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1.  Plasma sphingomyelin and longitudinal change in emphysema on computed tomography. The MESA Lung study 
Context
Ceramide causes endothelial apoptosis and emphysema-like changes in animal models.
Objectives
Test if plasma sphingomyelin, a major precursor of ceramide, would predict longitudinal increase in the percentage of emphysema-like lung on computed tomography (CT).
Materials and methods
3,840 participants had their plasma sphingomyelin measured at baseline examination and their pulmonary emphysema measured on cardiac CT scans at baseline and on follow-up visits. Mixed effects models were used to adjust for potential confounders.
Results
one standard deviation increase in sphingomyelin predicted a 0.12 % per year (95% CI: 0.02 to 0.22; p = 0.019) greater increase of percent emphysema.
Discussion and conclusion
Higher plasma levels of sphingomyelin predicted greater annual increase in quantitatively measured percent emphysema.
doi:10.3109/1354750X.2014.896414
PMCID: PMC4088962  PMID: 24649875
Sphingomyelin; Ceramide; Emphysema; Computed Tomography
2.  Ethnicity and Sex Modify the Association of Serum C-Reactive Protein with Microalbuminuria 
Ethnicity & disease  2008;18(3):324-329.
Objectives
To study the association between serum C-reactive protein (CRP) and urinary albumin excretion in the Multi-Ethnic Study of Atherosclerosis and to assess whether the association is modified by ethnicity, sex, or systolic blood pressure.
Methods
This was a cross-sectional study of 6675 participants who were free from macro albuminuria and clinical cardiovascular disease (mean age 62.1 years, 53% female; 39% White, 27% African American, 22% Hispanic, and 12% Chinese). Urinary albumin excretion was measured by spot urine albumin-to-creatinine ratio (ACR). Effect modifications were tested after adjusting for age, diabetes, body mass index, smoking, use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, other antihypertensive drugs, estrogens, statins, and high-density lipoprotein cholesterol and triglyceride levels.
Results
The association between CRP and ACR was modified by ethnicity (P=.01) and sex (P<.001), but not by systolic blood pressure. After multivariate adjustment, the association remained in Chinese, African American, and Hispanic men and African American women (P<.02 for African American men, and P<.04 for the other subgroups).
Conclusions
The association between CRP and ACR was modified by ethnicity and sex; it was stronger in non-White men and African American women. These interactions have not been reported before, and future studies should consider them.
PMCID: PMC4089959  PMID: 18785447
Albuminuria; C-Reactive Protein; Ethnicity; Gender
3.  Pentraxin-3 and the right ventricle: the Multi-Ethnic Study of Atherosclerosis–Right Ventricle Study 
Pulmonary Circulation  2014;4(2):250-259.
Pentraxin-3 (PTX3) is a protein mediator of innate immunity that is elevated in the setting of left heart disease and pulmonary arterial hypertension. The relationship between PTX3 and right ventricular (RV) structure and function is not known. We included men and women with magnetic resonance imaging assessment of RV structure and function and measurement of PTX3 from the Multi-Ethnic Study of Atherosclerosis, a study of individuals free of clinical cardiovascular disease. Multivariable linear regression estimated associations between PTX3 protein levels and RV measures after adjusting for demographic characteristics, anthropometrics, smoking status, diabetes mellitus, hypertension, and corresponding left ventricular (LV) parameters. Instrumental variable analysis exploiting Mendelian randomization was attempted using two-stage least squares regression. The study sample included 1,779 participants with available PTX3 levels, RV measures, and all covariables. Mean PTX3 level was 2.1 ng/mL. Higher PTX3 was independently associated with greater RV mass and larger RV end-diastolic volume with and without adjustment for the corresponding LV parameters or C-reactive protein (all P < .05). There was no association between PTX3 and RV ejection fraction or stroke volume. Single-nucleotide polymorphisms were not associated with PTX3 protein levels or RV measures after accounting for race. Instrumental variable analysis could not be reliably performed. Higher PTX3 protein levels were associated with greater RV mass and larger RV end-diastolic volume. These associations were independent of common cardiovascular risk factors and LV morphologic changes. Inflammation is associated with differences in the pulmonary circulation-RV axis in adults without clinical cardiovascular disease.
doi:10.1086/675988
PMCID: PMC4070771
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
4.  Quantitative and Semi-quantitative Measures of Regional Pulmonary Parenchymal Perfusion by Magnetic Resonance Imaging and their Relationships to Global Lung Perfusion and Lung Diffusing Capacity – The MESA COPD Study 
Investigative radiology  2013;48(4):223-230.
Objectives
To evaluate quantitative and semi-quantitative measures of regional pulmonary parenchymal perfusion in patients with COPD in relationship to global lung perfusion (GLP) and lung diffusing capacity (DLCO).
Materials and Methods
One hundred and forty three participants in the MESA COPD Study were examined by dynamic contrast-enhanced pulmonary perfusion MRI at 1.5 T. Pulmonary blood flow (PBF) was calculated on a pixel-by-pixel basis by using a dual-bolus technique and the Fermi function model. Semi-quantitative parameters for regional lung perfusion were calculated from signal-intensity time curves in the lung parenchyma. Intra- and inter-observer coefficients of variation (CV) and correlations between quantitative and semi-quantitative MRI parameters and with GLP and DLCO were determined.
Results
Quantitative and semi-quantitative parameters of pulmonary parenchymal perfusion were reproducible with CVs for all <10%. Furthermore, these MRI parameters were correlated with GLP and DLCO and there was good agreement between PBF and GLP. Quantitative and semi-quantitative MRI parameters were closely correlated (e.g., r=0.86 for maximum signal increase with PBF). In participants without COPD, the physiological distribution of pulmonary perfusion could be determined by regional MRI measurements.
Conclusion
Regional pulmonary parenchymal perfusion can reliably be quantified from dynamic contrast-enhanced MRI. MRI-derived quantitative and semi-quantitative perfusion measures correlate with GLP and DLCO.
doi:10.1097/RLI.0b013e318281057d
PMCID: PMC3952075  PMID: 23385398
Pulmonary perfusion; chronic obstructive pulmonary disease (COPD); dynamic contrast-enhanced MRI; quantitative perfusion maps; diffusing lung capacity
5.  The Epidemiology of Vascular Dysfunction Relating to Chronic Obstructive Pulmonary Disease and Emphysema 
Cor pulmonale has long been described in very severe chronic obstructive pulmonary disease (COPD) and emphysema. Cross-sectional results from population-based studies show that left ventricular filling and a variety of vascular measures in the systemic circulation are abnormal in preclinical COPD and emphysema and that a predominant vascular change in COPD and emphysema is endothelial and microvascular dysfunction. These findings suggest that pulmonary vascular changes may occur early in COPD and emphysema and might contribute to pathogenesis. However, longitudinal epidemiologic studies with direct measures of the pulmonary vasculature are lacking; therefore, inferences are limited at present. New imaging-based approaches to the assessment of the pulmonary vasculature are applicable to epidemiologic studies and may help in defining the relationship of pulmonary vascular damage to progression of COPD and emphysema. These measures may also provide imaging-based surrogate markers, and novel therapeutics targeted to the pulmonary vasculature might reduce symptoms and improve function in these common diseases.
doi:10.1513/pats.201101-008MW
PMCID: PMC3359073  PMID: 22052931
chronic obstructive pulmonary disease; pulmonary emphysema; pulmonary hypertension; vascular disease; pulmonary vasculature
6.  Asthma and lung structure on CT: The MESA Lung Study 
Background
The potential consequences of asthma in childhood and young adulthood on lung structure in older adults have not been studied in a large, population-based cohort.
Objective
The authors hypothesized that a history of asthma onset in childhood (age 18 or before) or young adulthood (age 19 to 45) was associated with altered lung structure on computed tomography (CT) in later life.
Methods
The Multi-Ethnic Study of Atherosclerosis Lung Study recruited 3,965 participants and assessed asthma history using standardized questionnaires, spirometry following guidelines, and segmental airway dimensions and percent low attenuation areas on CT scans.
Results
Asthma with onset in childhood and young adulthood was associated with large decrements in the forced expiratory volume in one second among participants with a mean age of 66 years (−365 ml and −343 ml, respectively; P<0.001). Asthma with onset in childhood and young adulthood was associated with increased mean airway wall thickness standardized to an internal perimeter of 10 mm (Pi10) (0.1 mm, P<0.001 for both), predominantly from narrower segmental airway lumens (−0.39 mm and −0.34 mm, respectively; P<0.001). Asthma with onset in childhood and young adulthood also was associated with a greater percentage of low attenuation areas (1.69% and 4.30%, respectively; P<0.001). Findings were similar among never smokers except that differential percentage of low attenuation areas in child-onset asthma was not seen in them.
Conclusion
Asthma with onset in childhood or young adulthood, was associated with reduced lung function, narrower airways and, among asthmatics who smoked, greater percentage of low attenuation areas in later life.
doi:10.1016/j.jaci.2012.11.036
PMCID: PMC3564253  PMID: 23374265
airway remodeling; airway structure; asthma; emphysema; epidemiology
7.  Associations among Lung Function, Arterial Elasticity and Circulating Endothelial and Inflammation Markers: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(2):542-548.
A parallel physiologic pathway for elastic changes is hypothesized for declines in arterial elasticity and lung function. Endothelial dysfunction and inflammation could potentially decrease elasticity of both vasculature and lung tissue. We examined biomarkers, large (LAE) and small (SAE) arterial elasticity, and forced vital capacity (FVC) in a period cross-sectional design in the Multi-Ethnic Study of Atherosclerosis, which recruited 1,823 women and 1,803 men, age range 45–84 years, black, white, Hispanic, and Chinese, free of clinically recognized CVD. Radial artery tonometric pulse waveform registration was performed and LAE and SAE were derived from diastole. Spirometric data and markers of endothelial dysfunction and inflammation (soluble intracellular adhesion molecule-1, fibrinogen, hs-C-reactive protein, and interleukin-6) were obtained. Mean LAE was 13.7 ± 5.5 ml/mmHgx10 and SAE was 4.6 ± 2.6 ml/mmHgx100. Mean FVC was 3,192 ± 956.0 mL and FEV1 was 2,386 ± 734.5 mL. FVC was about 40 ± 5 mL higher per SD of SAE, stronger in men than women. The association was slightly weaker with LAE, with no sex interaction. After regression adjustment for demographic, anthropometric, and cardiovascular risk factors, the biomarkers tended to be related to reduced SAE and FVC, particularly in men. These biomarker associations suggest important CVD risk alterations that occur concurrently with lower arterial elasticity and lung function. The observed positive association of SAE with FVC and with FEV1 in middle-aged to older free-living people is consistent with the hypothesis of parallel physiologic pathways for elastic changes in the vasculature and in lung parenchymal tissue.
doi:10.1161/HYPERTENSIONAHA.111.00272
PMCID: PMC3586233  PMID: 23283358
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
8.  Comparison of serum, EDTA plasma and P100 plasma for luminex-based biomarker multiplex assays in patients with chronic obstructive pulmonary disease in the SPIROMICS study 
Background
As a part of the longitudinal Chronic Obstructive Pulmonary Disease (COPD) study, Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS), blood samples are being collected from 3200 subjects with the goal of identifying blood biomarkers for sub-phenotyping patients and predicting disease progression. To determine the most reliable sample type for measuring specific blood analytes in the cohort, a pilot study was performed from a subset of 24 subjects comparing serum, Ethylenediaminetetraacetic acid (EDTA) plasma, and EDTA plasma with proteinase inhibitors (P100™).
Methods
105 analytes, chosen for potential relevance to COPD, arranged in 12 multiplex and one simplex platform (Myriad-RBM) were evaluated in duplicate from the three sample types from 24 subjects. The reliability coefficient and the coefficient of variation (CV) were calculated. The performance of each analyte and mean analyte levels were evaluated across sample types.
Results
20% of analytes were not consistently detectable in any sample type. Higher reliability and/or smaller CV were determined for 12 analytes in EDTA plasma compared to serum, and for 11 analytes in serum compared to EDTA plasma. While reliability measures were similar for EDTA plasma and P100 plasma for a majority of analytes, CV was modestly increased in P100 plasma for eight analytes. Each analyte within a multiplex produced independent measurement characteristics, complicating selection of sample type for individual multiplexes.
Conclusions
There were notable detectability and measurability differences between serum and plasma. Multiplexing may not be ideal if large reliability differences exist across analytes measured within the multiplex, especially if values differ based on sample type. For some analytes, the large CV should be considered during experimental design, and the use of duplicate and/or triplicate samples may be necessary. These results should prove useful for studies evaluating selection of samples for evaluation of potential blood biomarkers.
doi:10.1186/1479-5876-12-9
PMCID: PMC3928911  PMID: 24397870
Chronic obstructive pulmonary disease; COPD; SPIROMICS; Biomarkers; Blood analytes; Multiplex assays; P100 plasma; Serum; EDTA plasma; Pilot study
9.  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
10.  Similar Relation of Age and Height to Lung Function Among Whites, African Americans, and Hispanics 
American Journal of Epidemiology  2011;173(4):376-387.
Current guidelines recommend separate spirometry reference equations for whites, African Americans, and Mexican Americans, but the justification for this recommendation is controversial. The authors examined the statistical justification for race/ethnic-specific reference equations in adults in the Third National Health and Nutrition Examination Survey (1988–1994) and the Multi-Ethnic Study of Atherosclerosis Lung Study (2000–2006). Spirometry was measured following American Thoracic Society guidelines. “Statistical justification” was defined as the presence of effect modification by race/ethnicity among never-smoking participants without respiratory disease or symptoms and was tested with interaction terms for race/ethnicity (× age and height) in regression models. There was no evidence of effect modification by race/ethnicity for forced expiratory volume in 1 second, forced vital capacity, or the forced expiratory volume in 1 second/forced vital capacity ratio among white, African-American, and Mexican-American men or women on an additive scale or a log scale. Interaction terms for race/ethnicity explained less than 1% of variability in lung function. The mean lung function for a given age, gender, and height was the same for whites and Mexican Americans but was lower for African Americans. Findings were similar in the Multi-Ethnic Study of Atherosclerosis Lung Study. The associations of age and height with lung function are similar across the 3 major US race/ethnic groups. Multiethnic rather than race/ethnic-specific spirometry reference equations are applicable for the US population.
doi:10.1093/aje/kwq417
PMCID: PMC3032806  PMID: 21242304
African Americans; age groups; body height; European continental ancestry group; Hispanic Americans; respiratory function tests; spirometry
11.  Cigarette smoking and airway wall thickness on CT scan in a multi-ethnic cohort: The MESA Lung Study 
Respiratory medicine  2012;106(12):1655-1664.
Background
Autopsy studies show that smoking contributes to airway wall hyperplasia and narrowing of the airway lumen. Studies of smoking and airway measures on computed tomography (CT) scan are limited to case-control studies of measures that combine airway lumen and wall thickness.
Objectives
We hypothesized that cumulative cigarette smoking would be associated with increased airway wall thickness in a large, population-based cohort.
Methods
The Multi-Ethnic Study of Atherosclerosis enrolled participants age 45-84 years from the general population. Smoking history was assessed via standardized questionnaire items; current smoking was confirmed in half the cohort with cotinine. Airway lumen and wall thickness were measured in two dimensions in posterior basal segmental bronchi on cardiac-gated CT scans. Analyses were adjusted for age, gender, genetic ancestry, education, height, weight, asthma history, particulate matter, scanner type, and scanner current.
Results
Half of the 7,898 participants had smoked and 14% were current smokers. Pack-years of smoking were associated with thicker airway walls (mean increase 0.002 mm per ten pack-years [95% CI: 0.00002, 0.004] p=0.03). Current smoking was associated with narrower airway lumens (mean decrease −0.11 mm [95% CI: −0.2, −0.02] p=0.02). There was no evidence that either association was modified by genetic ancestry, and findings persisted among participants without clinical disease.
Conclusions
Long-term cigarette smoking was associated with subclinical increases in wall thickness of sub-segmental airways whereas current smoking was associated with narrower airway lumen diameters. Smoking may contribute to airway wall thickening prior to the development of overt chronic obstructive pulmonary disease.
doi:10.1016/j.rmed.2012.08.006
PMCID: PMC3549633  PMID: 22974831
smoking; airway remodeling; Pi10; wall thickness; lumen; chronic obstructive pulmonary disease
12.  Vascular Responses to Long- and Short-Term Exposure to Fine Particulate Matter 
Objectives
This study evaluated the association of long- and short-term air pollutant exposures with flow-mediated dilation (FMD) and baseline arterial diameter (BAD) of the brachial artery using ultrasound in a large multicity cohort.
Background
Exposures to ambient air pollution, especially long-term exposure to particulate matter <2.5 μm in aerodynamic diameter (PM2.5), are linked with cardiovascular mortality. Short-term exposure to PM2.5 has been associated with decreased FMD and vasoconstriction, suggesting that adverse effects of PM2.5 may involve endothelial dysfunction. However, long-term effects of PM2.5 on endothelial dysfunction have not been investigated.
Methods
FMD and BAD were measured by brachial artery ultrasound at the initial examination of the Multi-Ethnic Study of Atherosclerosis. Long-term PM2.5 concentrations were estimated for the year 2000 at each participant’s residence (n = 3,040) using a spatio-temporal model informed by cohort-specific monitoring. Short-term PM2.5 concentrations were based on daily central-site monitoring in each of the 6 cities.
Results
An interquartile increase in long-term PM2.5 concentration (3 μg/m3) was associated with a 0.3% decrease in FMD (95% confidence interval [CI] of difference: −0.6 to −0.03; p = 0.03), adjusting for demographic characteristics, traditional risk factors, sonographers, and 1/BAD. Women, nonsmokers, younger participants, and those with hypertension seemed to show a greater association of PM2.5 with FMD. FMD was not significantly associated with short-term variation in PM2.5 (−0.1% per 12 μg/m3 daily increase [95% CI: −0.2 to 0.04] on the day before examination).
Conclusions
Long-term PM2.5 exposure was significantly associated with decreased endothelial function according to brachial ultrasound results. These findings may elucidate an important pathway linking air pollution and cardiovascular mortality.
doi:10.1016/j.jacc.2012.08.973
PMCID: PMC3665082  PMID: 23103035
air pollution; atherosclerosis; cardiovascular mortality; endothelial function; flow-mediated dilation; traffic
13.  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
14.  Right Ventricular Structure is Associated with the Risk of Heart Failure and Cardiovascular Death: The MESA-Right Ventricle Study 
Circulation  2012;126(14):1681-1688.
Background
Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure (HF) or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline.
Methods and Results
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging (MRI) on 5098 participants between 2000–2002 with follow-up for incident heart failure and cardiovascular death (“death”) until January 2008. RV volumes and mass were available for 4204 participants. The study sample (N = 4,144) was 61.4 ± 10.1 years old and 47.6 % male. The presence of RV hypertrophy (increased RV mass) was associated with a more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (HR = 2.52, 95%CI 1.55–4.10, p < 0.001) and a doubling of risk (or more) with left ventricular mass at the mean value or lower (p for interaction = 0.05).
Conclusions
RV hypertrophy was associated with the risk of heart failure or death in a multi-ethnic population free of clinical cardiovascular disease at baseline.
doi:10.1161/CIRCULATIONAHA.112.095216
PMCID: PMC3532921  PMID: 22932258
right ventricle; pulmonary heart disease; magnetic resonance imaging; pulmonary hypertension; survival
15.  Does the relationship between asthma and obesity differ by neighborhood? 
Respiratory medicine  2008;102(12):1797-1804.
doi:10.1016/j.rmed.2008.06.018
PMCID: PMC3695444  PMID: 18707858
epidemiology; survey; urban health
16.  Pulmonary Function is Associated with Distal Aortic Calcium, not Proximal Aortic Distensibility. MESA Lung Study 
COPD  2011;8(2):71-78.
Forced expiratory volume in one second strongly predicts mortality from cardiovascular disease. FEV1 has been associated with aortic stiffness a strong independent predictor of cardiovascular mortality. However, the anatomical site and possible mechanisms linking aortic stiffness and lung function are unknown. We therefore examined if FEV1 and CT percent emphysema were associated with calcification of the abdominal aorta or reduced distensibility of the proximal thoracic aorta.
The Multi-Ethnic Study of Atherosclerosis (MESA) measured aortic calcification on cardiac and abdominal CT scans and proximal aortic distensibility using magnetic resonance among participants aged 45–84 years without clinical cardiovascular disease. Spirometry was measured following ATS/ERS guidelines and percent emphysema was measured in the lung fields of cardiac CT scans. Multivariate analyses adjusted for age, sex, race/ethnicity and cardiovascular risk factors.
Of 1,917 participants with aortic distensibility measures, 13% were current and 38% were former smokers. Eighteen percent had airflow limitation without asthma. FEV1 was associated with the extent of distal aortic calcification (0.76; 95%CI 0.60–0.97, p=0.02) but not proximal aortic calcification or proximal aortic distensibility (−0.04 mmHg−1; 95%CI −0.16–0.09 mmHg−1, p=0.60). Percent emphysema was associated with neither measure.
FEV1 was associated with severity of distal aortic calcification where it was present independently of smoking and other cardiovascular risk factors but not with distensibility or calcification of the proximal aorta.
doi:10.3109/15412555.2011.558543
PMCID: PMC3629728  PMID: 21495835
forced expiratory volume; pulmonary emphysema; aorta; calcification; compliance
17.  Performance of Maximal Inspiratory Pressure Tests and MIP Reference Equations for Four Ethnic Groups 
Respiratory care  2009;54(10):1321-1328.
Background
Maximal inspiratory pressure (MIP) is an important and non-invasive index of diaphragm strength and an independent predictor of all-cause mortality. The ability of adults over a wide age range and multiple ethnicities to perform MIP tests has previously not been evaluated.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) recruited white, African-American, Hispanic and Chinese-American participants ages 45–84 years and free of clinical cardiovascular disease in six US cities. MIP was measured using standard techniques among 3849 MESA participants. The MIP quality goal was 5 maneuvers, with the two largest values matching within 10 cmH2O. Correlates of MIP quality and values were assessed in logistic and linear regression models.
Results
The 3849 MESA-Lung participants with MIP measures were 51% female, 35% white, 26% African-American, 23% Hispanic, and 16% Chinese-American. Mean MIP±SD was 73±26 cmH2O for women and 97±29 cmH2O for men. The quality goal was achieved by 83% of the cohort and was associated with female gender, older age, race/ethnicity, study site, low FEV1/FVC ratio, and wheeze with dyspnea. The multivariate correlates of MIP were male gender, younger age, higher BMI, shorter height, higher FVC, higher systolic blood pressure (in women) and health status (in men). There were no clinically important race/ethnic differences in MIP values.
Conclusion
Race-specific reference equations for MIP are unnecessary in the United States. More than 80% of adults can be successfully coached for 5 maneuvers with repeatability within 10 cmH2O.
PMCID: PMC3616895  PMID: 19796411
diaphragm strength; respiratory muscle strength; maximal inspiratory pressure; quality control; pulmonary function testing
18.  Associations of dairy intake with CT lung density and lung function 
Objective
Dairy products contain vitamin D and other nutrients that may be beneficial for lung function, but are also high in fats that may have mixed effects on lung function. However, the overall associations of dairy intake with lung density and lung function have not been studied.
Methods
We examined the cross-sectional relations between dairy intake and CT lung density and lung function in the Multi-Ethnic Study of Atherosclerosis (MESA). Total, low-fat and high-fat dairy intakes were quantified from food frequency questionnaire responses of men and women, aged 45–84 years, free of clinical cardiovascular disease. The MESA-Lung Study assessed CT lung density from cardiac CT imaging and prebronchodilator spirometry among 3,965 MESA participants.
Results
Total dairy intake was inversely associated with apical-basilar difference in percent emphysema and positively associated with FVC (the multivariate-adjusted mean difference between the highest and the lowest quintile of total dairy intake was −0.92 (p for trend=0.04) for apical-basilar difference in percent emphysema and 72.0 mL (p=0.01) for FVC). Greater low-fat dairy intake was associated with higher alpha (higher alpha values indicate less emphysema) and lower apical-basilar difference in percent emphysema (corresponding differences in alpha and apical-basilar difference in percent emphysema were 0.04 (p=0.02) and −0.98 (p=0.01) for low-fat dairy intake, respectively). High-fat dairy intake was not associated with lung density measures. Greater low- or high-fat dairy intake was not associated with higher FEV1, FVC and FEV1/FVC.
Conclusions
Higher low-fat dairy intake but not high-fat dairy intake was associated with moderately improved CT lung density.
PMCID: PMC3616890  PMID: 21504976
dairy intake; lung density; emphysema; lung function; chronic obstructive pulmonary disease
19.  Subclinical Atherosclerosis, Airflow Obstruction and Emphysema: the MESA Lung Study 
Airflow obstruction is independent risk factor for cardiovascular events in the general population. The affected vascular bed and contribution of emphysema to cardiovascular risk are unclear. We examined if an obstructive pattern of spirometry and quantitatively defined emphysema were associated with subclinical atherosclerosis in the carotid, peripheral and coronary circulations.
The Multi-Ethnic Study of Atherosclerosis recruited participants age 45–84 years without clinical cardiovascular disease. Spirometry, carotid intima-media thickness, ankle-brachial index and coronary artery calcium were measured using standard protocols. Percent of emphysema-like lung was measured in the lung windows of cardiac computed tomography scans among 3,642 participants. Multiple linear regression was used to adjust for cardiac risk factors including C-reactive protein.
Decrements in the FEV1 and FEV1/FVC were associated with greater internal carotid intima-media thickness among smokers (P=0.03 and P<0.001, respectively) whereas percent emphysema was associated with reduced ankle-brachial index regardless of smoking history (P=0.004). Coronary artery calcium was associated with neither lung function (prevalence ratio for severe airflow obstruction: 0.99; 95% CI, 0.91 to 1.07) nor percent emphysema.
An obstructive pattern of spirometry and emphysema are associated distinctly and independently with subclinical atherosclerosis in the carotid arteries and peripheral circulation, respectively, and were not independently related to coronary artery calcium.
doi:10.1183/09031936.00165410
PMCID: PMC3616898  PMID: 22034646
20.  Airflow obstruction, lung function, and risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) study 
European Journal of Heart Failure  2012;14(4):414-422.
Aims
We examined the relationship between forced expiratory volume in 1 s (FEV1), airflow obstruction, and incident heart failure (HF) in black and white, middle-aged men and women in four US communities.
Methods and results
Lung volumes by standardized spirometry and information on covariates were collected on 15 792 Atherosclerosis Risk in Communities (ARIC) cohort participants in 1987–89. Incident HF was ascertained from hospital records and death certificates up to 2005 in 13 660 eligible participants. Over an average follow-up of 14.9 years, 1369 (10%) participants developed new-onset HF. The age- and height-adjusted hazard ratios (HRs) for HF increased monotonically over descending quartiles of FEV1 for both genders, race groups, and smoking status. After multivariable adjustment for traditional cardiovascular risk factors and height, the HRs [95% confidence intervals (CIs)] of HF comparing the lowest with the highest quartile of FEV1 were 3.91 (2.40–6.35) for white women, 3.03 (2.12–4.33) for white men, 2.11 (1.33–3.34) for black women, and 2.23 (1.37–3.59) for black men. The association weakened but remained statistically significant after additional adjustment for systemic markers of inflammation. The multivariable adjusted incidence of HF was higher in those with FEV1/forced vital capacity <70% vs. ≥70%: HR 1.44 (95% CI 1.20–1.74) among men and 1.40 (1.13–1.72) among women. A consistent and positive association with HF was seen for self-reported diagnosis of emphysema and chronic obstructive pulmonary disease, but not for asthma.
Conclusions
In this large population-based cohort with long-term follow-up, low FEV1 and an obstructive respiratory disease were strongly and independently associated with the risk of incident HF.
doi:10.1093/eurjhf/hfs016
PMCID: PMC3530346  PMID: 22366234
Lung function; COPD; Heart failure; Risk factors; Cohort study
21.  Reproducibility and Validity of a Handheld Spirometer 
Respiratory care  2008;53(4):433-441.
Background
Handheld spirometers have several advantages over desktop spirometers but worries persist regarding their reproducibility and validity. We undertook an independent examination of an ultrasonic flow-sensing handheld spirometer.
Methods
Laboratory methods included reproducibility and validity testing using a waveform generator with standard American Thoracic Society (ATS) waveforms, in-line testing, calibration adaptor testing, and compression of the mouthpiece. Clinical testing involved repeated testing of 24 spirometry-naive volunteers and comparison to a volume-sensing dry rolling seal spirometer.
Results
The EasyOne Diagnostic spirometer exceeded standard thresholds of acceptability for ATS waveforms. In-line testing yielded valid results with relative differences (mean ± SD) between the EasyOne and the reference spirometer for the forced vital capacity (FVC) of 0.03±0.23 L and the forced expiratory volume in one second (FEV1) of −0.06±0.09 L. The calibration adaptor showed no appreciable problems, but extreme compression of the mouthpiece reduced measures. In clinical testing, coefficients of variation and limits of agreement were, respectively: 3.3% and 0.24 L for the FVC; 2.6% and 0.18 L for the FEV1; and 1.9% and 0.05 for the FEV1/FVC ratio. The EasyOne yielded lower values than the reference spirometry (FVC: −0.12 L; FEV1: −0.17 L; FEV1/FVC ratio: −0.02). Limits of agreement were within criteria for FVC but not for the FEV1, possibly due to a training effect.
Conclusion
The EasyOne spirometer yielded generally reproducible results that were generally valid compared to laboratory-based spirometry. The use of this handheld spirometer in clinical, occupational and research settings seems justified.
PMCID: PMC3595551  PMID: 18364054
22.  Right Ventricular Morphology and the Onset of Dyspnea: The MESA-Right Ventricle Study 
PLoS ONE  2013;8(2):e56826.
Background
The association of right ventricular (RV) structure and function with symptoms in individuals without cardiopulmonary disease is unknown. We hypothesized that greater RV mass and RV end-diastolic volume (RVEDV), smaller RV stroke volume (RVSV), and lower RV ejection fraction (RVEF) measured by cardiac magnetic resonance imaging (MRI) in participants free of clinical cardiovascular disease at baseline would be associated with a greater risk of self-reported dyspnea.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRIs on participants without clinical cardiovascular disease between 2000 and 2002. We excluded subjects who reported “prevalent” dyspnea at the first assessment (24 months). The presence of dyspnea was assessed at 24 months, 42 months, and 60 months from baseline. Cox proportional hazards models were used to examine the relationship between RV measures and incident dyspnea.
Results
In the final study sample (N = 2763), there were significant interactions between RV measures and sex in terms of the risk of dyspnea (p<0.05). Among men (N = 1453), lower RV mass (p = 0.003), smaller RVEDV (p<0.001), smaller RV end-systolic volume (RVESV) (p = 0.03) and decreased RVSV (p<0.001) were associated with an increased risk of developing dyspnea after adjusting for covariates. Associations remained after adjusting for left ventricular function and lung function. However, there were no significant associations between RV measures and the risk of dyspnea in women.
Conclusions
Lower RV mass and smaller RV volumes were associated with an increased risk of dyspnea in men, but not in women.
doi:10.1371/journal.pone.0056826
PMCID: PMC3574101  PMID: 23457622
23.  Impact of Subclinical Atherosclerosis on Cardiovascular Disease Events in Individuals With Metabolic Syndrome and Diabetes 
Diabetes Care  2011;34(10):2285-2290.
OBJECTIVE
While metabolic syndrome (MetS) and diabetes confer greater cardiovascular disease (CVD) risk, recent evidence suggests that individuals with these conditions have a wide range of risk. We evaluated whether screening for coronary artery calcium (CAC) and carotid intimal-medial thickness (CIMT) can improve CVD risk stratification over traditional risk factors (RFs) in people with MetS and diabetes.
RESEARCH DESIGN AND METHODS
We assessed CAC and CIMT in 6,603 people aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression examined the association of CAC and CIMT with coronary heart disease (CHD) and CVD over 6.4 years in MetS and diabetes.
RESULTS
Of the subjects, 1,686 (25%) had MetS but no diabetes and 881 (13%) had diabetes. Annual CHD event rates were 1.0% among MetS and 1.5% for diabetes. Ethnicity and RF-adjusted hazard ratios for CHD for CAC 1–99 to ≥400 vs. 0 in subjects with neither MetS nor diabetes ranged from 2.6 to 9.5; in those with MetS, they ranged from 3.9 to 11.9; and in those with diabetes, they ranged from 2.9 to 6.2 (all P < 0.05 to P < 0.001). Findings were similar for CVD. CAC increased the C-statistic for events (P < 0.001) over RFs and CIMT in each group while CIMT added negligibly to prediction over RFs.
CONCLUSIONS
Individuals with MetS or diabetes have low risks for CHD when CAC or CIMT is not increased. Prediction of CHD and CVD events is improved by CAC more than by CIMT. Screening for CAC or CIMT can stratify risk in people with MetS and diabetes and support the latest recommendations regarding CAC screening in those with diabetes.
doi:10.2337/dc11-0816
PMCID: PMC3177707  PMID: 21844289
24.  A Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension: ASA-STAT 
Circulation  2011;123(25):2985-2993.
Background
Pulmonary arterial hypertension (PAH) is a progressive disease which causes exercise limitation, heart failure, and death. We aimed to determine the safety and efficacy of aspirin and simvastatin in PAH.
Methods and Results
We performed a randomized, double-blind, placebo-controlled 2 × 2 factorial clinical trial of aspirin and simvastatin in patients with PAH receiving background therapy at four centers. A total of 92 patients with PAH were to be randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was six-minute walk distance (6MWD) at six months. Sixty-five subjects were randomized when the trial was terminated by the DSMB after an interim analysis showed futility in reaching the primary end point for simvastatin. After adjustment for baseline 6MWD, there was no significant difference in the 6MWD at six months between aspirin (n = 32) and placebo (n = 33) [placebo-corrected difference = −0.5 m (95%CI, −28.4 – 27.4 m), p = 0.97] or between simvastatin (n = 32) and placebo (n = 33) [placebo-corrected difference = −27.6 m (95%CI, −59.6 – 4.3 m), p = 0.09]. There tended to be more major bleeding episodes with aspirin compared to placebo (4 events vs. 1 event, respectively, p = 0.17).
Conclusions
Neither aspirin nor simvastatin had a significant effect on the 6MWD, although patients randomized to simvastatin tended to have a lower 6MWD at six months. These results do not support the routine treatment of patients with PAH with these medications.
doi:10.1161/CIRCULATIONAHA.110.015693
PMCID: PMC3427737  PMID: 21593252
pulmonary hypertension; clinical trial; anti-platelet agents; endothelial dysfunction
25.  Validation of self-reported chronic obstructive pulmonary disease among patients in the ED☆ 
Background
To determine whether the self-reported diagnosis of adults who present to the emergency department (ED) with an acute exacerbation of either asthma or chronic obstructive pulmonary disease (COPD) is validated by medical record review.
Methods
This is cross-sectional study of 78 consecutive adults, 55 years and older, presenting to 3 EDs with symptoms suggestive of an exacerbation of asthma or COPD. We used current spirometric guidelines for a “spirometrically validated” diagnosis of COPD (eg, postbronchodilator forced expiratory volume in 1 second/forced ventilatory capacity b70%). Patients without office spirometry result were classified with COPD using clinical validation based on at least one of the following: primary care physician diagnosis of COPD, chronic bronchitis, or emphysema in the medical record or chest radiography, chest computed tomography, or arterial blood gas (ABG) diagnostic of COPD.
Results
Among 60 patients who self-reported diagnosis of COPD, 98% (95% confidence interval, 89-100) had clinically validated or spirometrically validated COPD. In addition, 83% (95% confidence interval, 59-96) of patients who reported either asthma only or no respiratory disease had clinically validated or spirometrically validated COPD. In no case was the chest radiograph or the ABG useful as a stand-alone test in establishing the diagnosis of COPD.
Conclusions
Patients 55 years and older presenting to the ED with acute asthma or COPD, even those with clinical symptoms but no diagnosis of COPD, are likely to have COPD. Clinicians should maintain a high index of suspicion for COPD when older asthma patients deny COPD.
doi:10.1016/j.ajem.2008.01.011
PMCID: PMC3422655  PMID: 19371527

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