  PMID: 21247534
6.  Retinal Microvascular Signs and Disability in the Cardiovascular Health Study 
Archives of ophthalmology  2011;130(3):350-356.
Objective
Retinal microvascular signs are associated with systemic conditions and cognitive decline. We studied the associations of microvascular changes, measured by retinal signs, with disability in performing activities of daily living (ADL).
Design
Prospective cohort study.
Setting
Community.
Participants
1487 participants in the Cardiovascular Health Study (mean age 78 years) who were free of ADL disability and had available data on retinal signs and carotid intima-media thickness (IMT) at the 1998–99 visit.
Main Outcome Measure
Incident ADL disability, defined as self-reported difficulty in performing any ADLs, by the presence of retinal signs and advanced carotid atherosclerosis, defined by carotid IMT ≥ 80th percentile or ≥ 25% stenosis; and potential mediation by cerebral microvascular disease on brain imaging or by executive dysfunction, slow gait, and depressive mood that are symptoms of frontal subcortical dysfunction.
Results
During the median follow-up of 3.1 years (maximum 7.8 years), participants with ≥ 2 retinal signs had a higher rate of disability than those with < 2 retinal signs (10.1% versus 7.1%; adjusted hazards ratio, 1.45; 95% confidence interval, 1.24–1.69; P < 0.001). There was no evidence of interaction by advanced carotid atherosclerosis (P > 0.10). The association seemed to be partially mediated by executive dysfunction, slow gait, and depressive symptoms, but not by cerebral microvascular disease on brain imaging.
Conclusions
These results provide further support for the pathophysiologic and prognostic significance of microvascular disease in age-related disability. However, it remains to be determined how to best utilize retinal photography in the clinical risk prediction.
doi:10.1001/archophthalmol.2011.360
PMCID: PMC3520093  PMID: 22084159
7.  Prediction of Coronary Artery Calcium Progression in Individuals with Low Framingham Risk Score: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Jacc. Cardiovascular Imaging  2012;5(2):144-153.
Objectives
We sought to determine whether novel markers not involving ionizing radiation could predict CAC progression in a low-risk population.
Background
Increase in coronary artery calcium (CAC) scores over time (CAC progression) improves prediction of coronary heart disease (CHD) events. Due to radiation exposure, CAC measurement represents an undesirable method for repeated risk assessment, particularly in low predicted risk individuals (Framingham Risk Score [FRS] <10%).
Methods
From 6814 MESA participants, 2620 individuals were classified as low risk for CHD events (FRS <10%), and had follow-up CAC measurement. In addition to traditional risk factors [(RFs) - base model], various combinations of novel-marker models were selected based on data-driven, clinical, or backward stepwise selection techniques.
Results
Mean follow-up was 2.5 years. CAC progression occurred in 574 participants (22% overall; 214 of 1830 with baseline CAC =0, and 360 of 790 with baseline CAC >0). Addition of various combinations of novel markers to the base model (c-statistic =0.711), showed improvements in discrimination of approximately only 0.005 each (c-statistics 0.7158, 0.7160 and 0.7164) for the best-fit models. All 3 best-fit novel-marker models calibrated well but were similar to the base model in predicting individual risk probabilities for CAC progression. The highest prevalence of CAC progression occurred in the highest compared to the lowest probability quartile groups (39.2–40.3% versus 6.4–7.1%).
Conclusions
In individuals at low predicted risk by FRS, traditional RFs predicted CAC progression in the short term with good discrimination and calibration. Prediction improved minimally when various novel markers were added to the model.
doi:10.1016/j.jcmg.2011.11.008
PMCID: PMC3310187  PMID: 22340820
coronary calcium; Framingham risk score; risk factors; progression
8.  Association Between Sleep Apnea, Snoring, Incident Cardiovascular Events and All-Cause Mortality in an Adult Population. MESA 
Atherosclerosis  2011;219(2):963-968.
Background
We assessed the association between sleep apnea, snoring, incident cardiovascular (CV) events and all-cause mortality in the Multi Ethnic Study of Atherosclerosis (MESA) cohort.
Methods
Out of 5338 respondents to a sleep questionnaire administered during the second MESA exam period, 208 had physician-diagnosed sleep apnea (PDSA), 1452 were habitual snorers (HS) and 3678 were neither a habitual snorer nor had PDSA (normal participants). Cox proportional hazard analysis was used to assess the associations adjusting for age, gender, race/ethnicity, smoking, diabetes mellitus, total cholesterol, HDL, triglycerides, BMI, current alcohol use, benzodiazepine use, BP medications and statin use.
Results
Over a 7.5 year average follow-up period, 310 adjudicated CV events including MI, stroke, angina, resuscitated cardiac arrest, stroke death and CVD death and 189 deaths occurred. Compared to HS, PDSA was associated with higher incident CV rates in both univariate and multivariable models [hazard ratio (95%); 1.89(1.22–2.93), p=0.004 and 1.91(1.20 –3.04), p=0.007 respectively]. PDSA was also associated with a higher death rates compared with HS [hazard ratio (95%); 2.13(1.25 – 3.63), p=0.006 and 2.70(1.52– 4.79), p=0.007 respectively]. Compared with normal participants, PDSA had higher incident CV event rates in both univariate and multivariable models [hazard ratio (95%); 2.23[1.39–3.60], p=0.001 and 2.16[1.30–3.58], p=0.003 respectively]. Similarly, PDSA had a higher death rate compared with normal participants in both the univariate and multivariable models [hazard ratio (95%CI); 2.44(1.36 – 4.37), p=0.003 and 2.71(1.45 – 5.08), p=0.002 respectively]. Habitual snorers had similar incident CV event rates and death rates in both univariate and multivariable models compared with normal participants.
Conclusion
PDSA but not habitual snoring was associated with high incident CV events and all-cause mortality in a multi-ethnic population based study of adults free of clinical CV disease at baseline.
doi:10.1016/j.atherosclerosis.2011.08.021
PMCID: PMC3255297  PMID: 22078131
Obstructive sleep apnea; habitual snorers; cardiovascular events; mortality; population
9.  Impaired Fasting Glucose And The Risk Of Incident Diabetes Mellitus And Cardiovascular Events In An Adult Population: The Multi-Ethnic Study of Atherosclerosis 
Objective
To assess the cardiovascular risk of impaired fasting glucose (IFG).
Background
The association between IFG, incident type 2 diabetes mellitus (T2DM) and cardiovascular (CV) events remains unclear.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) included participants aged 45–84 free of clinical CV disease at baseline (2000–2002). T2DM was defined as fasting glucose >125mg/dl or anti-diabetes medication at baseline and follow-up exams, IFG as no T2DM and fasting glucose 100–125.mg/dl. Cox proportional hazard analysis was used to assess the association between IFG and incident DM and also with incident CV events.
Results
Of 6753 participants included in these analyses 840 (12.7%) had T2DM, 940 (13.8%) had IFG at the baseline exam. During 7.5 years of follow-up there were 418 adjudicated CV events. T2DM was associated with an increased CV incidence in the univariate [hazard ratio (HR); 2.83(2.25–3.56), p<0.0001] and multivariable models (adjusted for demographics and traditional risk factors) [HR; 1.87(1.47 – 2.37), p<0.0001] compared with subjects without T2DM (IFG + NFG). IFG was associated with increased incidence of T2DM [HR; 13.2 (95%CI 10.8–16.2), p<0.001] that remained after adjusting for demographics, highest educational level, physical activity and BMI [HR; 10.5(8.4–13.1), p<0.001] compared to NFG. IFG was associated with incident CV events in the univariate [HR; 1.64(1.26 – 2.14), p=<0.001] but not in the full multivariable model [HR; 1.16(95% CI 0.88–1.52), p=0.3] compared with NFG.
Conclusion
Having IFG was not independently associated with an increased short-term risk for incident CV events. These data reiterate the importance of intervention in persons with IFG to reduce their incidence of T2DM.
doi:10.1016/j.jacc.2011.03.025
PMCID: PMC3146297  PMID: 21718910
Impaired fasting glucose; diabetes mellitus; cardiovascular events; population
10.  Ethnic Differences in Hypertension Incidence among Middle-Aged and Older U. S. Adults: The Multi-Ethnic Study of Atherosclerosis 
Hypertension  2011;57(6):1101-1107.
The prevalence of hypertension is higher among African-Americans than whites. However, inconsistent findings have been reported on the incidence of hypertension among middle-aged and older African-Americans and whites and limited data are available on the incidence of hypertension among Hispanics and Asians in the US. Therefore, this study investigated the age-specific incidence of hypertension by ethnicity for 3,146 participants from the Multi-Ethnic Study of Atherosclerosis. Participants, age 45–84 years at baseline, were followed for a median of 4.8 years for incident hypertension, defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the initiation of antihypertensive medications. The crude incidence rate of hypertension, per 1,000 person-years, was 56.8 for whites, 84.9 for African-Americans, 65.7 for Hispanics, and 52.2 for Chinese. After adjustment for age, gender, and study site, the incidence rate ratio (IRR) for hypertension was increased for African-Americans age 45–54 (IRR=2.05, 95% CI=1.47, 2.85), 55–64 (IRR=1.63, 95% CI=1.20, 2.23), and 65–74 years (IRR=1.67, 95% CI=1.21, 2.30) compared with whites, but not for those 75–84 years of age (IRR=0.97, 95% CI=0.56, 1.66). Additional adjustment for health characteristics attenuated these associations. Hispanic participants also had a higher incidence of hypertension compared with whites; however, hypertension incidence did not differ for Chinese and white participants. In summary, hypertension incidence was higher for African-Americans compared with whites between 45 and 74 years of age but not after age 75 years. Public health prevention programs tailored to middle-age and older adults are needed to eliminate ethnic disparities in incident hypertension.
doi:10.1161/HYPERTENSIONAHA.110.168005
PMCID: PMC3106342  PMID: 21502561
hypertension; race/ethnicity; epidemiology; incidence
11.  Retinal Microvascular Signs and Functional Loss in Older Persons: The Cardiovascular Health Study 
Background and Purpose
We hypothesized that retinal microvascular signs are associated with executive dysfunction, slow gait, and depressive mood that are characteristic features of microvascular disease affecting frontal subcortical regions of the brain.
Methods
In the Cardiovascular Health Study, 1744 participants (mean age 78) free of stroke had retinal photographs and carotid ultrasound during the 1997–1998 visit. We examined the cross-sectional association of retinal signs with the digit-symbol substitution test (DSST) score, gait speed, the Center for Epidemiologic Studies – Depression (CES-D) score, and depressive mood, defined as CES-D score > 9 or antidepressant use.
Results
After adjusting for potential confounders, retinal signs were associated with lower DSST score (generalized arteriolar narrowing and arteriovenous nicking), slower gait (retinopathy), and depressive mood (generalized arteriolar narrowing). A higher number of retinal signs was associated with lower DSST score (−0.76 and −2.79 points for 1 sign and ≥ 2 signs versus none; P < 0.001) and slower gait (−0.009 and −0.083 m/sec; P = 0.047), but not with the square root of CES-D score (0.079 and −0.208; P = 0.072). In addition, coexistence of retinal signs (generalized arteriolar narrowing and arteriovenous nicking) and carotid atherosclerosis was associated with lower DSST score compared with either process alone (P for interaction < 0.01). Notably, further adjustment for ventricular size, white matter disease, and infarcts on magnetic resonance imaging did not attenuate the association.
Conclusions
Retinal signs are associated with executive dysfunction and slow gait, and possibly with depressive mood, suggesting a common process involving small vessels.
doi:10.1161/STROKEAHA.110.605261
PMCID: PMC3127407  PMID: 21493913
Retinal Microvascular Signs; Executive Function; Gait Speed; Depression
12.  Distribution of Coronary Artery Calcium Scores by Framingham 10-Year Risk Strata in the Multi-Ethnic Study of Atherosclerosis (MESA): Potential Implications for Coronary Risk Assessment 
Objectives
By examining the distribution of CAC across FRS strata in a large, multi-ethnic, community-based sample of men and women, we sought to determine if lower risk persons could potentially benefit from CAC screening.
Background
The 10-year Framingham risk scores (FRS) and coronary artery calcium (CAC) are predictors of coronary heart disease (CHD). CAC ≥300 is associated with the highest risk for CHD even in low risk (FRS <10%) persons; however expert groups have suggested CAC screening only in intermediate risk (FRS 10–20%) groups.
Methods
We included 5660 MESA participants. The number needed to screen [number of people that need to be screened to detect one person with CAC above the specified cut-point (NNS)] was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using chi-square tests.
Results
CAC >0, ≥100 and ≥300 were present in 46.4%, 20.6% and 10.1% of participants, respectively. Prevalence and amount of CAC increased with higher FRS. CAC ≥300 was observed in 1.7% and 4.4% of those with FRS 0–2.5% and 2.6–5%, respectively (NNS =59.7 and 22.7). Likewise, CAC ≥300 was observed in 24% and 30% of those with FRS 15.1–20% and >20%, respectively (NNS =4.2 and 3.3). Trends were similar when stratified by age, gender and race/ethnicity.
Conclusions
Our study suggests that in very low risk individuals (FRS ≤5%), the yield of screening and probability of identifying persons with clinically significant levels of CAC is low, but becomes greater in low and intermediate risk persons (FRS 5.1–20%).
doi:10.1016/j.jacc.2010.11.053
PMCID: PMC3268231  PMID: 21527159
Framingham risk score; coronary calcium; coronary heart disease; number needed to screen; risk factors; population; atherosclerosis; low risk
13.  Alcohol and coronary artery calcium prevalence, incidence and progression: results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Alcohol use has been consistently found to have a J-shaped association with coronary heart disease, with moderate drinkers exhibiting a decreased risk compared to both heavy drinkers and non-drinkers. However, studies of the association between alcohol use and subclinical coronary artery disease have conflicted.
Objective
To determine whether alcohol is associated with the presence, amount, or progression of coronary calcium over a 2- to 4-year period.
Design
MESA is a prospective community-based cohort study of subclinical cardiovascular disease in a multi-ethnic cohort. In 2000–2002, 6814 participants free of clinical cardiovascular disease were enrolled at 6 participating centers.
Results
There were 3766 (55.5%) current drinkers, 1635 (24.1%) former drinkers, and 1390 (20.5%) never drinkers included in the analysis. Although light to moderate alcohol consumption was associated with lower coronary heart disease risk, we found no evidence of a protective or J-shaped association of alcohol and coronary artery calcium (CAC). In fact there was evidence that heavy consumption of hard liquor was associated with greater CAC accumulation. Other alcoholic beverages were not associated with CAC prevalence, incidence or progression.
Conclusions
This is the first large study to evaluate the association of alcohol and coronary artery calcium in four racial/ethnic groups, and to evaluate progression of calcification. These results suggest that the cardiovascular benefits that may be derived from light to moderate alcohol consumption are not mediated through reduced CAC accumulation.
doi:10.3945/ajcn.2008.26420
PMCID: PMC3319440  PMID: 19064520
14.  The association between non-subcutaneous adiposity and calcified coronary plaque: A substudy of the Multi-Ethnic Study of Atherosclerosis 
Background
Excessive non-subcutaneous fat deposition may impair the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids.
Objective
We examined the cross-sectional association between non-subcutaneous adiposity and calcified coronary plaque, a non-invasive measure of coronary artery disease burden.
Design
Participants in the Multi-Ethnic Study of Atherosclerosis underwent CT assessment of calcified coronary plaque. We measured multiple fat depots in 398 white and black participants (47% men and 43% black), ages 47–86 years, from Forsyth County, NC during 2002–2005, using cardiac and abdominal CT scans. In addition to examining each depot separately, we also created a non-subcutaneous fat index using the standard scores of non-subcutaneous fat depots.
Results
A total of 219 participants (55%) were found to have calcified coronary plaque. After adjusting for demographics, lifestyle factors and height, calcified coronary plaque was associated with a one standard deviation increment in the non-subcutaneous fat index (OR = 1.41; 95% CI: 1.08, 1.84), pericardial fat (OR = 1.38; 95% CI: 1.04, 1.84), abdominal visceral fat (OR = 1.35; 95% CI: 1.03, 1.76), but not with fat content in the liver, intermuscular fat, or abdominal subcutaneous fat. The relation between non-subcutaneous fat index and calcified coronary plaque remained after further adjustment for abdominal subcutaneous fat (OR = 1.40; 95% CI: 1.00, 1.94). The relation did not differ by gender and ethnicity.
Conclusions
The overall burden of non-subcutaneous fat deposition, but not abdominal subcutaneous fat, may be a correlate of coronary atherosclerosis.
PMCID: PMC3282464  PMID: 18779279
15.  Comparison of the Racial/Ethnic Prevalence of Regular Aspirin Use for the Primary Prevention of Coronary Heart Disease from the Multi-Ethnic Study of Atherosclerosis 
In 2002 the United States Preventive Services Task Force and the American Heart Association recommended aspirin for the primary prevention of Coronary Heart Disease (CHD) in individuals with a Framingham risk score ≥ 6% or ≥ 10%, respectively. The regular use of aspirin (≥ 3 days per week) was examined in a cohort of 6452 White, Black, Hispanic, and Chinese individuals without cardiovascular disease in 2000-2002 and 5181 individuals from the same cohort in 2005-2007. Framingham risk scores were stratified into low (< 6%), increased (6% to 9.9%), and high risk (≥ 10%). In 2000-2002 the prevalence of aspirin use was 18% and 27% for those at increased and high risk, respectively. Whites (25%) used aspirin more than Blacks (14%), Hispanics (12%), or Chinese (14%) (P < 0.001) in the increased risk group. Corresponding prevalences for the high risk group were 38%, 25%, 17%, and 21%, respectively (P < 0.001). In 2005-2007 the prevalence of aspirin use was 31% and 44% for those at increased and high risk, respectively. Whites (41%) used aspirin more than Blacks (27%), Hispanics (24%), or Chinese (15%) in the increased risk group (P < 0.001). Corresponding prevalences for the high risk group were 53%, 43%, 38%, and 28%, respectively (P < 0.001). Racial/ethnic differences persisted after adjustment for age, gender, diabetes, income, and education. In conclusion, regular aspirin use in adults at increased and high risk for CHD remains suboptimal. Important racial/ethnic disparities exist for unclear reasons.
doi:10.1016/j.amjcard.2010.08.041
PMCID: PMC3021117  PMID: 21146684
Framingham risk score; aspirin; coronary heart disease; race and ethnicity
16.  Cardiovascular Imaging for Assessing Cardiovascular Risk in Asymptomatic Men Versus Women 
Background
Coronary artery calcium (CAC), carotid intima-media thickness, and left ventricular (LV) mass and geometry offer the potential to characterize incident cardiovascular disease (CVD) risk in clinically asymptomatic individuals. The objective of the study was to compare these cardiovascular imaging measures for their overall and sex-specific ability to predict CVD.
Methods and Results
The study sample consisted of 4965 Multi-Ethnic Study of Atherosclerosis participants (48% men; mean age, 62±10 years). They were free of CVD at baseline and were followed for a median of 5.8 years. There were 297 CVD events, including 187 coronary heart disease (CHD) events, 65 strokes, and 91 heart failure (HF) events. CAC was most strongly associated with CHD (hazard ratio [HR], 2.3 per 1 SD; 95% CI, 1.9 to 2.8) and all CVD events (HR, 1.7; 95% CI, 1.5 to 1.9). Most strongly associated with stroke were LV mass (HR, 1.3; 95% CI, 1.1 to 1.7) and LV mass/volume ratio (HR, 1.3; 95% CI, 1.1 to 1.6). LV mass showed the strongest association with HF (HR, 1.8; 95% CI, 1.6 to 2.1). There were no significant interactions for imaging measures with sex and ethnicity for any CVD outcome. Compared with traditional risk factors alone, overall risk prediction (C statistic) for future CHD, HF, and all CVD was significantly improved by adding CAC, LV mass, and CAC, respectively (all P<0.05).
Conclusions
There was no evidence that imaging measures differed in association with incident CVD by sex. CAC was most strongly associated with CHD and CVD; LV mass and LV concentric remodeling best predicted stroke; and LV mass best predicted HF.
doi:10.1161/CIRCIMAGING.110.959403
PMCID: PMC3037859  PMID: 21068189
imaging; cardiovascular diseases; sex
17.  Pericardial Fat and Myocardial Perfusion in Asymptomatic Adults from the Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2011;6(12):e28410.
Background
Pericardial fat has adverse effects on the surrounding vasculature. Previous studies suggest that pericardial fat may contribute to myocardial ischemia in symptomatic individuals. However, it is unknown if pericardial fat has similar effects in asymptomatic individuals.
Methods
We determined the association between pericardial fat and myocardial blood flow (MBF) in 214 adults with no prior history of cardiovascular disease from the Minnesota field center of the Multi-Ethnic Study of Atherosclerosis (43% female, 56% Caucasian, 44% Hispanic). Pericardial fat volume was measured by computed tomography. MBF was measured by MRI at rest and during adenosine-induced hyperemia. Myocardial perfusion reserve (PR) was calculated as the ratio of hyperemic to resting MBF.
Results
Gender-stratified analyses revealed significant differences between men and women including less pericardial fat (71.9±31.3 vs. 105.2±57.5 cm3, p<0.0001) and higher resting MBF (1.12±0.23 vs. 0.93±0.19 ml/min/g, p<0.0001), hyperemic MBF (3.49±0.76 vs. 2.65±0.72 ml/min/g, p<0.0001), and PR (3.19±0.78 vs. 2.93±0.89, p = 0.03) in women. Correlations between pericardial fat and clinical and hemodynamic variables were stronger in women. In women only (p = 0.01 for gender interaction) higher pericardial fat was associated with higher resting MBF (p = 0.008). However, this association was attenuated after accounting for body mass index or rate-pressure product. There were no significant associations between pericardial fat and hyperemic MBF or PR after multivariate adjustment in either gender. In logistic regression analyses there was also no association between impaired coronary vasoreactivity, defined as having a PR <2.5, and pericardial fat in men (OR, 1.18; 95% CI, 0.82–1.70) or women (OR, 1.11; 95% CI, 0.68–1.82).
Conclusions
Our data fail to support an independent association between pericardial fat and myocardial perfusion in adults without symptomatic cardiovascular disease. Nevertheless, these findings highlight potentially important differences between asymptomatic and symptomatic individuals with respect to the underlying subclinical disease burden.
doi:10.1371/journal.pone.0028410
PMCID: PMC3235122  PMID: 22174800
18.  Validation of an Atrial Fibrillation Risk Algorithm in Whites and African-Americans 
Archives of internal medicine  2010;170(21):1909-1917.
Background
We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other race/ethnic groups.
Methods
We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n=4764 participants) and two geographically and ethnically diverse cohorts: AGES (Age, Gene/Environment Susceptibility-Reykjavik Study, n=4238), and CHS (Cardiovascular Health Study, n=5410 of whom 874 (16.2%) were African Americans (AA)); aged 45–95 years. The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR-interval, hypertension treatment, and heart failure.
Results
We observed 1359 incident AF events in 100,074 person-years of follow-up. Unadjusted five-year event-rates differed by cohort (AGES 12.8 cases/1000 person-years; CHS whites 22.7 cases/1000 person-years; FHS 4.5 cases/1000 person-years) and race/ethnicity (CHS AA 18.4 cases/1000 person-years).
The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm performed reasonably well in all samples (AGES C-statistic 0.67, 95% confidence interval 0.64–0.71; CHS whites, 0.68, 0.66–0.70; CHS AA 0.66, 0.61–0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population attributable risk.
Conclusions
Risk of incident AF in community-dwelling whites and AA can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% percent of risk.
doi:10.1001/archinternmed.2010.434
PMCID: PMC3021784  PMID: 21098350
atrial fibrillation; risk score; epidemiology; cohort study; race/ethnicity
19.  Inflammation and the Incidence of Type 2 Diabetes 
Diabetes Care  2010;33(4):804-810.
OBJECTIVE
Many studies have documented associations between inflammation and type 2 diabetes incidence. We assessed potential variability in this association in the major U.S. racial/ethnic groups.
RESEARCH DESIGN AND METHODS
Incident type 2 diabetes was assessed among men and women aged 45–84 years without prior clinical cardiovascular disease or diabetes in the prospective Multi-Ethnic Study of Atherosclerosis. Interleukin (IL)-6, fibrinogen, and C-reactive protein (CRP) were measured at baseline (2000–2002); fasting glucose and diabetes medication use was assessed at baseline and three subsequent in-person exams through 2007. Type 2 diabetes was defined as use of diabetes drugs or glucose ≥126 mg/dl. Covariates included baseline demographics, clinic, smoking, alcohol, exercise, hypertension medication, systolic blood pressure, insulin resistance, and BMI. Cox proportional hazards regression was used to calculate hazard ratios (HRs) by quartiles of CRP, IL-6, and fibrinogen.
RESULTS
Among 5,571 participants (mean age 61.6 years, 53% female, 42.1% white, 11.5% Chinese, 25.7% black, and 20.7% Hispanic), 410 developed incident diabetes during a median follow-up time of 4.7 years (incidence 16.8 per 1,000 person-years). CRP, IL-6, and fibrinogen levels were associated with incident diabetes in the entire sample. After adjustment, the associations were attenuated; however, quartile 4 (versus quartile 1) of IL-6 (HR 1.5 [95% CI 1.1–2.2]) and CRP (1.7 [1.3–2.4]) remained associated with incident diabetes. In stratified analyses, similar associations were observed among white, black, and Hispanic participants.
CONCLUSIONS
Higher levels of inflammation predict short-term incidence of type 2 diabetes in a multiethnic American sample.
doi:10.2337/dc09-1679
PMCID: PMC2845031  PMID: 20097779
20.  Association of Plasma Sphingomyelin levels and Incident Coronary Heart Disease Events in an Adult Population: Multi Ethnic Study of Atherosclerosis 
Objectives
High plasma sphingomyelin level has been associated with subclinical atherosclerosis, coronary artery disease and worse prognosis in subjects with acute coronary syndromes. We assess the predictive value of plasma sphingomyelin levels for incident CHD events in the Multi Ethnic Study of atherosclerosis (MESA).
Method and Results
Plasma sphingomyelin was measured in 6809 out of 6814 subjects with mean age 62.2 ± 10.2 years, participating in the MESA study, a population based cohort study of adults free of clinical CVD at baseline recruited at six clinic sites in USA. The subjects consisted of 52.8% females, 38.5% Caucasian, 11.8% Chinese, 27.8% African Americans and 21.9% Hispanics. Cox proportional hazard analysis was used to examine the association between plasma sphingomyelin and five years of adjudicated incident CHD events including MI, resuscitated cardiac arrest, angina, CHD death and revascularization (CABG or PTCA). Mean (SD) plasma sphingomyelin level was 48 mg/dl (16.0). One hundred and eighty-nine subjects had an adjudicated CHD event during the five years of follow up. In the Kaplan meier analysis, subjects with plasma sphingomyelin level above the sex specific median had similar event free survival rate compared with subjects with plasma sphingomyelin level below or equal to the sex specific median (97.16% vs 97.0%, log rank p= 0.713). In the univariate Cox proportional hazard analysis, plasma sphingomyelin was not a predictor of incident CHD event [hazard ratio 0.992(0.982 – 1.004), p=0.09]. In our multistage multivariable Cox models, higher plasma sphingomyelin had modest negative association with incident CHD events when total cholesterol, HDL and triglycerides were included in the model [hazard ratio 0.985 (0.973 – 0.996), p=0.008] and also in our full model after adjusting for age, gender, total cholesterol, HDL, triglycerides, diabetes, cigarette smoking, systolic BP, diastolic BP, BP medication use, HMG CoA use [hazard ratio 0.984 (0.973 – 0.996), p=0.002]. In other models, plasma sphingomyelin was not associated with incident CHD events.
Conclusion
High plasma sphingomyelin level is not associated with increased risk of incident coronary heart disease in population based adults free of clinical cardiovascular disease at baseline.
doi:10.1161/ATVBAHA.109.199281
PMCID: PMC2862629  PMID: 20032291
Plasma sphingomyelin; prognosis; coronary heart disease events; epidemiology
21.  The Impact of Obesity on the Left Ventricle 
JACC. Cardiovascular imaging  2010;3(3):266-274.
OBJECTIVES
The purpose of this study was to evaluate the relationship of left ventricular (LV) remodeling assessed by cardiac magnetic resonance to various measures of obesity in a large population-based study.
BACKGROUND
Obesity is a well-known risk factor for cardiovascular disease, yet its relationship with LV size and function is poorly understood.
METHODS
A total of 5,098 participants (age 45 to 84 years; 48% men) in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cardiovascular disease underwent cardiac magnetic resonance to assess LV size and function as well as measures of obesity, including body mass index, waist-to-hip ratio and waist circumference, and cardiovascular risk factors. Fat mass (FM) was estimated based on height-weight models derived from bioelectrical impedance studies. The associations of obesity measures with LV size and function were evaluated using linear spline regression models for body mass index and multivariable regression models for other measures of obesity; they were displayed graphically using generalized additive models.
RESULTS
LV mass and end-diastolic volume were positively associated with measures of obesity in both sexes after adjustment for risk factors (e.g., 5.7-g and 6.9-g increase in LV mass per 10-kg increase in FM in women and men, respectively [p < 0.001]). LV mass-to-volume ratio was positively associated with increased body mass index, waist-to-hip ratio, waist circumference, and estimated FM (e.g., 0.02-g/ml and 0.06-g/ml increase in mass-to-volume ratio per 10-kg increase in FM in women and men, respectively [p < 0.001]). The increased mass-to-volume ratio was due to a greater increase in LV mass relative to LV end-diastolic volume. All associations were stronger for men than for women. Ejection fraction showed no significant association with measures of obesity.
CONCLUSIONS
Obesity was associated with concentric LV remodeling without change in ejection fraction in a large, multiethnic cohort study.
doi:10.1016/j.jcmg.2009.10.012
PMCID: PMC3037096  PMID: 20223423
cardiac magnetic resonance; cardiac morphology; epidemiology; left ventricular function; obesity
22.  Differences in the Incidence of Congestive Heart Failure by Ethnicity 
Archives of internal medicine  2008;168(19):2138-2145.
Background
The relationship between incident congestive heart failure (CHF) and ethnicity as well as racial/ethnic differences in the mechanisms leading to CHF have not been demonstrated in a multiracial, population-based study. Our objective was to evaluate the relationship between race/ethnicity and incident CHF.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study of 6814 participants of 4 ethnicities: white (38.5%), African American (27.8%), Hispanic (21.9%), and Chinese American (11.8%). Participants with a history of cardiovascular disease at baseline were excluded. Cox proportional hazards models were used for data analysis.
Results
During a median follow-up of 4.0 years, 79 participants developed CHF (incidence rate: 3.1 per 1000 person-years). African Americans had the highest incidence rate of CHF, followed by Hispanic, white, and Chinese American participants (incidence rates: 4.6, 3.5, 2.4, and 1.0 per 1000 person-years, respectively). Although risk of developing CHF was higher among African American compared with white participants (hazard ratio, 1.8; 95% confidence interval, 1.1-3.1), adding hypertension and/or diabetes mellitus to models including ethnicity eliminated statistical ethnic differences in incident CHF. Moreover, African Americans had the highest proportion of incident CHF not preceded by clinical myocardial infarction (75%) compared with other ethnic groups (P = .06).
Conclusions
The higher risk of incident CHF among African Americans was related to differences in the prevalence of hypertension and diabetes mellitus as well as socioeconomic status. The mechanisms of CHF also differed by ethnicity; interim myocardial infarction had the least influence among African Americans, and left ventricular mass increase had the greatest effect among Hispanic and white participants.
doi:10.1001/archinte.168.19.2138
PMCID: PMC3038918  PMID: 18955644
23.  Coronary Artery Calcium Score and Risk Classification for Coronary Heart Disease Prediction: The Multi-Ethnic Study of Atherosclerosis 
Context
Coronary artery calcium score (CACS) has been shown to predict future coronary heart disease (CHD) events. However, the extent to which adding CACS to traditional CHD risk factors improves classification of risk is unclear.
Objective
To determine whether adding CACS to a prediction model based on traditional risk factors improves classification of risk.
Design, Setting and Participants
CACS was measured by computed tomography on 6,814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort without known cardiovascular disease. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2008. Participants with diabetes were excluded for the primary analysis. Five-year risk estimates for incident CHD were categorized as 0-<3%, 3-<10%, and ≥10% using Cox proportional hazards models. Model 1 used age, gender, tobacco use, systolic blood pressure, antihypertensive medication use, total and high-density lipoprotein cholesterol, and race/ethnicity. Model 2 used these risk factors plus CACS. We calculated the net reclassification improvement (NRI) and compared the distribution of risk using Model 2 versus Model 1.
Main Outcome Measures
Incident CHD events
Results
Over 5.8 years median follow-up, 209 CHD events occurred, of which 122 were myocardial infarction, death from CHD, or resuscitated cardiac arrest. Model 2 resulted in significant improvements in risk prediction compared to Model 1 (NRI=0.25, 95% confidence interval 0.16-0.34, P<0.001). With Model 1, 69% of the cohort was classified in the highest or lowest risk categories, compared to 77% with Model 2. An additional 23% of those who experienced events were reclassified to high risk, and an additional 13% without events were reclassified to low risk using Model 2.
Conclusions
In the MESA cohort, addition of CACS to a prediction model based on traditional risk factors significantly improved the classification of risk and placed more individuals in the most extreme risk categories.
doi:10.1001/jama.2010.461
PMCID: PMC3033741  PMID: 20424251
24.  Age-Modification of Lipoprotein, Lipid, and Lipoprotein Ratio-Associated Risk for Coronary Artery Calcium (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2009;105(3):352-358.
Though abnormal lipoproteins and lipoprotein ratios are powerful risk factors for clinical cardiovascular (CV) events, these associations are stronger in younger compared to older age. Whether age modifies the relationships of lipoproteins and lipoprotein ratios to the relative risk for subclinical CV disease (CVD), as assessed by coronary artery calcium (CAC) scores, has not been examined in a contemporary, multi-ethnic cohort. We performed multivariate relative risk regression to determine the relative risks (RRs) for associations of lipoproteins and lipoprotein ratios with prevalent CAC in participants in MESA. Participants were community-dwelling adults ages 45–84 years without baseline clinically apparent CVD. We excluded those on lipid lowering therapy (15%), and stratified results by decades of age. 5,092 participants met inclusion criteria. In fully adjusted models, per standard deviation (SD) of low-density lipoprotein (LDL), age-stratified, adjusted relative risks (RRs) for CAC were 1.17 (95% Confidence Interval (CI) 1.07–1.28) for those aged 45–54 but 1.05 (95% CI 1.01–1.10) for those aged 75–84 (p-interaction = 0.12). The RR per SD of Total/HDL cholesterol ratio was 1.20 (95% CI 1.12–1.29) for those aged 45–54 but only 1.04 (1.00–1.09) for those aged 75–84 (p-interaction <0.001). Lipoproteins and lipoprotein ratios were associated with increased RRs for CAC across all age categories. However, these associations were markedly attenuated by age. In conclusion, abnormal lipoproteins in middle age are a powerful risk factor for early atherosclerosis as manifested by prevalent CAC.
doi:10.1016/j.amjcard.2009.09.040
PMCID: PMC2855892  PMID: 20102947
lipoproteins; age; coronary artery calcium
25.  Combined Association of Lipids and Blood Pressure in Relation to Incident Cardiovascular Disease in the Elderly: The Cardiovascular Health Study 
American Journal of Hypertension  2010;23(2):161-167.
Background
Hypertension and dyslipidemia are highly prevalent in the elderly. We studied the combined impact of both conditions on cardiovascular disease (CVD) events.
Methods
We studied 4,311 participants aged 65–98 (61.2% female) from the Cardiovascular Health Study (CHS), a longitudinal epidemiologic study, with no prior CVD. We evaluated the relation of low-density lipoprotein (LDL), high-density lipoprotein (HDL), or non-HDL-cholesterol combined with blood pressure (BP) categories to incident CVD—including coronary heart disease (CHD) (angina, myocardial infarction (MI), angioplasty, coronary bypass surgery, or CHD death), stroke, claudication, and CVD death over 15 years.
Results
CVD incidence (per 1,000 person years) ranged from 38.4 when BP <120/80mmHg and LDL-C <100mg/dl to 94.8 when BP ≥160/100mmHg and LDL-C ≥160mg/dl, and from 28.9 when BP <120/80mmHg and HDL >60mg/dl to 87.1 for a BP ≥160/100 and HDL-C <40mg/dl. Compared with those with BP <120/80mmHg with either LDL-C <100mg/dl or HDL-C >60mg/dl, hazard ratios (HRs) for CVD events were 2.1 when BP ≥160/100mmHg and LDL-C ≥160mg/dl and 2.1 when BP ≥160/100 and HDL-C <40mg/dl (all P < 0.01), with similar results for non-HDL-C. Elevated BP was associated with increased risk across all lipid levels. Increased LDL-C added risk mainly when BP <140/90mmHg, but lower HDL-C also predicted CVD in those with higher BP.
Conclusion
Increased BP confers increased risks for CVD in elderly persons across all lipid levels. Although increased LDL-C added risk mainly when BP <140/90mmHg, low HDL-C added risk also in those with hypertension. These results document the importance of combined hypertension and dyslipidemia.
doi:10.1038/ajh.2009.216
PMCID: PMC3803135  PMID: 19927131
blood pressure; cardiovascular disease; dyslipidemia; hypertension; risk factors

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