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1.  Race/Ethnic And Sex Differences In Large And Small Artery Elasticity – Results Of The Multi-Ethnic Study Of Atherosclerosis (MESA) 
Ethnicity & disease  2009;19(3):243-250.
Reduction in arterial elasticity marks progression toward cardiovascular morbidity and mortality. Variability in arterial elasticity may help account for race/ethnic and gender differences in cardiovascular risk.
Cross-sectional study.
Whites, African Americans, Hispanics and Chinese aged 45–84 years free of clinically recognized cardiovascular disease were recruited in six US communities.
We examined 3,316 women and 3,020 men according to race/ethnicity and sex.
Main Outcome Measures
Large (LAE) and small artery (SAE) elasticity, derived from radial artery diastolic pulse wave contour registration in all subjects in a supine position using tonometry. LAE and SAE were adjusted for ethnicity, age, clinical site, height, heart rate, blood pressure, antihypertensive medication and body mass index, diabetes, smoking, and circulating lipids.
Much of the sex difference in arterial elasticity was explained by height. After adjustment, LAE did not differ by race/ethnicity, but mean SAE in African Americans was 4.2 mL/mm Hg × 100 and 4.4 mL/mm Hg × 100 in Hispanics compared to means of 4.6 mL/mm Hg × 100 in Whites, and 4.8 mL/mm Hg × 100 in Chinese.
Reduced SAE may indicate earlier vascular disease in African Americans and Hispanics than other groups.
PMCID: PMC2924814  PMID: 19769004
Blood Pressure; Arterial Elasticity; MESA Study
2.  Associations among Lung Function, Arterial Elasticity and Circulating Endothelial and Inflammation Markers: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(2):542-548.
A parallel physiologic pathway for elastic changes is hypothesized for declines in arterial elasticity and lung function. Endothelial dysfunction and inflammation could potentially decrease elasticity of both vasculature and lung tissue. We examined biomarkers, large (LAE) and small (SAE) arterial elasticity, and forced vital capacity (FVC) in a period cross-sectional design in the Multi-Ethnic Study of Atherosclerosis, which recruited 1,823 women and 1,803 men, age range 45–84 years, black, white, Hispanic, and Chinese, free of clinically recognized CVD. Radial artery tonometric pulse waveform registration was performed and LAE and SAE were derived from diastole. Spirometric data and markers of endothelial dysfunction and inflammation (soluble intracellular adhesion molecule-1, fibrinogen, hs-C-reactive protein, and interleukin-6) were obtained. Mean LAE was 13.7 ± 5.5 ml/mmHgx10 and SAE was 4.6 ± 2.6 ml/mmHgx100. Mean FVC was 3,192 ± 956.0 mL and FEV1 was 2,386 ± 734.5 mL. FVC was about 40 ± 5 mL higher per SD of SAE, stronger in men than women. The association was slightly weaker with LAE, with no sex interaction. After regression adjustment for demographic, anthropometric, and cardiovascular risk factors, the biomarkers tended to be related to reduced SAE and FVC, particularly in men. These biomarker associations suggest important CVD risk alterations that occur concurrently with lower arterial elasticity and lung function. The observed positive association of SAE with FVC and with FEV1 in middle-aged to older free-living people is consistent with the hypothesis of parallel physiologic pathways for elastic changes in the vasculature and in lung parenchymal tissue.
PMCID: PMC3586233  PMID: 23283358
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
3.  Untreated HIV Infection and Large and Small Artery Elasticity 
Untreated HIV infection may increase risk for cardiovascular disease, and arterial elasticity is a marker of cardiovascular risk and early disease.
HIV-infected participants not taking antiretroviral therapy (n = 32) were compared with HIV-negative controls (n = 30). Large and small artery elasticity (LAE and SAE) were estimated via analysis of radial pulse waveforms. Differences in LAE and SAE by HIV status were compared using analysis of covariance, with and without adjustment for Framingham risk (model 1); covariates that differed between groups [smoking, injection drug use, hepatitis C, and high-density lipoprotein cholesterol (HDLc); model 2]; or age, sex, race/ethnicity, smoking, injection drug use, hepatitis C, HDLc, and non-HDLc (model 3).
HIV infection was associated with impaired LAE (−2.55 mL/mm Hg × 10; P = 0.02) and SAE (−1.50 mL/mm Hg × 100; P = 0.02). Associations with traditional risk factors were often stronger for SAE than LAE, including with Framingham score (per 1% higher; SAE −0.18, P = 0.01; LAE −0.19, P = 0.13). Fasting lipid levels were not significantly associated with LAE and SAE. After adjustment, differences between HIV-infected and HIV-uninfected participants were similar in model 1 (−2.36 for LAE, P = 0.04; −1.31 for SAE, P = 0.04), model 2 (−2.67 for LAE, P = 0.02; −1.13 for SAE, P = 0.07) and model 3 (−2.91 for LAE, P = 0.02; −1.34 for SAE, P = 0.03). CD4 count and HIV RNA level were not associated with LAE and SAE among HIV-infected participants.
Untreated HIV infection is associated with impaired arterial elasticity, of both the large and small vasculature, after controlling for additional risk factors. Pulse waveform analysis is a noninvasive technique to assess cardiovascular disease risk that should be evaluated in larger studies of HIV-infected persons.
PMCID: PMC2764552  PMID: 19731451
arterial elasticity; arterial stiffness; cardiovascular disease; endothelial dysfunction; HIV; untreated HIV infection
4.  Association between Endothelial Biomarkers and Arterial Elasticity in Young Adults – The CARDIA Study 
Reduced arterial elasticity and endothelial dysfunction both may indicate early cardiovascular (CV) disease in young adults. Pulse waveform analysis estimates large (LAE) and small (SAE) artery elasticity noninvasively. We assessed the associations between LAE and SAE and markers of endothelial dysfunction and CV risk factors.
The Coronary Artery Risk Development in Young Adults (CARDIA) assessed arterial elasticity and other characteristics cross-sectionally in 389 men and 381 women aged 27–42 years in 1995 (CARDIA year 10) and circulating levels of P-selectin and soluble intercellular adhesion molecule 1 (sICAM-1) in 2000. We adjusted for variables included in the estimation of arterial elasticity (year 10 height, body mass index, age, heart rate, and blood pressure) and other year 10 characteristics.
Mean adjusted SAE was 8.5 vs. 7.6 ml/mmHg ×100 in those with urine albumin/creatinine ratio ≤4 vs. microalbuminuria (ratio > 25; ptrend =0.008). Mean LAE was 25.6 vs. 24.2 ml/mmHg ×10 in the lowest vs. highest quintile of P-selectin (ptrend =0.004). sICAM-1 was unrelated to either LAE or SAE. Plasma triglycerides were inversely related to LAE (ptrend =0.029). Cigarette smokers had lower SAE than nonsmokers (ptrend = 0.009).
In addition to smoking and triglycerides, biomarkers for endothelial dysfunction were associated with impaired LAE and SAE in young adults.
PMCID: PMC2390876  PMID: 19343081
Blood lipids; smoking; albuminuria; endothelial dysfunction
5.  Association of Self-Reported Race/Ethnicity and Genetic Ancestry with Arterial Elasticity: The Multi-Ethnic Study of Atherosclerosis (MESA) 
African-Americans have a disproportionate burden of hypertension compared to Caucasians, while data on Hispanics is less well-defined. Mechanisms underlying these differences are unclear, but could be due in part to ancestral background and vascular function.
Methods and Results
660 African-Americans and 635 Hispanics from the Multi-Ethnic Study of Atherosclerosis (MESA) with complete data on genetic ancestry, pulse pressure (PP), and large and small arterial elasticity (LAE, SAE) were studied. LAE and SAE were obtained using the HDI PulseWave CR-2000 Research CardioVascular Profiling Instrument. Among African-Americans higher European ancestry was marginally associated with higher LAE (p=0.05) and lower PP (p=0.05) among African-Americans; results for LAE were attenuated after adjustment for potential mediators (p=0.30). Ancestry was not associated with SAE in African-Americans. Among Hispanics, higher Native American ancestry was associated with higher SAE (p=0.0006); higher African ancestry was marginally associated with lower SAE (p=0.07). Ancestry was not significantly associated with LAE or PP in Hispanics.
Among African-Americans, higher European ancestry may be associated with less large artery damage as measured by LAE and PP, although these associations warrant further study. Among Hispanics, ancestry is strongly associated with SAE. Future studies should consider information on genetic ancestry when studying hypertension burden in race/ethnic minorities, particularly among Hispanics.
PMCID: PMC3218223  PMID: 21890448
large artery elasticity; small artery elasticity; admixture; pulse pressure
6.  Association of Pulse Pressure, Arterial Elasticity, and Endothelial Function With Kidney Function Decline Among Adults With Estimated GFR > 60 mL/min/1.73 m2: The Multi-Ethnic Study of Atherosclerosis 
The association of subclinical vascular disease and early declines in kidney function has not been well studied.
Study Design
Prospective cohort study
Setting & Participants
MESA participants with eGFR ≥60 ml/min/1.73m2 with follow-up of 5 years
Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.
kidney function decline
SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was measured by serum creatinine- and cystatin C-based eGFR.
Among 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared to persons with pulse pressure 40–50mmHg, eGFRSCysC decline was 0.29 (p=0.006), 0.56 (p<0.001), and 0.91 (p<0.001) ml/min/1.73m2/year faster among persons with pulse pressure 50–60, 60–70, and >70mmHg, respectively. Compared to the highest quartile of SAE (most elastic), eGFRSCysC decline was 0.26 (p=0.009), 0.35 (p=0.001), and 0.70 (p<0.001) ml/min/1.73m2/year faster for the second, third and fourth quartiles respectively. For LAE, compared to the highest quartile, eGFRSCysC decline was 0.28 (p=0.004), 0.58 (p<0.001), and 0.83 (p<0.001) ml/min/1.73m2/year faster for each decreasing quartile of LAE. Findings were similar with creatinine-based eGFR. In contrast, among 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not significantly associated with kidney function decline. For every 1-SD greater flow-mediated dilation, eGFRSCysC and eGFRSCr changed by 0.05 ml/min/1.73m2/year (p=0.3) and 0.06 ml/min/1.73m2/year (p=0.04), respectively.
We had no direct measure of GFR, in common with nearly all large population based studies.
Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were linearly and independently associated with faster kidney function decline among persons with eGFR ≥60 ml/min/1.73m2. Future studies investigate whether treatments to lower stiffness of large and small arteries may slow the rate of kidney function loss.
PMCID: PMC3242889  PMID: 22000727
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
7.  The Differential Association of Kidney Dysfunction With Small and Large Arterial Elasticity 
American Journal of Epidemiology  2009;169(6):740-748.
Vascular remodeling may be a mechanism linking chronic kidney disease to cardiovascular disease. Whether early kidney dysfunction is associated with small and large arterial remodeling is not well understood. Using multivariable linear regression, back-transforming beta-coefficients to relative difference, the authors studied the association of cystatin C, creatinine-based estimated glomerular filtration rate (GFR), and albuminuria with small (SAE) and large (LAE) arterial elasticity and aortic distensibility among 6,282 participants in the Multiethnic Study of Atherosclerosis at baseline (2000–2002). Compared with the lowest quintile, higher quintiles of cystatin C were incrementally associated with lower SAE: third quintile relative difference = −5% (95% confidence interval (CI): −8, −2); fourth quintile relative difference = −10% (95% CI: −13, −8); and highest quintile relative difference = −16% (95% CI: −20, −12). By use of creatinine, the association was observed only among those with chronic kidney disease (estimated GFR, <60 mL/minute/1.73 m2): relative difference = −9% (95% CI: −13, −4). Albuminuria was significantly associated with lower SAE: relative difference = −6% (95% CI: −10, −1). Cystatin C was associated with lower LAE only at the highest quintile (relative difference = −3%, 95% CI: −6, 0) compared with the lowest quintile. By use of creatinine, chronic kidney disease was not independently associated with LAE (P = 0.912). Cystatin C, estimated GFR, and albuminuria were not associated with aortic distensibility (P = 0.26, 0.48, 0.45). Early kidney dysfunction is significantly associated with decreased arterial elasticity in smaller arteries and, to a lesser degree, in larger arteries.
PMCID: PMC2727212  PMID: 19131564
albuminuria; cystatin C; elasticity; kidney; kidney diseases
8.  Cardiovascular Imaging for Assessing Cardiovascular Risk in Asymptomatic Men Versus Women 
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).
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.
PMCID: PMC3037859  PMID: 21068189
imaging; cardiovascular diseases; sex
9.  Age-Related Macular Degeneration and Incident Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Ophthalmology  2011;119(4):765-770.
To determine whether age-related macular degeneration (AMD) is a risk indicator for coronary heart disease (CHD) and cardiovascular disease (CVD) events independent of other known risk factors in a multi-ethnic cohort.
Population-based prospective cohort study.
A diverse population sample of 6233 men and women aged 45–84 without known CVD from the Multi-Ethnic Study of Atherosclerosis (MESA).
Participants in the MESA had retinal photographs taken between 2002 and 2003. Photographs were evaluated for AMD. Incident CHD/CVD events were ascertained during clinical follow-up visits for up to 8 years after the retinal images were taken.
Main Outcome Measures
Incident CHD/CVD events.
Of the 6814 persons at risk of CHD, there were 893 participants with early AMD (13.1%) and 27 (0.5%) at baseline. Over a mean follow-up period of 5.4 years, there was no statistically significant difference in incident CHD or CVD between the AMD and non-AMD groups (5.0%vs. 3.9%, p=0.13 for CHD and 6.6 vs. 5.5%, p=0.19 for CVD, respectively). In Cox regression models adjusting for CVD risk factors, there was no significant relationship between presence of any AMD and any CHD/CVD events (HR=0.99, 95% CI 0.74–1.33, p=0.97). No significant association was found between subgroups of early AMD or late AMD and incident CHD/CVD events.
In persons without a history of cardiovascular disease, AMD was not associated with an increased risk of CHD or CVD.
PMCID: PMC3314126  PMID: 22197438
10.  Erectile dysfunction, physical activity and metabolic syndrome: differences in markers of atherosclerosis 
Erectile dysfunction (ED), impaired arterial elasticity, elevated resting heart rate as well as increased levels of oxidized LDL and fibrinogen associate with future cardiovascular events. Physical activity is crucial in the prevention of cardiovascular diseases (CVD), while metabolic syndrome (MetS) comprises an increased risk for CVD events. The aim of this study was to assess whether markers of subclinical atherosclerosis are associated with the presence of ED and MetS, and whether physical activity is protective of ED.
57 MetS (51.3 ± 8.0 years) and 48 physically active (PhA) (51.1 ± 8.1 years) subjects participated in the study. ED was assessed by the International Index of Erectile Function (IIEF) questionnaire, arterial elasticity by a radial artery tonometer (HDI/PulseWave™ CR-2000) and circulating oxLDL by a capture ELISA immunoassay. Fibrinogen and lipids were assessed by validated methods. The calculation of mean daily energy expenditure of physical exercise was based on a structured questionnaire.
ED was more often present among MetS compared to PhA subjects, 63.2% and 27.1%, respectively (p < 0.001). Regular physical exercise at the level of > 400 kcal/day was protective of ED (OR 0.12, 95% CI 0.017-0.778, p = 0.027), whereas increased fibrinogen (OR 4.67, 95% CI 1.171-18.627, p = 0.029) and elevated resting heart rate (OR 1.07, 95% CI 1.003-1.138, p = 0.04) were independently associated with the presence of ED. In addition, large arterial elasticity (ml/mmHgx10) was lower among MetS compared to PhA subjects (16.6 ± 4.0 vs. 19.6 ± 4.2, p < 0.001), as well as among ED compared to non-ED subjects (16.7 ± 4.6 vs. 19.0 ± 3.9, p = 0.008). Fibrinogen and resting heart rate were highest and large arterial elasticity lowest among subjects with both MetS and ED.
Markers of subclinical atherosclerosis associated with the presence of ED and were most evident among subjects with both MetS and ED. Thus, especially MetS patients presenting with ED should be considered at high risk for CVD events. Physical activity, on its part, seems to be protective of ED.
Trial registration NCT01119404
PMCID: PMC3157429  PMID: 21707993
11.  Atherosclerosis profile and incidence of cardiovascular events: a population-based survey 
Atherosclerosis is a chronic progressive disease often presenting as clinical cardiovascular disease (CVD) events. This study evaluated the characteristics of individuals with a diagnosis of atherosclerosis and estimated the incidence of CVD events to assist in the early identification of high-risk individuals.
Respondents to the US SHIELD baseline survey were followed for 2 years to observe incident self-reported CVD. Respondents had subclinical atherosclerosis if they reported a diagnosis of narrow or blocked arteries/carotid artery disease without a past clinical CVD event (heart attack, stroke or revascularization). Characteristics of those with atherosclerosis and incident CVD were compared with those who did not report atherosclerosis at baseline but had CVD in the following 2 years using chi-square tests. Logistic regression model identified characteristics associated with atherosclerosis and incident events.
Of 17,640 respondents, 488 (2.8%) reported having subclinical atherosclerosis at baseline. Subclinical atherosclerosis was associated with age, male gender, dyslipidemia, circulation problems, hypertension, past smoker, and a cholesterol test in past year (OR = 2.2) [all p < 0.05]. Incident CVD was twice as high in respondents with subclinical atherosclerosis (25.8%) as in those without atherosclerosis or clinical CVD (12.2%). In individuals with subclinical atherosclerosis, men (RR = 1.77, p = 0.050) and individuals with circulation problems (RR = 2.36, p = 0.003) were at greatest risk of experiencing CVD events in the next 2 years.
Self-report of subclinical atherosclerosis identified an extremely high-risk group with a >25% risk of a CVD event in the next 2 years. These characteristics may be useful for identifying individuals for more aggressive diagnostic and therapeutic efforts.
PMCID: PMC2753582  PMID: 19754940
12.  Coronary Artery Calcification Compared with Carotid Intima-Media Thickness in Prediction of Cardiovascular Disease Incidence: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Archives of internal medicine  2008;168(12):1333-1339.
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence.
To assess whether maximum carotid IMT or CAC (Agatston Score) is the better predictor of incident CVD.
Design, Setting, Patients
Prospective cohort study of 45–84 year-olds initially free of CVD (n = 6,698) in four ethnic groups, with standardized carotid IMT and CAC measures at baseline, in six field centers of the Multi-Ethnic Study of Atherosclerosis (MESA).
Main Outcome Measure(s)
Incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up.
There were 222 CVD events during follow-up. CAC was associated more strongly than carotid IMT with risk of incident CVD. After adjustment for each other and traditional CVD risk factors, the hazard of CVD increased 2.1-fold (95% CI 1.8–2.5) for each standard deviation greater level of log-transformed CAC, versus 1.3-fold (95% CI 1.1–1.4) for each standard deviation greater maximum IMT. For coronary heart disease, the hazard ratios per standard deviation increment were 2.5-fold (95% CI 2.1–3.1) for CAC and 1.2-fold (95% CI 1.0–1.4) for IMT. An ROC analysis also suggested that CAC predicted incident CVD better than IMT did.
Although whether and how to clinically use bio-imaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC predicts subsequent CVD events better than does carotid IMT.
PMCID: PMC2555989  PMID: 18574091
13.  The Effect of Including Cystatin C or Creatinine in a Cardiovascular Risk Model for Asymptomatic Individuals 
American Journal of Epidemiology  2011;174(8):949-957.
The authors studied the incremental value of adding serum cystatin C or creatinine to the Framingham risk score variables (FRSVs) for the prediction of incident cardiovascular disease (CVD) among 6,653 adults without clinical CVD utilizing the Multi-Ethnic Study of Atherosclerosis (2000–2008). CVD events included coronary heart disease, heart failure, stroke, and peripheral arterial disease. Variables were transformed to yield optimal prediction of 6-year CVD events in sex-stratified models with FRSVs alone, FRSVs + cystatin C, and FRSVs + creatinine. Risk prediction in the 3 models was assessed by using the C statistic, and net reclassification improvement was calculated. The mean ages were 61.9 and 64.6 years for individuals with and without diabetes, respectively. After 6 years of follow-up, 447 (7.2%) CVD events occurred. In the total cohort, no significant change in the C statistic was noted with FRSVs + cystatin C and FRSVs + creatinine compared with FRSVs alone, and net reclassification improvement for CVD risk was extremely small and not significant with the addition of cystatin C or creatinine to FRSVs. Similar findings were noted after stratifying by baseline presence of diabetes. In conclusion, the addition of cystatin C or serum creatinine to FRSVs does not improve CVD risk prediction among adults without clinical CVD.
PMCID: PMC3218629  PMID: 21880578
cardiovascular diseases; creatinine; cystatin C; risk model
14.  Carotid arterial wall characteristics are associated with incident ischemic stroke but not coronary heart disease in the ARIC Study 
Background and Purpose
Ultrasound measurements of arterial stiffness are associated with atherosclerosis risk factors, but limited data exist on their association with incident cardiovascular events. We evaluated the association of carotid ultrasound derived arterial stiffness measures with incident coronary heart disease (CHD) and ischemic stroke in the ARIC study.
Carotid arterial strain (CAS) and compliance (AC), distensibility (AD) and stiffness indices (SI), pressure-strain (Ep) and Young’s elastic moduli (YEM) were measured in 10,407 individuals using ultrasound. Hazard ratios for incident CHD (myocardial infarction [MI], fatal CHD, coronary revascularization) and stroke in minimally adjusted (age, sex, center, race) and fully adjusted models (minimally adjusted model + diabetes, height, weight, total cholesterol, high-density lipoprotein cholesterol, tobacco use, systolic blood pressure, antihypertensive medication use, and carotid intima-media thickness (CIMT) were calculated.
The mean age was 55.3 years. Over a mean follow up of 13.8 years, 1,267 incident CHD and 383 ischemic stroke events occurred. After full adjustment for risk factors and CIMT, all arterial stiffness parameters [CAS HR (95% confidence interval [CI]) =1.14 (1.02, 1.28); AD HR=1.19 (1.02, 1.39); SI HR=1.14 (1.04, 1.25); Ep HR=1.17 (1.06, 1.28); YEM HR=1.13 (1.03, 1.24)], except arterial compliance HR=1.02 (0.90, 1.16), were significantly associated with incident stroke but not with CHD.
After adjusting for cardiovascular risk factors, ultrasound measures of carotid arterial stiffness are associated with incident ischemic stroke but not incident CHD events, despite that the 2 outcomes sharing similar risk factors.
PMCID: PMC3246524  PMID: 22033999
arterial stiffness; carotid ultrasound; coronary heart disease; stroke; ARIC
15.  Associations of factor VIIIc, D-dimer and plasmin-antiplasmin with incident cardiovascular disease and all-cause mortality 
American journal of hematology  2009;84(6):349-353.
To examine the associations of three understudied hemostatic factors – D-dimer, factor VIIIc, and antiplasmin (PAP) complex -- with incident CVD and all cause mortality in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Hemostatic factors were measured at baseline in 45–84 year olds (n =6,391) who were free of clinically recognized CVD. Over 4.6 years of follow-up, we identified 307 CVD events, 207 hard coronary heart disease (CHD) events, and 210 deaths. D-dimer, factor VIIIc, and PAP were not associated with CVD incidence after adjustment for other risk factors. In contrast, each factor was associated positively with total mortality, and D-dimer and factor VIIIc were associated positively with cancer mortality. When modeled as ordinal variables and adjusted for risk factors, total mortality was greater by 33% (95% CI = 15–54%) for each quartile increment of D-dimer, 26% (11–44%) for factor VIIIc, and 20% (4–38%) for PAP. This prospective cohort study did not find D-dimer, factor VIIIc, or PAP to be risk factors for CVD. Instead, elevated levels of these three hemostatic factors were associated independently with increased risk of death. Elevated D-dimer and factor VIIIc were associated with increased cancer death.
PMCID: PMC2950108  PMID: 19472201
cancer; cardiovascular disease; CHD; D-dimer; factor VIII; plasmin-antiplasmin
16.  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.
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
17.  Is Diabetic Retinopathy Related to Subclinical Cardiovascular Disease? 
Ophthalmology  2010;118(5):860-865.
Persons with diabetic retinopathy (DR) have an increased risk of clinical cardiovascular events. Our study aimed to determine whether DR is associated with a range of measures of subclinical cardiovascular disease (CVD) in persons without clinical CVD.
Population-based, cross-sectional epidemiologic study
Nine hundred and twenty seven persons with diabetes without clinical CVD in the Multi-Ethnic Study of Atherosclerosis.
DR was ascertained from retinal photographs according to modification of the Airlie House Classification system. Vision threatening DR (VTDR) was defined as severe non-proliferative DR, proliferative DR or clinically significant macular edema. Subclinical CVD measures were assessed and defined as follows: high coronary artery calcium (CAC) score, defined as CAC score≥400; low ankle-brachial index (ABI), defined as ABI<0.9; high ABI, defined as ABI≥1.4; high carotid intima-media thickness (IMT), defined as highest 25% of IMT; and carotid stenosis, defined as >25% stenosis or presence of carotid plaque.
Associations between DR and subclinical CVD measures.
The prevalence of DR and VTDR in this sample was 30.0% and 7.2%, respectively. VTDR was associated with a high CAC score (odds ratio [OR] 2.33, 95% condifence interval [CI] 1.15–4.73), low ABI (OR 2.54; 95%CI, 1.08–5.99) and high ABI (OR 12.6, 95% CI, 1.14, 140.6), after adjusting for risk factors including hemoglobin A1c level and duration of diabetes. The association between VTDR and high CAC score remained significant after further adjustment for hypoglycemic, anti-hypertensive and cholesterol-lowering medications. DR was not significantly associated with measures of carotid artery disease.
In persons with diabetes without a history of clinical CVD, the presence of advanced stage of DR is associated with subclinical coronary artery disease. These findings emphasize the need to be careful about the use of anti-vascular endothelial growth factor for the treatment of DR.
PMCID: PMC3087839  PMID: 21168222
18.  Predictive Value of Brachial Flow-Mediated Dilation for Incident Cardiovascular Events in a Population-Based Study: The Multi-Ethnic Study of Atherosclerosis 
Circulation  2009;120(6):502-509.
Although brachial artery flow-mediated dilation (FMD) predicts recurrent cardiovascular events, its predictive value for incident cardiovascular disease (CVD) events in adults free of CVD is not well established. We assessed the predictive value of FMD for incident CVD events in the Multi Ethnic Study of Atherosclerosis (MESA).
Methods and Results
Brachial artery FMD was measured in a nested case- cohort sample of 3026 out of 6814 subjects (mean ± SD age 61.2 ± 9.9 years), in MESA, a population-based cohort study of adults free of clinical CV disease at baseline recruited at six clinic sites in the USA. The sample comprised 50.2% females, 34.3% Caucasian, 19.7% Chinese, 20.8% African Americans and 25.1% Hispanics. Probability-weighted Cox proportional hazard analysis was used to examine the association between FMD and five years of adjudicated incident CVD events, including incident myocardial infarction, definite angina, coronary revascularization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty or other revascularization), stroke, resuscitated cardiac arrest and CVD death.
Mean (SD) FMD of the cohort was 4.4 (2.8) %. In probability-weighted Cox models, FMD/unit SD was significantly associated with incident cardiovascular events in both the univariate(adjusted for age and gender) [hazard ratio; 0.79(95% CI, 0.65–0.97), p=0.01], after adjusting for the Framingham Risk Score (FRS) [hazard ratio; 0.80(95%CI, 0.62–0.97), p=0.025] and also in multivariable models [hazard ratio; 0.84(95%CI, 0.71–0.99), p=0.04] after adjusting for age, gender, diabetes mellitus, cigarette smoking status, systolic blood pressure, HDL, LDL, triglycerides, heart rate, statin use and blood pressure medication use. The c statistic (AUC) of FMD, FRS, FRS + FMD) were 0.65, 0.74 and 0.74 respectively. Compared with the FRS alone, the addition of FMD to the FRS net correctly re-classifies 52% of subjects with no incident CVD event, but net incorrectly reclassifies 23% of subjects with an incident CVD event; an overall net correct re-classification of 29% (p < 0.001).
Brachial FMD is a predictor of incident cardiovascular events in population based adults. Even though the addition of FMD to the FRS did not improve discrimination of subjects at risk of CVD events in ROC analysis, it did improve the classification of subjects as low, intermediate and high CVD risk compared to the FRS.
PMCID: PMC2740975  PMID: 19635967
Endothelial dysfunction; brachial flow-mediated dilation; incident cardiovascular event; healthy adults
19.  Modulation of Cystatin A Expression in Human Airway Epithelium Related to Genotype, Smoking, COPD and Lung Cancer* 
Cancer research  2011;71(7):2572-2581.
Cystatin A (gene: CSTA), is up-regulated in non-small-cell lung cancer(NSCLC) and dysplastic vs normal human bronchial epithelium. In the context that chronic obstructive pulmonary disease (COPD), a small airway epithelium (SAE) disorder, is independently associated with NSCLC(especially squamous cell carcinoma, SCC), but only occurs in a subset of smokers, we hypothesized that genetic variation, smoking and COPD modulate CSTA gene expression levels in SAE, with further up-regulation in SCC. Gene expression was assessed by microarray in SAE of 178 individuals [healthy nonsmokers (n=60), healthy smokers (n=82), and COPD smokers (n=36)], with corresponding large airway epithelium (LAE) data in a subset (n=52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were all significantly associated with CSTA SAE gene expression(p<0.04 to 5 × 10 −4). CSTA gene expression levels in SAE were higher in COPD smokers (28.4 ± 2.0) than healthy smokers (19.9 ± 1.4, p<10−3), who in turn had higher levels than nonsmokers(16.1 ± 1.1, p<0.04). CSTA LAE gene expression was also smoking-responsive (p<10−3). Using comparable publicly available NSCLC expression data, CSTA was up-regulated in SCC vs LAE (p<10−2) and down-regulated in adenocarcinoma vs SAE (p <10−7). All phenotypes were associated with significantly different proportional gene expression of CSTA to cathepsins. The data demonstrate that regulation of CSTA expression in human airway epithelium is influenced by genetic variability, smoking, and COPD, and is further up-regulated in SCC, all of which should be taken into account when considering the role of CSTA in NSCLC pathogenesis.
PMCID: PMC3209453  PMID: 21325429
cystatin; small airway epithelium; gene expression; genotype; COPD
20.  Predictors of Residual Cardiovascular Risk in Patients on Statin Therapy for Primary Prevention 
Cardiology  2011;119(4):187-190.
Low-density lipoprotein cholesterol-lowering therapy is an important aspect of primary prevention of cardiovascular disease (CVD). Statins are the most widely used drug therapy for achieving low-density lipoprotein goals based on an individual's 10-year risk. However, substantial risk of CVD events still exists even when a person is on statins. We sought to explore the predictors of future CVD events in individuals on statins with no pre-existing CVD.
The analysis was done on subjects who were on statins (n = 919) at baseline in the Multi-Ethnic Study of Atherosclerosis limited access dataset from the National Heart, Lung and Blood Institute. The primary outcome variable was all-cause CVD events (n = 67). Multivariate regression Cox proportional hazard analysis was done to identify potential independent predictors of all-cause CVD.
Our cohort consisted of 47% males, with a mean age of 66 ± 9 years. Sixty-seven participants (7.3%) experienced CVD events during a mean follow-up of 4.4 years. A higher coronary artery calcium score, homocysteine levels, waist circumference and a lower large arterial elasticity index were identified as independent predictors of CVD events.
Homocysteine, waist circumference, coronary artery calcification and the large artery elasticity index appear to be the major independent predictors of CVD events in individuals on statins with no pre-existing CVD. In addition to emphasizing weight loss, alternative approaches beyond lipid reduction may need to be explored to better characterize and attenuate the residual risk in subjects on statin therapy for primary prevention.
PMCID: PMC3221246  PMID: 21968436
Statin; Primary prevention; Residual risk; Coronary artery calcium; Homocysteine; Waist circumference; Large artery elasticity index
21.  The Association of Incident Cardiovascular Disease with Progression of Sleep-disordered Breathing 
Circulation  2011;123(12):1280-1286.
Prospective data suggest that sleep-disordered breathing enhances risk for incident and recurrent cardiovascular disease (CVD). However, a reverse causal pathway whereby incident CVD causes or worsens sleep-disordered breathing has not been studied.
Methods and Results
2721 Sleep Heart Health Study participants (mean age 62 (SD10) years, 57% women, 23% minority) without CVD at baseline underwent two polysomnograms 5 years apart. Incident CVD events, including myocardial infarction, congestive heart failure and stroke, were ascertained and adjudicated. The relation of incident CVD to change in apnea-hypopnea index (AHI) between the two polysomnograms was tested using general linear models, adjusting for age, sex, race, study center, history of diabetes, change in BMI, change in neck circumference, percent sleep time spent in supine sleep and the time between the two polysomnograms. Incident CVD occurred in 95 participants between the first and second polysomnograms. Compared to participants without incident CVD, those with incident CVD experienced larger increases in AHI between polysomnograms. The difference in adjusted mean AHI change between subjects with and without incident CVD was 2.75 events per hour (95%CI 0.26, 5.24; p=0.032). This association persisted after excluding subjects with central sleep apnea. Compared to participants without incident CVD, participants with incident CVD had greater increases in both mean obstructive and central apnea indices, by 1.75 events per hour (95%CI 0.10, 1.75; p=0.04) and by 1.07 events per hour (95%CI 0.40, 1.74; p=0.001) respectively.
In a diverse, community-based sample of middle-aged and older adults, incident CVD was associated with worsening sleep-disordered breathing over 5 years.
PMCID: PMC3707123  PMID: 21403097
Epidemiology; sleep apnea; cardiovascular diseases
22.  Impact of Subclinical Atherosclerosis on Cardiovascular Disease Events in Individuals With Metabolic Syndrome and Diabetes 
Diabetes Care  2011;34(10):2285-2290.
While metabolic syndrome (MetS) and diabetes confer greater cardiovascular disease (CVD) risk, recent evidence suggests that individuals with these conditions have a wide range of risk. We evaluated whether screening for coronary artery calcium (CAC) and carotid intimal-medial thickness (CIMT) can improve CVD risk stratification over traditional risk factors (RFs) in people with MetS and diabetes.
We assessed CAC and CIMT in 6,603 people aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression examined the association of CAC and CIMT with coronary heart disease (CHD) and CVD over 6.4 years in MetS and diabetes.
Of the subjects, 1,686 (25%) had MetS but no diabetes and 881 (13%) had diabetes. Annual CHD event rates were 1.0% among MetS and 1.5% for diabetes. Ethnicity and RF-adjusted hazard ratios for CHD for CAC 1–99 to ≥400 vs. 0 in subjects with neither MetS nor diabetes ranged from 2.6 to 9.5; in those with MetS, they ranged from 3.9 to 11.9; and in those with diabetes, they ranged from 2.9 to 6.2 (all P < 0.05 to P < 0.001). Findings were similar for CVD. CAC increased the C-statistic for events (P < 0.001) over RFs and CIMT in each group while CIMT added negligibly to prediction over RFs.
Individuals with MetS or diabetes have low risks for CHD when CAC or CIMT is not increased. Prediction of CHD and CVD events is improved by CAC more than by CIMT. Screening for CAC or CIMT can stratify risk in people with MetS and diabetes and support the latest recommendations regarding CAC screening in those with diabetes.
PMCID: PMC3177707  PMID: 21844289
23.  The Population Effects of the Global Cardiovascular Risk Model in United States Adults: Findings from The National Health and Nutrition Surveys 2005–2006 
Journal of clinical lipidology  2011;5(3):166-172.
The Framingham Global Cardiovascular Disease (FRS-CVD) risk assessment is a proposed alternative to assessing hard coronary heart disease (FRS-CHD) event risk. Beyond heart attack and death, FRS-CVD risk adds the endpoints of cerebrovascular disease, angina, heart failure and peripheral vascular disease.
We sought to estimate the population impact of using FRS-CVD instead of FRS-CHD risk prediction on U.S. adults.
We analyzed FRS-CHD and FRS-CVD risk in men age 45–74 and women age 55–74 without cardiovascular disease or diabetes, using the National Health and Nutrition Examination Survey 2005–2006. We stratified the population into 10-year risk categories: low: <6%, moderate ≥6- <10%, moderate high ≥10- <20% and high ≥20% by both risk models, assessing change in risk category distribution and achievement of lipid goals.
We analyzed 1,020 subjects who statistically represent about 50 million U.S. adults. Using FRS-CVD, 63% of men and 74% of women increase at least one risk category compared to FRS-CHD. Overall, the low risk population drops from 52% to 16% and the high-risk group increases from 4% to 20%. Of the subjects changing risk categories, 30% will now fail to meet their new corresponding lipid goals.
FRS-CVD endpoints are more comprehensive, yet the population implications of such a change may be profound. Utilizing a FRS-CVD risk model significantly increases the intermediate and high-risk groups, thus increasing the number of individuals eligible for novel risk assessment tools such as hs-CRP, coronary calcium scoring and more frequent use of pharmacotherapy.
PMCID: PMC3100540  PMID: 21600521
NHANES; epidemiology; primary prevention; risk factors; risk models
24.  Small artery elasticity is decreased in patients with systemic lupus erythematosus without increased intima media thickness 
Arthritis Research & Therapy  2010;12(5):R181.
The objectives of this study were to determine small arterial elasticity (SAE) in systemic lupus erythematosus (SLE) and to investigate its relationship with intima media thickness (IMT), accumulation of advanced glycation end products (AGEs), endothelial activation and inflammation.
Thirty SLE patients with inactive disease and 30 age- and sex-matched healthy controls were included. Twenty patients with essential hypertension (EH) served as positive control. SAE was assessed by pulse-wave analysis using tonometric recordings of the radial artery. IMT of the carotid arteries was measured by ultrasound. AGE accumulation was assessed with an AGE-reader. Endothelial activation markers and C-reactive protein (CRP) were determined by enzyme-linked immunosorbent assay (ELISA).
SAE was decreased in SLE (P = 0.01) and further decreased in EH (P < 0.01) compared to healthy controls. IMT was increased in EH (P < 0.05), but not in SLE. AGE accumulation was increased in SLE (P < 0.05) and further increased in EH (P < 0.01) compared to healthy controls. Endothelial activation markers and CRP were increased in SLE but not in EH. SAE related to AGE accumulation (r = -0.370, P < 0.05), CRP (r = -0.429, P < 0.05) and creatinine clearance (r = 0.440, P < 0.05), but not to IMT and endothelial activation markers. In multivariate analysis SLE was an independent predictor of SAE.
SAE is decreased in SLE patients without increased IMT, independently of traditional cardiovascular risk factors. Longitudinal studies are needed to investigate whether SAE, endothelial activation and AGE accumulation are early markers for cardiovascular disease in SLE.
PMCID: PMC2991012  PMID: 20920173
25.  Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D Study 
HIV medicine  2011;12(7):412-421.
To estimate the rates of cardiovascular disease (CVD) events after stopping smoking in patients with HIV-infection.
Patients who reported smoking status, and no previous CVD prior to enrolment into D:A:D were included. Smoking status is collected at each visit as current smoker (yes/no) and ever smoker (yes/no). Duration since stopping smoking was calculated for persons who had reported current smoking during follow-up and no current smoking subsequently. Endpoints were: myocardial infarction (MI); coronary heart disease (CHD – MI plus invasive coronary artery procedure or death from other CHD); CVD (CVD – CHD plus carotid artery endarterectomy or stroke); and all-cause mortality.
Event rates were calculated for never, previous and current smokers, and smokers who stopped during follow-up. Incidence rate ratios (IRR) were determined using Poisson regression adjusted for age, sex, cohort, calendar year, family history of CVD, diabetes, lipids, blood pressure and antiretroviral treatment.
27,136 patients had smoking status reported, with a total of 432, 600, 746 and 1902 MI, CHD, CVD and mortality events respectively. The adjusted IRR of CVD in patients who stopped smoking during follow-up decreased from 2.32 within the first year of stopping to 1.49 after 3+ years compared to those who never smoked. Similar trends were observed for the MI and CHD endpoints. Reductions in risk were less pronounced for all cause mortality.
The risk of CVD events in HIV-positive patients decreased with increasing time since stopping smoking. Smoking cessation efforts should be a priority in the management of HIV positive patients.
PMCID: PMC3070963  PMID: 21251183
HIV-infection; smoking cessation; myocardial infarction; cardiovascular disease; cohort study

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