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1.  Amino terminal pro–B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy 
Background and Purpose
Because of its association with atrial fibrillation and heart failure, we hypothesized that amino terminal pro–B-type natriuretic peptide (NT-proBNP) would identify a subgroup of patients from the Warfarin–Aspirin Recurrent Stroke Study (WARSS), diagnosed with inferred non-cardioembolic ischemic strokes, where anticoagulation would be more effective than antiplatelet agents in reducing risk of subsequent events.
Methods
NT-proBNP was measured in stored serum collected at baseline from participants enrolled in WARSS, a previously reported randomized trial. Relative effectiveness of warfarin and aspirin in preventing recurrent ischemic stroke or death over two years was compared based on NT-proBNP concentrations.
Results
About 95% of 1028 patients with assays had NT-proBNP below 750 pg/mL, and among them, no evidence for treatment effect modification was evident. For 49 patients with NT-proBNP >750 pg/mL, the two-year rate of events per 100 person-years was 45.9 for the aspirin group and 16.6 for the warfarin group, while for 979 patients with NT-proBNP ≤750 pg/mL, rates were similar for both treatments. For those with NT-proBNP >750 pg/mL, the hazard ratio was 0.30 (95% confidence interval 0.12 to 0.84, p-value=0.021) significantly favoring warfarin over aspirin. A formal test for interaction of NT-proBNP with treatment was significant (p-value=0.01).
Conclusion
For secondary stroke prevention, elevated NT-proBNP concentrations may identify a subgroup of ischemic stroke patients without known atrial fibrillation, about 5% based on the current study, who may benefit more from anticoagulants than antiplatelet agents.
Clinical Trial Registration
This trial was not registered because enrollment began prior to 2005.
doi:10.1161/STROKEAHA.112.675942
PMCID: PMC3583375  PMID: 23339958
aspirin; warfarin; NT-proBNP; secondary stroke prevention
2.  Effects of respiratory and non-respiratory factors on disability among older adults with airway obstruction: The Cardiovascular Health Study 
COPD  2013;10(5):588-596.
Background:
High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation.
Methods:
We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing ≥1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic comorbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV1 and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years.
Results:
The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV1 and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years.
Conclusions:
Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non-respiratory factors contribute to disability in older adults with abnormal spirometry.
doi:10.3109/15412555.2013.781148
PMCID: PMC3903127  PMID: 23819728
Chronic airflow obstruction; instrumental activities of daily living; disability; disablement process
3.  Von Willebrand Factor and the Right Ventricle (The MESA-Right Ventricle Study) 
The American journal of cardiology  2012;110(12):1846-1851.
Elevation in plasma activity of von Willebrand Factor (vWF) reflects endothelial dysfunction and predicts death in pulmonary arterial hypertension (PAH). Higher vWF activity is also associated with lower right ventricular (RV) ejection fraction in PAH. Little is known about the relationship between vWF and RV structure and function in adults without cardiovascular disease. In the current investigation, we included 1,976 participants with MRI assessment of RV structure and function and measurement of vWF activity from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to estimate the associations between vWF activity and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking, diabetes mellitus, hypertension and the corresponding left ventricular (LV) parameter. The average vWF activity was 140.7 ± 57.2%. Elevated vWF activity was independently associated with lower RV mass, RV end-diastolic volume and RV stroke volume in models with and without adjustment for the corresponding LV parameter (all p < 0.05). There was no association observed between vWF activity and RV ejection fraction. In conclusion, higher vWF activity is associated with lower RV mass, RV end-diastolic volume and RV stroke volume. These associations are independent of common cardiovascular risk factors and LV morphologic changes.
doi:10.1016/j.amjcard.2012.08.022
PMCID: PMC3696516  PMID: 22995970
Cardiovascular Imaging; Biomarkers; Pulmonary Hypertension; Right Ventricle
4.  N-terminal pro-B-type Natriuretic Peptide is Associated with Sudden Cardiac Death Risk: the Cardiovascular Health Study 
Background
Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality, as well as sudden death in women.
Objective
To examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.
Methods
The risk of SCD associated with baseline NT-proBNP was examined in 5447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP
Results
Over a median follow-up of 12.5 years (maximum of 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% CI: 2.9, 6.1, p<0.001) in the highest quintile compared to the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk-factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the 5th versus the 1st quintile of 2.5 (95% CI: 1.6, 3.8, p<0.001).
Conclusion
NT-proBNP provides information regarding the risk of sudden cardiac death in a community based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.
doi:10.1016/j.hrthm.2010.10.038
PMCID: PMC3826546  PMID: 21044699
Sudden cardiac death; B-type natriuretic peptide; BNP; NT-proBNP
5.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
doi:10.1093/aje/kws169
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
6.  The impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study 
European Heart Journal  2012;33(21):2709-2717.
Aims
Atrial fibrillation (AF) is the most common sustained arrhythmia. Increased body size has been associated with AF, but the relationship is not well understood. In this study, we examined the effect of increased height on the risk of AF and explore potential mediators and implications for clinical practice.
Methods and results
We examined data from 5860 individuals taking part in the Cardiovascular Health Study, a cohort study of older US adults followed for a median of 13.6 (women) and 10.3 years (men). Multivariate linear models and age-stratified Cox proportional hazards and risk models were used, with focus on the effect of height on both prevalent and incident AF. Among 684 (22.6%) and 568 (27.1%) incident cases in women and men, respectively, greater height was significantly associated with AF risk [hazard ratio (HR)women per 10 cm 1.32, confidence interval (CI) 1.16–1.50, P < 0.0001; HRmen per 10 cm 1.26, CI 1.11–1.44, P < 0.0001]. The association was such that the incremental risk from sex was completely attenuated by the inclusion of height (for men, HR 1.48, CI 1.32–1.65, without height, and HR 0.94, CI 0.85–1.20, with height included). Inclusion of height in the Framingham model for incident AF improved discrimination. In sequential models, however, we found minimal attenuation of the risk estimates for AF with adjustment for left ventricular (LV) mass and left atrial (LA) dimension. The associations of LA and LV size measurements with AF risk were weakened when indexed to height.
Conclusion
Independent from sex, increased height is significantly associated with the risk of AF.
doi:10.1093/eurheartj/ehs301
PMCID: PMC3681530  PMID: 22977225
Atrial fibrillation; Cardiovascular risk factors; Echocardiography; Risk prediction
7.  Progression of coronary artery atherosclerosis in rheumatoid arthritis: comparison with participants from the Multi-Ethnic Study of Atherosclerosis 
Arthritis Research & Therapy  2013;15(5):R134.
Introduction
In cross-sectional studies, patients with rheumatoid arthritis (RA) have higher coronary artery calcium (CAC) than controls. However, their rate of progression of CAC and the predictors of CAC progression have heretofore remained unknown.
Methods
Incidence and progression of CAC were compared in 155 patients with RA and 835 control participants. The association of demographic characteristics, traditional cardiovascular risk factors, RA disease characteristics and selected inflammatory markers with incidence and progression of CAC were evaluated.
Results
The incidence rate of newly detected CAC was 8.2/100 person-years in RA and 7.3/100 person-years in non-RA control subjects [IRR 1.1 (0.7-1.8)]. RA patients who developed newly detectable CAC were older (59±7 vs. 55±6 years old, p=0.03), had higher triglyceride levels (137±86 vs. 97±60 mg/dL, p=0.03), and higher systolic blood pressure (129±17 vs. 117±15 mm Hg, p=0.01) compared to those who did not develop incident CAC. Differences in blood pressure and triglyceride levels remained significant after adjustment for age (p<=0.05). RA patients with any CAC at baseline had a median rate of yearly progression of 21 (7–62) compared to 21 (5–70) Agatston units in controls. No statistical differences between RA progressors and RA non-progressors were observed for inflammatory markers or for RA disease characteristics.
Conclusions
The incidence and progression of CAC did not differ between RA and non-RA participants. In patients with RA, incident CAC was associated with older age, higher triglyceride levels, and higher blood pressure, but not with inflammatory markers or RA disease characteristics.
doi:10.1186/ar4314
PMCID: PMC3978773  PMID: 24286380
8.  Decreased Naive and Increased Memory CD4+ T Cells Are Associated with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2013;8(8):e71498.
Background
Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4+ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.
Methods and Findings
We examined cross-sectional relationships of circulating CD4+ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4+ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI))  = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β =  0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].
Conclusions
These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4+ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.
doi:10.1371/journal.pone.0071498
PMCID: PMC3751895  PMID: 24009662
9.  Associations of Left Ventricular Hypertrophy with Prevalent and Incident Valve Calcification: The Multi-Ethnic Study of Atherosclerosis 
JACC. Cardiovascular imaging  2012;5(8):781-788.
Objectives
We aim to evaluate the relationship between percent of predicted left ventricular mass (%PredLVM) and valve calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).
Background
Cardiac valve calcification has been associated with left ventricular hypertrophy (LVH), which portends cardiovascular events. However, this relationship and its mediators are poorly understood.
Methods
MESA is a longitudinal cohort study of men and women aged 45-84 years without clinical cardiovascular disease in whom serial cardiac magnetic resonance and computed tomography imaging were performed. The relationships between baseline %PredLVM and the prevalence, severity, and incidence of aortic valve (AVC) and mitral annulus calcification (MAC) were determined by regression modeling.
Results
Prevalent AVC was observed in 630 and MAC in 442 of 5,042 subjects (median 55.9 and 71.1 Agatston units, respectively). After adjustment for age, gender, body mass index, ethnicity, socioeconomic status, physical activity, diabetes, cholesterol levels, blood pressure, smoking, kidney function, serum lipids, and antihypertensive and statin medications, %PredLVM was associated with prevalent AVC (OR=1.18 per SD increase in %PredLVM [95%CI 1.08 – 1.30]; p=0.0004) and MAC (OR=1.18 [95%CI 1.06 – 1.32]; p=0.002). Similarly, %PredLVM was associated with increased severity of prevalent AVC (risk difference = 0.26 [95%CI 0.15 – 0.38]; p<0.0001) and MAC (risk difference = 0.20 [95%CI 0.03 – 0.37]; p=0.02). During follow-up (mean 2.4±0.9 years), 153 subjects (4%) developed AVC and 198 (5%) MAC. %PredLVM was associated with incident AVC (OR=1.24 [95%CI 1.04 – 1.47]; p=0.02) and MAC (OR=1.18 [1.01-1.40]; p=0.04). Further adjustment for inflammatory markers and coronary artery calcification did not attenuate these associations. Specifically, concentric LVH most strongly predicted incident valve calcification.
Conclusions
Within the MESA cohort, LVH was associated with prevalence, severity, and incidence of valve calcification independent of hypertension and other identified confounders.
doi:10.1016/j.jcmg.2011.12.025
PMCID: PMC3426868  PMID: 22897991
aortic valve; calcification; left ventricular mass; mitral valve annulus
10.  SEMIPARAMETRIC ZERO-INFLATED MODELING IN MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) 
The annals of applied statistics  2012;6(3):1236-1255.
We analyze the Agatston score of coronary artery calcium (CAC) from the Multi-Ethnic Study of Atherosclerosis (MESA) using semi-parametric zero-inflated modeling approach, where the observed CAC scores from this cohort consist of high frequency of zeroes and continuously distributed positive values. Both partially constrained and unconstrained models are considered to investigate the underlying biological processes of CAC development from zero to positive, and from small amount to large amount. Different from existing studies, a model selection procedure based on likelihood cross-validation is adopted to identify the optimal model, which is justified by comparative Monte Carlo studies. A shrinkaged version of cubic regression spline is used for model estimation and variable selection simultaneously. When applying the proposed methods to the MESA data analysis, we show that the two biological mechanisms influencing the initiation of CAC and the magnitude of CAC when it is positive are better characterized by an unconstrained zero-inflated normal model. Our results are significantly different from those in published studies, and may provide further insights into the biological mechanisms underlying CAC development in human. This highly flexible statistical framework can be applied to zero-inflated data analyses in other areas.
PMCID: PMC3690929  PMID: 23805172
cardiovascular disease; coronary artery calcium; likelihood cross-validation; model selection; penalized spline; proportional constraint; shrinkage
11.  Determination of proportionality in two-part models and analysis of Multi-Ethnic Study of Atherosclerosis (MESA) 
Statistics and its interface  2011;4(4):475-487.
In MESA (Multi-Ethnic Study of Atherosclerosis), it is of interest to model the development and progression of CAC (coronary artery calcium). With about half of the CAC scores equal to zero and the rest continuously distributed, semiparametric two-part models are needed. Our main interest lies in determining the (partial) proportionality between the two covariate effects in two-part models. Such an investigation can provide important information on the mechanisms underlying CAC development. We propose a novel approach, which consists of penalized maximum likelihood estimation and a step-wise hypothesis testing procedure to determine proportionality. Simulation shows satisfactory performance of the proposed approach. Analysis of MESA suggests that proportionality holds for all covariates except LDL and HDL.
PMCID: PMC3680156  PMID: 23772262
Two-part models; Proportionality; Semiparametric estimation
12.  Aortic Valve Calcium Independently Predicts Coronary and Cardiovascular Events in a Primary Prevention Population 
Jacc. Cardiovascular Imaging  2012;5(6):619-625.
Objective
This study aimed to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population.
Background
Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial and it is unknown if this association extends to younger individuals.
Methods
We performed a prospective analysis of 6,685 participants in the Multi-Ethnic Study of Atherosclerosis. All subjects, aged 45-84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium (CAC) scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and non-fatal strokes, resuscitated cardiac arrest and cardiovascular death, while a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers and subclinical coronary atherosclerosis.
Results
Over a median follow up of 5.8 [IQR 5.6, 5.9] years, adjusting for demographics and cardiovascular risk factors, subjects with AVC (n=894, 13.4%) had higher risks of cardiovascular (HR, 1.50; 95% CI, 1.10-2.03) and coronary (HR, 1.72; 95% CI, 1.19-2.49) events compared to those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for CAC substantially attenuated both cardiovascular (HR, 1.32; 95% CI: 0.98-1.78) and coronary (HR, 1.41; 95% CI, 0.98-2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR, 2.51; 95% CI, 1.22-5.21).
Conclusions
In this multiethnic MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation.
doi:10.1016/j.jcmg.2011.12.023
PMCID: PMC3376353  PMID: 22698532
13.  T‐Helper Type 1 Bias in Healthy People Is Associated With Cytomegalovirus Serology and Atherosclerosis: The Multi‐Ethnic Study of Atherosclerosis 
Background
Although T‐helper type 1 (Th1) cells are considered important in atherosclerosis, the relationships between Th1 and Th2 cells and atherosclerosis have not been examined in population‐based studies.
Methods and Results
We measured Th cells as a percentage of lymphocytes by flow cytometry using CD4 staining (%CD4) in 917 participants of the Multi‐Ethnic Study of Atherosclerosis. We also measured interferon gamma–positive and interleukin‐4‐positive CD4+ cells, representing Th1 and Th2 subpopulations (%Th1 and %Th2), respectively. We found that %CD4 was 1.5% lower per 10 years of age (P<0.0001). Whites had higher %CD4 and lower %Th1 and %Th2 values than other race/ethnic groups. Body mass index (BMI) and blood pressure were associated with %CD4, but no traditional cardiovascular disease (CVD) risk factors were associated with %Th1 or %Th2. In multivariable models, the major independent variable associated with %Th1 was cytomegalovirus (CMV) antibody titer, with minor contributions from age, sex, seasonality, and interleukin‐6. In models with coronary artery calcification level as the outcome, significant independent variables included age, sex, smoking status, and %Th1 (β=0.25; P≤0.01). Both %Th1 and %Th2 were associated with common carotid intimal media thickness (β=0.02 and −0.02, respectively; both P<0.05), as were age, sex, race/ethnicity, blood pressure, and BMI.
Conclusions
Th1 bias is associated with subclinical atherosclerosis in a multiethnic population. The main Th1 correlate was CMV infectious burden. These findings are consistent with a role of Th1 cells in atherosclerosis and suggest the importance of prospective studies of T‐helper cell biasing in CVD.
doi:10.1161/JAHA.113.000117
PMCID: PMC3698770  PMID: 23688675
atherosclerosis; epidemiology; immunology; inflammation; T‐helper cell
14.  Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: The Cardiovascular Health Study 
Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages ≥65 years enrolled 1989–1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r2=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95% CI: 0.5–0.9 (CC vs. AC) and HR=0.5; 95% CI: 0.20–1.4 (CC vs. AA) (p-trend <0.01). For men there was no association, HR=1.0; 95% CI: 0.7–1.3 (CC vs. AC) and HR=1.7; 95% CI: 0.8–3.6 (CC vs. AA) (p-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.
doi:10.1016/j.mad.2012.03.002
PMCID: PMC3391009  PMID: 22449406
15.  Metabolic Syndrome, Diabetes, and Incidence and Progression of Coronary Calcium: The Multiethnic Study of Atherosclerosis (MESA) 
Jacc. Cardiovascular Imaging  2012;5(4):358-366.
Objectives
The purpose of the study was to examine and compare the incidence and progression of coronary artery calcium (CAC) among persons with metabolic syndrome (MetS) and diabetes mellitus (DM), compared to those with neither condition.
Background
MetS and DM are associated with subclinical atherosclerosis as evidenced by coronary artery calcium (CAC).
Methods
The Multiethnic Study of Atherosclerosis included 6,814 African-American, Asian, Caucasian, and Hispanic adults aged 45–84 free of cardiovascular disease at baseline. 5,662 subjects (51% female, mean age 61.0 ± 10.3 years) received baseline and follow-up (mean 2.4 years) cardiac CT scans. We compared the incidence of CAC in 2,927 subjects without CAC at baseline and progression of CAC in 2,735 subjects with CAC at baseline in those with MetS without DM (25.2%), DM without MetS (3.5%), or both DM and MetS (9.0%), compared to neither MetS nor DM (58%). Progression of CAC was also examined in relation to coronary heart disease events over an additional 4.9 years.
Results
Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals) for incident CAC were 1.7 (1.4–2.0), 1.9 (1.4–2.4), and 1.8 (1.4–2.2) (all p<0.01) and absolute differences in mean progression (volume score) were 7.8 (4.0–11.6; p<0.01), 11.6 (2.7–20.5; p<0.05), and 22.6 (17.2–27.9; p<0.01) for those with MetS without DM, DM without MetS, and both DM and MetS, respectively. Similar findings were seen in analysis using Agatston calcium score. In addition, progression predicted CHD events in those with MetS without DM (adjusted hazard ratio 4.1, 95% CI=2.0–8.5, p<0.01) and DM (4.9 [1.3–18.4], p<0.05) among those in highest tertile of CAC increase vs. no increase).
Conclusions
Individuals with MetS and DM have a greater incidence and absolute progression of CAC compared to individuals without these conditions, with progression also predicting CHD events in those with MetS and DM.
doi:10.1016/j.jcmg.2011.12.015
PMCID: PMC3327555  PMID: 22498324
atherosclerosis; diabetes; risk factors; calcification
16.  Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;200(2):359-367.
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
doi:10.1016/j.atherosclerosis.2007.12.038
PMCID: PMC3612981  PMID: 18243217
CETP; CVD; HDL; MESA
17.  INHALED HYPERTONIC SALINE IN INFANTS AND CHILDREN LESS THAN SIX YEARS OF AGE WITH CYSTIC FIBROSIS: THE ISIS RANDOMIZED TRIAL 
Context
Inhaled hypertonic saline is recommended as therapy for cystic fibrosis (CF) patients 6 years of age and older, but its efficacy has never been evaluated in CF patients <6 years of age.
Objective
To determine if hypertonic saline reduces the rate of protocol-defined pulmonary exacerbations in CF patients <6 years of age.
Design and Setting
A multicenter, randomized, double-blind placebo-controlled trial was conducted from April 2009 to October 2011 at 30 CF care centers in the United States and Canada.
Participants
Participants had an established diagnosis of CF and were 4 to 60 months of age. A total of 344 patients were assessed for eligibility; 321 participants were randomized; 29 (9%) withdrew prematurely.
Intervention
The active group (n=158) received 7% hypertonic saline and the control group (n=163) received 0.9% isotonic saline nebulized twice daily for 48 weeks. Both groups received albuterol or levalbuterol prior to each study drug dose.
Main Outcome Measures
the rate of protocol-defined pulmonary exacerbations during the 48 week treatment period treated with oral, inhaled or intravenous antibiotics.
Results
The mean pulmonary exacerbation rate (events/person-year) was 2.3 (95% CI, 2.0, 2.5) in the hypertonic saline group and 2.3 (95% CI, 2.1, 2.6) in the isotonic saline group; the rate ratio was 0.98 (95% CI, 0.84, 1.14)). Among participants with pulmonary exacerbations, the mean number of total antibiotic treatment days for a pulmonary exacerbation was 60 (95% CI 49, 70) in the hypertonic saline group and 52 (95% CI 43, 61) in the isotonic saline group. There was no significant difference in secondary endpoints including height, weight, respiratory rate, oxygen saturation, cough or respiratory symptom scores. Infant pulmonary function testing performed as an exploratory outcome in a subgroup (N=73, with acceptable measurements at 2 visits in 45) did not demonstrate significant differences between groups except for the mean change in forced expiratory volume in 0.5 seconds which was 38 ml greater (95% CI 1, 76) in the hypertonic saline group.
Adherence by returned study drug ampoules was at least 75% in each group. Adverse event profiles were also similar, with the most common adverse event of moderate or severe severity in each group being cough (39% of hypertonic saline group, 38% of isotonic saline group).
Conclusions
Among infants and children with cystic fibrosis less than 6 years old, the use of inhaled hypertonic saline compared with isotonic saline did not reduce the rate of pulmonary exacerbations over 48 weeks of treatment.
Trial Registration
www.clinicaltrials.gov NCT00709280
doi:10.1001/jama.2012.5214
PMCID: PMC3586815  PMID: 22610452
18.  Initial Pseudomonas aeruginosa Treatment Failure is Associated with Exacerbations in Cystic Fibrosis 
Pediatric Pulmonology  2011;47(2):125-134.
Rationale
The risk of pulmonary exacerbation following Pseudomonas aeruginosa (Pa) acquisition in children with cystic fibrosis (CF) is unknown.
Objectives
To determine if failure of antibiotic therapy to eradicate Pa and frequency of Pa recurrence are associated with increased exacerbation risk.
Methods
The cohort included 282 children with CF who participated in the EPIC trial ages 1–12 with newly acquired Pa, defined as either a first lifetime Pa positive respiratory culture or positive after two years of negative cultures (past isolation of Pa but >2 years prior to the trial). All received antibiotics to promote initial eradication followed by 15 months of intermittent maintenance antibiotics. Quarterly cultures were used to define initial eradication success and subsequent number of Pa recurrences. A standardized symptom-based definition of exacerbation was utilized. Cox proportional hazards models were used to estimate exacerbation risk.
Results
Failure to initially eradicate Pa was associated with exacerbation risk (hazard ratio [HR]: 2.49, 95% confidence interval [CI] 1.26,4.93). In 245/282 with successful initial eradication during the trial, past isolation of Pa >2 years before the trial was the most significant predictor of exacerbation (HR 1.62, 95% CI 1.12,2.35). In 37/282 who failed initial eradication, persistent Pa during the maintenance phase (1 or more Pa recurrences after failure to initially eradicate) added even greater exacerbation risk (HR 4.13, 95% CI 1.28, 13.32).
Conclusions
Children with CF who fail to eradicate after initial antibiotic treatment are at higher risk of subsequent exacerbation, suggesting clinical benefit to successful early eradication of Pa infection.
doi:10.1002/ppul.21525
PMCID: PMC3214247  PMID: 21830317
New acquisition; early intervention; eradication; clinical outcome
20.  Association of Small Artery Elasticity With Incident Cardiovascular Disease in Older Adults 
American Journal of Epidemiology  2011;174(5):528-536.
Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.
doi:10.1093/aje/kwr120
PMCID: PMC3202150  PMID: 21709134
arteries; cardiovascular diseases; elasticity; risk factors
21.  An alternative method for quantifying coronary artery calcification: the multi-ethnic study of atherosclerosis (MESA) 
BMC Medical Imaging  2012;12:14.
Background
Extent of atherosclerosis measured by amount of coronary artery calcium (CAC) in computed tomography (CT) has been traditionally assessed using thresholded scoring methods, such as the Agatston score (AS). These thresholded scores have value in clinical prediction, but important information might exist below the threshold, which would have important advantages for understanding genetic, environmental, and other risk factors in atherosclerosis. We developed a semi-automated threshold-free scoring method, the spatially weighted calcium score (SWCS) for CAC in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods
Chest CT scans were obtained from 6814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The SWCS and the AS were calculated for each of the scans. Cox proportional hazards models and linear regression models were used to evaluate the associations of the scores with CHD events and CHD risk factors. CHD risk factors were summarized using a linear predictor.
Results
Among all participants and participants with AS > 0, the SWCS and AS both showed similar strongly significant associations with CHD events (hazard ratios, 1.23 and 1.19 per doubling of SWCS and AS; 95% CI, 1.16 to 1.30 and 1.14 to 1.26) and CHD risk factors (slopes, 0.178 and 0.164; 95% CI, 0.162 to 0.195 and 0.149 to 0.179). Even among participants with AS = 0, an increase in the SWCS was still significantly associated with established CHD risk factors (slope, 0.181; 95% CI, 0.138 to 0.224). The SWCS appeared to be predictive of CHD events even in participants with AS = 0, though those events were rare as expected.
Conclusions
The SWCS provides a valid, continuous measure of CAC suitable for quantifying the extent of atherosclerosis without a threshold, which will be useful for examining novel genetic and environmental risk factors for atherosclerosis.
doi:10.1186/1471-2342-12-14
PMCID: PMC3443418  PMID: 22747658
22.  Hospitalization for infection and risk of acute ischemic stroke: The Cardiovascular Health Study 
Background and Purpose
Little is known about acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with short-term risk of stroke.
Methods
The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days prior to incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years prior to stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios and 95% confidence intervals (OR, 95% CI) were calculated using conditional logistic regression. Confirmatory analyses assessed hazard ratios (HR) of stroke from Cox regression models with hospitalization for infection as a time-varying exposure.
Results
During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days prior to stroke, OR=3.4 (95% CI 1.8–6.5). The point estimates of risks were higher when examining shorter intervals: for 30 days, OR= 7.3 (95% CI 1.9–40.9), and 14 days, OR=8.0 (95% CI 1.7–77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted HR=2.4 (95% CI 1.6–3.4).
Conclusions
Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.
doi:10.1161/STROKEAHA.110.608588
PMCID: PMC3125478  PMID: 21546476
Epidemiology; Cerebral Infarction; Infectious Diseases
23.  Sex and Race Differences in Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
Circulation  2011;123(22):2542-2551.
Background
Right ventricular (RV) morphology is an important predictor of outcomes in heart and lung disease, however determinants of RV anatomy have not been well-studied. We examined the demographic factors associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease.
Methods and Results
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging (MRI) on 5098 participants. RV volumes and mass were available for 4204 participants. Normative equations for RV parameters were derived using an allometric approach. The study sample (N = 4123) was 61.5 ± 10.1 years old and 47.5% male. Older age was associated with lower RV mass (~5% lower mass per decade) with larger age-related decrements in men than in women (p for interaction < 0.05). Older age was also associated with higher RV ejection fraction (RVEF), an association which differed between races/ethnicities (p for interaction ≤ 0.01). Overall, men had greater RV mass (~8%) and larger RV volumes than women, but had lower RVEF (4% in absolute terms) (p < 0.001). African Americans had lower RV mass than Caucasians (p ≤ 0.002), whereas Hispanics had higher RV mass (p ≤ 0.02). Using the derived normative equations, 7.3% (95%CI, 6.5–8.1%) met criteria for RV hypertrophy and 5.9% (95%CI, 5.2–6.6%) had RV dysfunction.
Conclusions
In conclusion, age, sex, and race are associated with significant differences in RV mass, RV volumes and RVEF, potentially explaining distinct responses of the RV to cardiopulmonary disease.
doi:10.1161/CIRCULATIONAHA.110.985515
PMCID: PMC3111939  PMID: 21646505
right ventricle; pulmonary heart disease; magnetic resonance imaging; pulmonary hypertension
24.  Reduced Kidney Function and Preclinical Atherosclerosis in HIV-Infected Individuals: The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) 
American Journal of Nephrology  2011;33(5):453-460.
Background/Aims
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Methods
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
Results
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
Conclusions
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
doi:10.1159/000327606
PMCID: PMC3100378  PMID: 21508633
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
25.  Alcohol and coronary artery calcium prevalence, incidence and progression: results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Alcohol use has been consistently found to have a J-shaped association with coronary heart disease, with moderate drinkers exhibiting a decreased risk compared to both heavy drinkers and non-drinkers. However, studies of the association between alcohol use and subclinical coronary artery disease have conflicted.
Objective
To determine whether alcohol is associated with the presence, amount, or progression of coronary calcium over a 2- to 4-year period.
Design
MESA is a prospective community-based cohort study of subclinical cardiovascular disease in a multi-ethnic cohort. In 2000–2002, 6814 participants free of clinical cardiovascular disease were enrolled at 6 participating centers.
Results
There were 3766 (55.5%) current drinkers, 1635 (24.1%) former drinkers, and 1390 (20.5%) never drinkers included in the analysis. Although light to moderate alcohol consumption was associated with lower coronary heart disease risk, we found no evidence of a protective or J-shaped association of alcohol and coronary artery calcium (CAC). In fact there was evidence that heavy consumption of hard liquor was associated with greater CAC accumulation. Other alcoholic beverages were not associated with CAC prevalence, incidence or progression.
Conclusions
This is the first large study to evaluate the association of alcohol and coronary artery calcium in four racial/ethnic groups, and to evaluate progression of calcification. These results suggest that the cardiovascular benefits that may be derived from light to moderate alcohol consumption are not mediated through reduced CAC accumulation.
doi:10.3945/ajcn.2008.26420
PMCID: PMC3319440  PMID: 19064520

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