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1.  Plasma and serum L-selectin and clinical and subclinical the Multi-Ethnic Study of Atherosclerosis (MESA)cardiovascular disease 
L-selectin has been suggested to play a role in atherosclerosis. Previous studies on cardiovascular disease (CVD) and serum or plasma L-selectin are inconsistent. The association of serum L-selectin (sL-selectin) with carotid intima-media thickness, coronary artery calcium, ankle-brachial index (subclinical CVD) and incident CVD was assessed within 2403 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Regression analysis and the Tobit model were used to study subclinical disease; Cox Proportional Hazards regression for incident CVD. Mean age was 63 ± 10, 47% were males; mean sL-selectin was significantly different across ethnicities. Within each race/ethnicity, sL-selectin was associated with age and sex; among Caucasians and African Americans, it was associated with smoking status and current alcohol use. sL-selectin levels did not predict subclinical or clinical CVD after correction for multiple comparisons. Conditional logistic regression models were used to study plasma L-selectin and CVD within 154 incident CVD cases, occurred in a median follow up of 8.5 years, and 306 age-, sex-, and ethnicity-matched controls. L-selectin levels in plasma were significantly lower than in serum and the overall concordance was low. Plasma levels were not associated with CVD. In conclusion, this large multi-ethnic population, soluble L-selectin levels did not predict clinical or subclinical CVD.
PMCID: PMC4029851  PMID: 24631064
atherosclerosis; cardiovascular diseases; ethnic groups; L-selectin
2.  Incident stroke is associated with common carotid artery diameter and not common carotid artery intima-media thickness 
Background and Purpose
The common carotid artery (CCA) inter-adventitial diameter (IAD) is measured on ultrasound images as the distance between the media-adventitia interfaces of the near and far walls. It is associated with common carotid intima-media thickness (IMT) and left ventricular mass and might therefore also have an association with incident stroke.
We studied 6255 individuals free of coronary heart disease and stroke at baseline with mean age of 62.2 years (47.3% men), members of a multi-ethnic community based cohort of whites, blacks, Hispanics, and Chinese. Ischemic stroke events were centrally adjudicated. CCA IAD and IMT were measured. Cases with incident atrial fibrillation (n = 385) were excluded. Multivariable Cox proportional hazards models were generated with time to ischemic event as outcome, adjusting for risk factors.
There were 115 first time ischemic strokes at 7.8 years of follow-up. CCA IAD was a significant predictor of ischemic stroke (Hazard ratio: 1.86; 95%CI 1.59, 2.17 per mm) and remained so after adjustment for risk factors and common carotid IMT with a hazard ratio of 1.52 per mm (95% CI: 1.22, 1.88). Common carotid IMT was not an independent predictor after adjustment (hazard ratio 0.14; 95% CI: 0.14, 1.19).
While common carotid IMT is not associated with stroke, inter-adventitial diameter of the common carotid artery is independently associated with first time incident ischemic stroke even after adjusting for IMT. Our hypothesis that this is in part due to the effects of exposure to blood pressure needs confirmation by other studies.
PMCID: PMC4270293  PMID: 24643408
3.  Carotid artery plaque and progression of coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis 
Carotid and coronary atherosclerosis are associated to each other in imaging and autopsy studies. We evaluated whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC).
Materials and Methods
We repeated Agatston calcium score measurements in 5445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 57.9 years; 62.9% female). Internal carotid artery lesions were graded as 0%, 1-24%, >25% diameter narrowing and intima-media thickness (IMT) was measured. Plaque was present for any stenosis > 0%. CAC progression was evaluated with multivariable relative risk regression in cases with CAC = 0 at baseline and with multivariable linear regression for CAC > 0 adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT.
CAC was positive at baseline in 2708/5445 (49.7%) participants and became positive in 458/2837 (16.1%) at mean interval of 2.4 years between repeat examinations. Plaque and ICA IMT were both strongly associated with presence of CAC. After statistical adjustment, presence of carotid artery plaque significantly predicted incident CAC with a relative risk(RR) of 1.37 (95% Confidence Intervals: 1.12, 1.67). Incident CAC was associated with ICA IMT with an RR of 1.13 (95% Confidence Intervals: 1.03, 1.25) for each mm increase. Progression of CAC was also significantly associated (p < 0.001) with plaque and ICA IMT.
In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.
PMCID: PMC4084492  PMID: 23522805
4.  Mediation of Cardiovascular Risk Factor Effects Through Subclinical Vascular Disease: The Multi-Ethnic Study of Atherosclerosis 
It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT) and brachial flow mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT and FMD.
Approach and Results
6355 out of 6814 MESA participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) were used to assess whether CAC, CIMT or FMD are mediators of the association between traditional risk factors and incident CVD event.
Mean age of 62, with 47% males, 12% diabetics and 13% current smokers. Mean follow up of 7.5 years, 539 CVD events were adjudicated. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes while current cigarette smoking had the least percent of total effect mediated via CAC [percent (95%CI: 80.2(58.8, 126.7) % vs. 10.6(6.1, 38.5) % respectively). BMI showed the highest percent of total effect mediated via CIMT [17.7(11.6, 38.9) %], only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD.
Many of the risk factors for incident CVD (other than age, sex and BMI) showed a modest level of mediation via CAC, CIMT and FMD suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification
PMCID: PMC4329880  PMID: 24876350
5.  Association of Parity with Carotid Diameter and Distensibility: Multi-Ethnic Study of Atherosclerosis 
Hypertension  2014;64(2):253-258.
Pregnancy and childbirth are associated with hemodynamic changes and vascular remodeling. It is not known whether parity is associated with later adverse vascular properties such as larger arterial diameter, wall thickness and lower distensibility.
We used baseline data from 3283 women free of cardiovascular disease aged 45-84 years enrolled in the population based Multi-Ethnic Study of Atherosclerosis. Participants self-reported parity status. Ultrasound derived carotid artery lumen diameters and brachial artery blood pressures were measured at peak-systole and end-diastole. Common carotid intima media thickness (cIMT) was also measured. Regression models to determine the association of carotid distensibility coefficient, lumen diameter, and cIMT with parity were adjusted for age, race, height, weight, diabetes, current smoking, BP medication use, total and high density lipoprotein cholesterol levels.
The prevalence of nulliparity was 18%. In adjusted models, carotid distensibility coefficient was 0.09 × 10−5Pa−1 lower (p = 0.009) in parous vs. nulliparous women. Among parous women, there was a nonlinear association with the greatest carotid DC seen in women with 2 live births, and significantly lower distensibility seen in primiparas (p=0.04) or with higher parity > 2 (p=0.005). No such pattern of association with parity was found for lumen diameter or cIMT.
Parity is associated with lower carotid artery distensibility, suggesting arterial remodeling that lasts beyond childbirth. These long-term effects on the vasculature may explain the association of parity with cardiovascular events later in life.
PMCID: PMC4184976  PMID: 24842921
common carotid artery; arterial stiffness; carotid intima-media thickness; women; pregnancy
6.  Variations in Common Carotid Artery Intima-Media Thickness (cIMT) during the Cardiac Cycle: Implications for Cardiovascular Risk Assessment 
Common carotid artery (CCA) intima-media thickness (cIMT), a measure of atherosclerosis, varies between peak-systole (PS) and end-diastole (ED). This difference might affect cardiovascular risk assessment.
Materials and methods
IMT measurements of the right and left CCA were synchronized with an electrocardiogram: R-wave for ED and T-wave for PS. IMT was measured in 2930 members of the Framingham Offspring Study. Multivariable regression models were generated with ED-IMT, PS-IMT and change in IMT as dependent variables and Framingham risk factors as independent variables. ED-IMT estimates were compared to the upper quartile of IMT based on normative data obtained at PS.
The average age of our population was 57.9 years. Average difference in IMT during the cardiac cycle was 0.037 mm (95% CI: 0.035–0.038 mm). ED-IMT and PS-IMT had similar associations with Framingham risk factors (total R2= 0.292 versus 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariable model, a thinner IMT at peak-systole was associated with pulse pressure (p < 0.0001), LDL-cholesterol (p = 0.0064), age (p = 0.046), and no other risk factors. Performing ED-IMT measurements while using upper quartile PS-IMT normative data lead to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category).
The difference in IMT between peak-systole and end-diastole is associated with pulse pressure, LDL-cholesterol, and age. In our study, mean IMT difference during the cardiac cycle lead to an overestimation by 42.1% of individuals at high risk for cardiovascular disease.
PMCID: PMC3544292  PMID: 22721828
Ultrasonics; Risk Factors; Carotid Arteries; Blood Pressure; systole; diastole
7.  Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events 
PLoS ONE  2015;10(7):e0132321.
Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity.
Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites.
The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.
PMCID: PMC4489855  PMID: 26134404
8.  Relationship of Change in Traditional Cardiometabolic Risk Factors to Change in Coronary Artery Calcification Among Individuals with Detectable Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis 
Data describing relationships between change in risk factors and coronary artery calcification (CAC) are lacking and could inform optimal cardiovascular disease prevention and treatment strategies. This study aimed to examine how change in traditional cardiometabolic risk factors related to change in CAC among individuals with detectable subclinical atherosclerosis.
Latent growth modeling was used to examine change in cardiometabolic risk factors (waist circumference, body mass index, systolic and diastolic blood pressure, high- and low-density lipoprotein cholesterol, triglycerides, and glucose) related to change in CAC up to an average 4.9-year follow-up in a multi-ethnic cohort of 3,398 asymptomatic individuals (57.8% men) who had detectable CAC (score > 0) at baseline, adjusting for baseline risk factor levels and CAC values, age, gender, race/ethnicity, smoking, family history of CVD, income, and use of antihypertensive, lipid-lowering, and glucose-lowering medications.
Greater declines in blood pressure (systolic and diastolic) and low-density lipoprotein cholesterol at follow-up were each associated with greater CAC progression. The observed inverse associations were attributable to greater CAC progression in participants taking antihypertensive and lipid-lowering drugs who, as expected, had declines in blood pressure and lipid levels, respectively. These inverse associations did not emerge in participants not taking these medications.
Among individuals with subclinical atherosclerosis, the unexpected inverse associations observed between change in blood pressure and lipid levels with CAC progression emphasize the importance of considering medication use, and, when feasible, the severity and duration of disease, in exploring associations between risk factors and CAC change.
PMCID: PMC4060615  PMID: 24698232
risk factors; coronary artery calcification; atherosclerosis
9.  Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis 
Annals of the rheumatic diseases  2014;74(6):1118-1123.
To estimate atherosclerosis progression and identify influencing factors in rheumatoid arthritis (RA).
We used carotid ultrasound to measure intima-media thickness (IMT) in RA patients, and ascertained cardiovascular (CV) risk factors, inflammation markers and medications. A second ultrasound was performed approximately 3 years later. We calculated the progression rate by subtracting the baseline from the follow-up IMT, divided by the time between the two scans. We used logistic regression to identify baseline factors predictive of rapid progression. We tested for interactions of erythrocyte sedimentation rate (ESR) with CV risk factors and medication use.
Results were available for 487 RA patients. The mean (SD) common carotid IMT at baseline was 0.571 mm (0.151). After a mean of 2.8 years, the IMT increased by 0.050 mm (0.055), p≤0.001, a progression rate of 0.018 mm/year (95% CI 0.016 to 0.020). Baseline factors associated with rapid progression included the number of CV risk factors (OR 1.27 per risk factor, 95% CI 1.01 to 1.61), and the ESR (OR 1.12 per 10 mm/h, 95% CI 1.02 to 1.23). The ESR×CV risk factor and ESR×medication product terms were significant, suggesting these variables modify the association between the ESR and IMT progression.
Systemic inflammation and CV risk factors were associated with rapid IMT progression. CV risk factors may modify the role of systemic inflammation in determining IMT progression over time. Methotrexate and antitumour necrosis factor agents may influence IMT progression by reducing the effect of the systemic inflammation on the IMT.
PMCID: PMC4239202  PMID: 24845391
10.  Cardiovascular Disease-Risk Markers in HIV Patients 
HIV-positive patients have an increased risk for CVD; however, the underlying mechanisms are not well understood. Our goal was to assess traditional and emerging CVD-risk factors in the CARE Study, a well-described cohort of HIV-infected adults.
We analyzed demographic and clinical (viral load, CD4 count, ART regimen, cIMT) data including markers of lipid and glucose homeostasis in 176 HIV-positive subjects receiving regular care for HIV infection.
No significant association between cIMT and LDL-C level was observed. HIV patients had significantly lower level of the large α-1 HDL particles and about 3-fold higher level of the small pre β-1 HDL particles than the normal population, but these parameters were not significantly associated with cIMT. Components of the metabolic syndrome, high TG/low HDL-C, insulin resistance and high BMI, as well as viral load were significant but moderate contributors to increased cIMT.
The major lipid disorder was low HDL-C and high TG level in this HIV-positive cohort. LDL-C was not elevated. These and previously published data indicate that HIV infection and HIV medications influence CVD risk by impairing cholesterol removal (efflux) via ABCA1 from macrophages. Decreasing CVD risk in HIV patients, with impaired cholesterol efflux from macrophages, may require a lower LDL-C goal than recommended for HIV-negative patients and also a better control of TG level.
PMCID: PMC4439003  PMID: 26005590
HIV; CVD risk; ART
11.  Fibroblast Growth Factor-23 and Cardiovascular Disease in the General Population: The Multi-Ethnic Study of Atherosclerosis 
Circulation. Heart failure  2014;7(3):409-417.
Fibroblast growth factor-23 (FGF-23) is a phosphate regulatory hormone that directly stimulates left ventricular hypertrophy in experimental models. The role of FGF-23 in cardiovascular disease development in the general population is unclear. We tested associations of FGF-23 with major subclinical and clinical cardiovascular disease outcomes in a large prospective cohort.
Methods and Results
We evaluated 6,547 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were initially free of cardiovascular disease. We measured serum FGF-23 using the Kainos immunoassay. The MESA measured left ventricular (LV) mass by magnetic resonance imaging, coronary calcium (CAC) by computed tomography, and carotid intima-medial thickness (IMT) by ultrasound. The MESA adjudicated incident heart failure, coronary heart disease, and stoke by medical record review. After adjustment, the highest FGF-23 quartile was associated with an estimated 2.4 gram greater LV mass (95% CI 0.4, 4.5 greater) and a 26% greater odds of higher CAC scores (95% CI 9% to 46% greater) compared to the lowest quartile. Over 7.5 years follow-up, each 20-pg/mL higher FGF-23 concentration was associated with a 19% greater risk of heart failure (95% CI 3% to 37% greater) and a 14% greater risk of coronary heart disease (95% CI 1% to 28% greater). FGF-23 was not associated with carotid IMT or stroke.
Higher serum FGF-23 concentrations are associated with subclinical cardiac disease and with new heart failure and coronary disease events, but not with carotid IMT or stroke. FGF-23 may be a novel cardiovascular risk factor in the general population.
PMCID: PMC4031265  PMID: 24668259
Fibroblast growth factor-23; FGF-23; left ventricular mass; left ventricular hypertrophy; coronary artery calcium; carotid intima-media thickness; heart failure; coronary heart disease; stroke; cardiovascular disease
12.  Common carotid artery intima-media thickness (IMT) progression as a predictor of stroke in MESA (Multi-Ethnic Study of Atherosclerosis) 
Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We study whether IMT rate-of-change is associated with stroke.
Materials and Methods
We studied 5028 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) composed of whites, Chinese, Hispanic and African-Americans free of cardiovascular disease. In this MESA IMT progression study, IMT rate-of-change (mm/year) was the difference in right common carotid artery (CCA) far-wall IMT (mm) divided by the interval between two ultrasound examinations (median interval of 32 months). CCA IMT was measured in a region free of plaque. Cardiovascular risk factors and baseline IMT were determined when IMT rate-of-change was measured. Multivariable Cox proportional hazards models generated Hazard risk Ratios (HR) with cardiovascular risk factors, ethnicity and education level/income as predictors.
There were 42 first time strokes seen during a mean follow-up of 3.22 years (median 3.0 years). Average age was 64.2 years, with 48% males. In multivariable models, age (HR: 1.05 per year), systolic blood pressure (HR 1.02 per mmHg), lower HDL cholesterol levels (HR: 0.96 per mg/dL) and IMT rate-of-change (HR 1.23 per 0.05 mm/year; 95% C.L. 1.02, 1.48) were significantly associated with incident stroke. The upper quartile of IMT rate-of-change had an HR of 2.18 (95% C.L.: 1.07, 4.46) compared to the lower three quartiles combined.
Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.
PMCID: PMC3202068  PMID: 21885840
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness; stroke
13.  Associations of cardiovascular risk factors, carotid intima-media thickness and left ventricular mass with inter-adventitial diameters of the common carotid artery: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2011;218(2):344-349.
Common carotid artery inter-adventitial diameter (IAD) and intima-media thickness (IMT) are measurable by ultrasound. IAD may be associated with left ventricular mass (LV mass) while IMT is a marker of subclinical atherosclerosis. It is not clear if IAD is associated with LV mass after accounting for IMT and traditional cardiovascular risk factors.
IAD and IMT were measured on participants of the Multi-Ethnic Study of Atherosclerosis (MESA) IMT progression study. A total of 5641 of the originally enrolled 6814 MESA participants were studied. LV mass was measured by magnetic resonance imaging. Multivariable linear regression was used with IAD as the outcome and adjustment for risk factors, as well as IMT and LV mass.
Traditional cardiovascular risk factors, height, weight and ethnicity were significantly associated with IAD. After adjustment for risk factors, a one mm difference in IMT was associated with a 1.802 mm (95% CI: 1.553, 2.051) higher mean IAD. A one gm difference in LV mass was associated with a 0.006 mm (95% CI: 0.005, 0.007) higher mean IAD. LV mass was independently associated with IAD after adjusting for cardiovascular risk factors and IMT. These associations were slightly different for men and women.
Inter-adventitial diameters are associated with left ventricular mass after adjusting for cardiovascular risk factors and IMT. IAD might serve as a surrogate for left ventricular mass and have predictive value for cardiovascular outcomes.
PMCID: PMC3186064  PMID: 21726862
carotid arteries; ultrasonics; hypertrophy; magnetic resonance imaging; remodeling; risk factors; left ventricle
14.  Biomarkers of Cardiovascular Stress and Subclinical Atherosclerosis in the Community 
Clinical chemistry  2014;60(11):1402-1408.
Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described.
Plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) were measured in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995 – 1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT > 1.5 mm), and mean common carotid artery IMT. Multivariable regressions for carotid measurements versus biomarkers were carried out using linear and logistic models; P < 0.0056 was deemed statistically significant.
Maximal ICA IMT was significantly associated with plasma GDF-15 (β-estimate 0.04 per 1 unit increase in log-GDF-15 SE 0.01, P < 0.0001). Similarly, the odds of having carotid plaque increased 33% (OR 1.33 per 1-unit increase in log-GDF-15, 95% CI 1.20-1.48, P < 0.0001). In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the three biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together.
Higher GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted.
PMCID: PMC4376479  PMID: 25237063
carotid intima-media thickness; atherosclerosis; biomarkers
15.  Changes in Carotid Intima-Media Thickness During the Cardiac Cycle: The Multi-Ethnic Study of Atherosclerosis 
Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.
Methods and Results
Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole.
Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole.
Clinical Trial Registration
URL: Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.)
PMCID: PMC3487346  PMID: 23130162
atherosclerosis; blood pressure; carotid arteries; diastole; epidemiology; risk factors; systole; ultrasonics
16.  Cost-Effectiveness of Coronary Artery Calcium Testing for Coronary Heart and Cardiovascular Disease Risk Prediction to Guide Statin Allocation: The Multi-Ethnic Study of Atherosclerosis (MESA) 
PLoS ONE  2015;10(3):e0116377.
The Multi-Ethnic Study of Atherosclerosis (MESA) showed that the addition of coronary artery calcium (CAC) to traditional risk factors improves risk classification, particularly in intermediate risk asymptomatic patients with LDL cholesterol levels <160 mg/dL. However, the cost-effectiveness of incorporating CAC into treatment decision rules has yet to be clearly delineated.
To model the cost-effectiveness of CAC for cardiovascular risk stratification in asymptomatic, intermediate risk patients not taking a statin. Treatment based on CAC was compared to (1) treatment of all intermediate-risk patients, and (2) treatment on the basis of United States guidelines.
We developed a Markov model of first coronary heart disease (CHD) and cardiovascular disease (CVD) events. We modeled statin treatment in intermediate risk patients with CAC≥1 and CAC≥100, with different intensities of statins based on the CAC score. We compared these CAC-based treatment strategies to a “treat all” strategy and to treatment according to the Adult Treatment Panel III (ATP III) guidelines. Clinical and economic outcomes were modeled over both five- and ten-year time horizons. Outcomes consisted of CHD and CVD events and Quality-Adjusted Life Years (QALYs). Sensitivity analyses considered the effect of higher event rates, different CAC and statin costs, indirect costs, and re-scanning patients with incidentalomas.
We project that it is both cost-saving and more effective to scan intermediate-risk patients for CAC and to treat those with CAC≥1, compared to treatment based on established risk-assessment guidelines. Treating patients with CAC≥100 is also preferred to existing guidelines when we account for statin side effects and the disutility of statin use.
Compared to the alternatives we assessed, CAC testing is both effective and cost saving as a risk-stratification tool, particularly if there are adverse effects of long-term statin use. CAC may enable providers to better tailor preventive therapy to patients' risks of CVD.
PMCID: PMC4364761  PMID: 25786208
17.  Lipoprotein-Associated Phospholipase A2, a Novel Cardiovascular Inflammatory Marker, in HIV-Infected Patients 
Lipoprotein-associated phospholipase A2, an emerging biomarker of cardiovascular disease that is highly abnormal in HIV-infected patients and associated with several cardiometabolic and treatment-specific risk factors, may be used as an additional and more vascular specific biomarker for cardiovascular risk stratification.
Background. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging biomarker of cardiovascular disease. This study was conducted to describe the distribution of Lp-PLA2 in a cohort of human immunodeficiency virus (HIV)–infected adults and to determine associations between Lp-PLA2, cardiometabolic risk factors, and subclinical atherosclerosis in this population.
Methods. Lp-PLA2 was assessed in 341 (25% women, 52% white, 74% on highly active antiretroviral therapy [HAART]) participants of a cohort with detailed characterization of atherogenic risk factors, including surrogate markers of carotid and coronary atherosclerosis.
Results. Mean Lp-PLA2 mass was 313 ± 105 ng/mL and activity 173 ± 49 nmol/minute/mL. Seventy-five percent of participants had abnormal Lp-PLA2. Those in the highest Framingham Risk Score tertile had significantly higher Lp-PLA2 activity. Participants with abnormal carotid intima-media thickness (cIMT) had higher Lp-PLA2 mass and activity. Those with coronary artery calcium (CAC) scores >100 had significantly higher Lp-PLA2 mass than those with lower or nondetectable calcium. Those on HAART and protease inhibitor (PI)–based treatment had significantly higher Lp-PLA2 mass and activity than those who were treatment-naive or not on PIs. In multivariate regression, HAART and PI use were positively associated with Lp-PLA2 activity and mass after adjusting for age, race, sex, low-density and high-density lipoprotein cholesterol levels, triglyceride level, and smoking. Adding Lp-PLA2 activity tertiles to the model improved the predictive value for abnormal common cIMT, but not internal cIMT or CAC score.
Conclusions. Lp-PLA2 is highly abnormal in HIV-infected patients and is associated with several cardiovascular and HIV treatment-specific risk factors. Lp-PLA2 may be used as an additional and more vascular specific biomarker for cardiovascular risk stratification in HIV-positive patients.
PMCID: PMC3935500  PMID: 24336757
HIV; cardiovascular; inflammation; LpPLA2; atherosclerosis
18.  Associations of edge detected and manual traced common carotid intima-media thickness (IMT) measurements with Framingham risk factors: the Multi-Ethnic Study of Atherosclerosis 
Carotid intima-media thickness (IMT) is a marker of cardiovascular disease derived from ultrasound images of the carotid artery. In most outcome studies, human readers identify and trace the key IMT interfaces. We evaluate an alternate approach using automated edge detection.
We study a subset of 5640 participants with an average age 61.7 years (48% men) of the Multi-Ethnic Study of Atherosclerosis composed of whites, Chinese, Hispanic and African-Americans that are part of the MESA IMT progression study. Manual tracing IMT (mt_IMT) and edge-detected IMT (ed_IMT) measurements of the far wall of the common carotid artery (CCA) served as outcome variables for multivariable linear regression models using Framingham cardiovascular risk factors and ethnicity as independent predictors.
Measurements of mt_IMT was obtainable in 99.9% (5633/5640) and of ed_IMT in 98.9% (5579/5640) of individuals. Average ed_IMT was 0.19 mm larger than mt_IMT. Inter-reader systematic differences (bias) in IMT measurements were apparent for mt_IMT but not ed_IMT. Based on complete data on 5538 individuals, associations of IMT with risk factors were stronger (p < 0.0001) for mt_IMT (model r2: 19.5%) than ed_IMT (model r2: 18.5%).
We conclude that this edge-detection process generates IMT values equivalent to manually traced ones since it preserves key associations with cardiovascular risk factors. It also decreases inter-reader bias, potentially making it applicable for use in cardiovascular risk assessment.
PMCID: PMC3169166  PMID: 21546477
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness
Little is known about whether the childhood family psychosocial environment (characterized by cold, unaffectionate interactions, conflict, aggression, neglect and/or low nurturance) affects coronary heart disease (CHD) risk. Objectives were to evaluate associations of childhood family psychosocial environment with carotid intima media thickness (IMT), a subclinical measure of atherosclerosis. The study population included 2,659 CARDIA study participants, aged 37-52 years. Childhood family psychosocial environment was measured using a risky family questionnaire via self-report. Carotid IMT was calculated using the average of 20 measurements of mean common carotid, bulb and internal carotid IMT, assessed using high-resolution B-mode ultrasound images. Utilizing linear regression analyses adjusted for age, a 1-unit (range 0-21) increase in risky family score was associated with 0.0036 (95% CI:0.0006,0.0066 mm) and 0.0020 (95% CI:0.0002,0.0038) mm increase in mean IMT in white males and females, respectively. Formal mediation analyses and covariate adjustments suggested childhood socioeconomic position and smoking may be important mechanisms in white males and females, as well as education and depressive symptomatology in white males. No associations were found in black participants. Formal statistical tests for interaction between risky family score and sex, and between risky family score and race/ethnicity, demonstrated borderline evidence of interactions for both sex (p=0.12) and race/ethnicity (p=0.14) with risky family score for associations with mean IMT. In conclusion, childhood family psychosocial environment was positively associated with IMT in white participants, with little evidence of association in black participants. Mechanisms in white participants may include potential negative impacts of socioeconomic constraints on parenting quality, potentially influencing offspring's cardiovascular risk factors (e.g. smoking), socioeconomic position (e.g. education), and/or psychosocial functioning (e.g. depression), which may in turn lead to atherosclerotic processes. Borderline racial/ethnic differences in findings should be replicated, but add to literature exploring race/ethnicity-specific associations of parenting approaches with health outcomes.
PMCID: PMC4017861  PMID: 24581057
20.  Associations of Carotid Artery Intima-Media Thickness (IMT) With Risk Factors and Prevalent Cardiovascular Disease 
The goal of this study was to compare internal carotid artery (ICA) intima-media thickness (IMT) with common carotid artery (CCA) IMT as global markers of cardiovascular disease (CVD).
Cross-sectional measurements of the mean CCA IMT and maximum ICA IMT were made on ultrasound images acquired from the Framingham Offspring cohort (n = 3316; mean age, 58 years; 52.7% women). Linear regression models were used to study the associations of the Framingham risk factors with CCA and ICA IMT. Multivariate logistic regression models and receiver operating characteristic (ROC) curve analysis were used to compare the associations of prevalent CVD with CCA and ICA IMT and determine sensitivity and specificity.
The association between age and the mean CCA IMT corresponded to an increase of 0.007 mm/y; the increase was 0.037 mm/y for the ICA IMT. Framingham risk factors accounted for 28.6% and 27.5% of the variability in the CCA and ICA IMT, respectively. Age and gender contributed 23.5% to the variability of the CCA IMT and 22.5% to that of the ICA IMT, with the next most important factor being systolic blood pressure (1.9%) for the CCA IMT and smoking (1.6%) for the ICA IMT. The CCA IMT and ICA IMT were statistically significant predictors of prevalent CVD, with the ICA IMT having a larger area under the ROC curve (0.756 versus 0.695).
Associations of risk factors with CCA and ICA IMT are slightly different, and both are independently associated with prevalent CVD. Their value for predicting incident cardiovascular events needs to be compared in outcome studies.
PMCID: PMC3186063  PMID: 21098848
atherosclerosis; carotid artery; disease prevalence; intima-media thickness; risk factors
21.  Segment-Specific Associations of Carotid IMT with Cardiovascular Risk Factors: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Background and Purpose
We propose to study possible differences in the associations between risk factors for cardiovascular disease (myocardial infarction and stroke) and Carotid Intima-Media thickness (IMT) measurements made at three different levels of the carotid bifurcation. Methods: Cross-sectional study of a cohort of Whites and African Americans of both genders with mean age 45 years. Traditional cardiovascular risk factors were determined in cohort members. Carotid IMT was measured from high-resolution B-mode ultrasound images at three levels: the common carotid artery (CCA), the carotid artery bulb (Bulb) and the internal carotid artery (ICA). Associations with risk factors were evaluated by multivariate linear regression analyses.
Of 3258 who underwent carotid IMT measurements, CCA, Bulb, and ICA IMT were measured at all three separate levels in 3023 (92.7%). A large proportion of the variability of CCA IMT was explained by cardiovascular risk factors (26.8%) but less so for the Bulb (11.2%) and ICA (8.0%). Carotid IMT was consistently associated with age, LDL-cholesterol, smoking and hypertension in all segments. Associations with fasting glucose and diastolic blood pressure were stronger for CCA than for the other segments. Hypertension, diabetes and current smoking had qualitatively stronger associations with Bulb IMT, and LDL cholesterol with ICA IMT. Conclusion: In our cohort of relatively young white and African-American men and women, a greater proportion of the variability in common carotid IMT can be explained by traditional cardiovascular risk factors than for the carotid artery bulb and internal carotid arteries.
PMCID: PMC3163306  PMID: 19910544
Carotid Intimal Medial Thickness; Risk Factors; Carotid Ultrasound
22.  Carotid Artery Plaque Morphology and Composition in Relation to Incident Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Radiology  2014;271(2):381-389.
Our results support the concept that adverse carotid arterial remodeling and a lipid core at MR imaging confer increased risk for subsequent cardiovascular events in asymptomatic individuals.
To determine if carotid plaque morphology and composition with magnetic resonance (MR) imaging can be used to identify asymptomatic subjects at risk for cardiovascular events.
Materials and Methods
Institutional review boards at each site approved the study, and all sites were Health Insurance Portability and Accountability Act (HIPAA) compliant. A total of 946 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated with MR imaging and ultrasonography (US). MR imaging was used to define carotid plaque composition and remodeling index (wall area divided by the sum of wall area and lumen area), while US was used to assess carotid wall thickness. Incident cardiovascular events, including myocardial infarction, resuscitated cardiac arrest, angina, stroke, and death, were ascertained for an average of 5.5 years. Multivariable Cox proportional hazards models, C statistics, and net reclassification improvement (NRI) for event prediction were determined.
Cardiovascular events occurred in 59 (6%) of participants. Carotid IMT as well as MR imaging remodeling index, lipid core, and calcium in the internal carotid artery were significant predictors of events in univariate analysis (P < .001 for all). For traditional risk factors, the C statistic for event prediction was 0.696. For MR imaging remodeling index and lipid core, the C statistic was 0.734 and the NRI was 7.4% and 15.8% for participants with and those without cardiovascular events, respectively (P = .02). The NRI for US IMT in addition to traditional risk factors was not significant.
The identification of vulnerable plaque characteristics with MR imaging aids in cardiovascular disease prediction and improves the reclassification of baseline cardiovascular risk.
© RSNA, 2014
PMCID: PMC4263652  PMID: 24592924
24.  Relation of Leptin to Left Ventricular Hypertrophy (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;112(5):726-730.
Increasing adiposity increases the risk for left ventricular hypertrophy. Adipokines are hormone-like substances from adipose tissue that influence several metabolic pathways relevant to LV hypertrophy. Data was from participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent magnetic resonance imaging of the heart and who also had fasting venous blood assayed for 4 distinct adipokines (adiponectin, leptin, tumor necrosis factor – alpha and resistin). 1,464 MESA participants had complete data. The mean age was 61.5 years, the mean body mass index was 27.6 kg/m2 and 49% were female. With adjustment for age, sex, race, height and weight, multivariable linear regression modeling revealed that a 1-SD increment in leptin was significantly associated with smaller LV mass (ß: −4.66 % predicted, p-value: < 0.01), LV volume (−5.87 % predicted, < 0.01), stroke volume (−3.23 ml, p < 0.01) and cardiac output (−120 mL/min, p = 0.01) as well as a lower odds ratio for the presence of LV hypertrophy (OR: 0.65, p < 0.01), but a higher ejection fraction (0.44%, p = 0.05). Additional adjustment for the traditional cardiovascular disease (CVD) risk factors, insulin resistance, physical activity, education, income, inflammatory biomarkers, other selected adipokines and pericardial fat did not materially change the magnitude or significance of the associations. The associations between the other adipokines and LV structure and function were inconsistent and largely non-significant. In conclusion, the results indicate that higher levels of leptin are associated with more favorable values of several measures of LV structure and function.
PMCID: PMC3745795  PMID: 23711806
leptin; left ventricle; hypertrophy; mass
25.  Progression of Carotid Intima-Media Thickness and Coronary Artery Calcium over Six Years in an HIV-infected Cohort 
Journal of acquired immune deficiency syndromes (1999)  2013;64(1):10.1097/QAI.0b013e31829ed726.
To evaluate changes in cardiovascular disease risk surrogate markers in a longitudinal cohort of HIV-infected adults over 6 years.
Internal and common carotid artery intima-media thickness, coronary artery calcium, vascular and HIV risk factors were prospectively examined over 6 years in HIV-infected adults from 2002 to 2010.
Longitudinal cohort study with participants from urban center and surrounding communities.
Subjects, participants
345 HIV-infected participants were recruited from a longitudinal cohort study. 211 participants completed the study and were included in this analysis.
Main Outcome Measures
Total and yearly internal and common carotid artery intima-media thickness change; coronary artery calcium score progression.
Participants were 27% female and 49% non-white; mean age at start was 45 ± 7 years. The median change in internal and common carotid arteries over six years was 0.15mm (0.08,0.28) and 0.12mm (0.09,0.15), respectively. Age, baseline triglycerides ≥ 150mg/dL, and pack-years smoking were associated with internal carotid artery intima-media thickness change; age, cholesterol, nadir CD4+ count, and protease inhibitor use were associated with common carotid artery intima-media thickness change. Diabetes, HIV viral load, and HAART duration were associated with coronary artery calcium progression.
Carotid intima-media thickness and coronary artery calcium progressed in this HIV-infected cohort. Some HIV-specific characteristics were associated with surrogate marker changes, but the majority of risk factors continue to be traditional. Aggressive identification and management of modifiable risk factors may reduce progression of cardiovascular disease risk in this population.
PMCID: PMC3815556  PMID: 23945252

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