Karen Hinckley Stukovsky

Performance of American Thoracic Society-Recommended Spirometry Reference Values in a Multiethnic Sample of Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study

BACKGROUND The American Thoracic Society recommends race-specific spirometric reference values from the National Health and Nutrition Survey (NHANES) III for clinical evaluation of pulmonary function in whites, African-Americans, and Mexican-Americans in the United States and a correction factor of 0.94 for Asian-Americans. We aimed to validate the NHANES III reference equations and the correction factor for Asian-Americans in an independent, multiethnic sample of US adults. METHODS The Multi-Ethnic Study of Atherosclerosis (MESA) recruited self-identified non-Hispanic white, African-American, Hispanic, and Asian-American participants aged 45 to 84 years at six US sites. The MESA-Lung Study assessed prebronchodilator spirometry among 3,893 MESA participants who performed acceptable tests, of whom 1,068 were asymptomatic healthy nonsmokers who performed acceptable spirometry. RESULTS The 1,068 participants were mean age 65 +/- 10 years, 60% female, 25% white, 20% African-American, 23% Hispanic, and 32% Asian-American. Observed values of FEV(1), FEV(6), and FVC among whites, African-Americans, and Hispanics of Mexican origin in MESA-Lung were slightly lower than predicted values based on NHANES III. Observed values among Hispanics of non-Mexican origin were consistently lower. Agreement in classification of participants with airflow obstruction based on lower limit of normal criteria was good (overall kappa = 0.88). For Asian-Americans, a correction factor of 0.88 was more accurate than 0.94. CONCLUSIONS The NHANES III reference equations are valid for use among older adults who are white, African-American, or Hispanic of Mexican origin. Comparison of white and Asian-American participants suggests that a correction factor of 0.88, applied to the predicted and lower limits of normal values, is more appropriate than the currently recommended value of 0.94.

Simultaneous low-density lipoprotein-c lowering and high-density lipoprotein-c elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials

Purpose of review Our analysis presents an alternative hypothesis to the prevailing view that low-density lipoprotein-C is the only important target of lipid therapy. Recent findings Two recently published studies showed surprising results. In the Armed Forces Regression Study, low-density lipoprotein-C was lowered only 22% with cholystyramine, niacin and gemfibrozil. Coronary stenosis regressed, however, and the primary clinical event rate was reduced by 54%. Conversely, in the FIELD trial, the primary event rate reduction was only 11% (P = NS). These differences appeared to be explained largely by the difference in high-density lipoprotein response to these regimens (38 vs. 3%). This meta-analysis of 23 trials strongly supports the notion that the sum of percent reduction in low-density lipoprotein-C plus percent increase in high-density lipoprotein-C predicts benefits much more effectively than either lipoprotein component. Summary Epidemiology suggests that the cardiovascular event rate is reduced by nearly 1% for each 1% reduction in low-density lipoprotein-C and by at least 1% for each 1% increase in high-density lipoprotein. These effects are statistically independent; thus, for moderate lipid changes, they are additive. If this simple algorithm is proven accurate, a 30% high-density lipoprotein-C increase and a 40% low-density lipoprotein-C reduction would result in a nearly 70% CHD risk reduction – and a revolution in cardiovascular prevention.

Original ResearchLung FunctionPerformance of American Thoracic Society-Recommended Spirometry Reference Values in a Multiethnic Sample of Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study

BACKGROUND The American Thoracic Society recommends race-specific spirometric reference values from the National Health and Nutrition Survey (NHANES) III for clinical evaluation of pulmonary function in whites, African-Americans, and Mexican-Americans in the United States and a correction factor of 0.94 for Asian-Americans. We aimed to validate the NHANES III reference equations and the correction factor for Asian-Americans in an independent, multiethnic sample of US adults. METHODS The Multi-Ethnic Study of Atherosclerosis (MESA) recruited self-identified non-Hispanic white, African-American, Hispanic, and Asian-American participants aged 45 to 84 years at six US sites. The MESA-Lung Study assessed prebronchodilator spirometry among 3,893 MESA participants who performed acceptable tests, of whom 1,068 were asymptomatic healthy nonsmokers who performed acceptable spirometry. RESULTS The 1,068 participants were mean age 65 +/- 10 years, 60% female, 25% white, 20% African-American, 23% Hispanic, and 32% Asian-American. Observed values of FEV(1), FEV(6), and FVC among whites, African-Americans, and Hispanics of Mexican origin in MESA-Lung were slightly lower than predicted values based on NHANES III. Observed values among Hispanics of non-Mexican origin were consistently lower. Agreement in classification of participants with airflow obstruction based on lower limit of normal criteria was good (overall kappa = 0.88). For Asian-Americans, a correction factor of 0.88 was more accurate than 0.94. CONCLUSIONS The NHANES III reference equations are valid for use among older adults who are white, African-American, or Hispanic of Mexican origin. Comparison of white and Asian-American participants suggests that a correction factor of 0.88, applied to the predicted and lower limits of normal values, is more appropriate than the currently recommended value of 0.94.

Fine Particulate Matter Air Pollution, Proximity to Traffic, and Aortic Atherosclerosis

Background: The initiation and acceleration of atherosclerosis is hypothesized as a physiologic mechanism underlying associations between air pollution and cardiovascular effects. Despite toxicologic evidence, epidemiologic data are limited. Methods: In this cross-sectional analysis we investigated exposure to fine particulate matter (PM2.5) and residential proximity to major roads in relation to abdominal aortic calcification, a sensitive indicator of systemic atherosclerosis. Aortic calcification was measured by computed tomography among 1147 persons, in 5 US metropolitan areas, enrolled in the Multi-Ethnic Study of Atherosclerosis. The presence and quantity of aortic calcification were modeled using relative risk regression and linear regression, respectively, with adjustment for potential confounders. Results: We observed a slightly elevated risk of aortic calcification (RR = 1.06; 95% confidence interval = 0.96–1.16) with a 10 &mgr;g/m3 contrast in PM2.5. The PM2.5-associated risk of aortic calcification was stronger among participants with long-term residence near a PM2.5 monitor (RR = 1.11; 1.00–1.24) and among participants not recently employed outside the home (RR = 1.10; 1.00–1.22). PM2.5 was not associated with an increase in the quantity of aortic calcification (Agatston score) and no roadway proximity effects were noted. There was indication of PM2.5 effect modification by lipid-lowering medication use, with greater effects among users, and PM2.5 associations were observed most consistently among Hispanics. Conclusions: Although we did not find persuasive associations across our full study population, associations were stronger among participants with less exposure misclassification. These findings support the hypothesis of a relationship between particulate air pollution and systemic atherosclerosis.

Reproducibility and validity of lung density measures from cardiac CT Scans--The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study.

RATIONALE AND OBJECTIVES Cardiac computed tomographic (CT) scans for the assessment of coronary calcium scores include approximately 70% of the lung volume and may be useful for the quantitative assessment of emphysema. The reproducibility of lung density measures from cardiac computed tomography and their validity compared to lung density measures from full-lung scans is unknown. MATERIALS AND METHODS The Multi-Ethnic Study of Atherosclerosis (MESA) performed paired cardiac CT scans for 6814 participants at baseline and at follow-up. The MESA-Lung Study assessed lung density measures in the lung fields of these cardiac scans, counting voxels below -910 HU as moderate-to-severe emphysema-like lung regions. We evaluated: 1) the reproducibility of lung density measures among 120 randomly selected participants; 2) the comparability of measures acquired on electron beam CT (EBCT) and multidetector CT (MDCT) scanners among 10 participants; and 3) the validity of these measures compared to full-lung scans among 42 participants. Limits of agreement were determined using Bland-Altman approaches. RESULTS Percent emphysema measures from paired cardiac scans were highly correlated (r = 0.92-0.95) with mean difference of -0.05% (95% limits of agreement: -8.3, 8.4%). Measures from EBCT and MDCT scanners were comparable (mean difference -0.9%; 95% limits of agreement: -5.1, 3.3%). Percent emphysema measures from MDCT cardiac and MDCT full-lung scans were highly correlated (r = 0.93) and demonstrated reasonable agreement (mean difference 2.2%; 95% limits of agreement: -9.2, 13.8%). CONCLUSIONS Although full-lung imaging is preferred for the quantification of emphysema, the lung imaging from paired cardiac computed tomography provided a reproducible and valid quantitative assessment of emphysema in a population-based sample.

Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study

RATIONALE Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering. OBJECTIVES To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States. METHODS We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than -950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity. MEASUREMENTS AND MAIN RESULTS Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10(-8)) and PPT2 (rs10947233; P = 3.2 × 10(-8)), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 × 10(-9); minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10(-8); MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 10(-6); MAF, 13.3%) was associated with percent emphysema. CONCLUSIONS Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.

Associations of occupation, job control and job demands with intima-media thickness: The Multi-Ethnic Study of Atherosclerosis (MESA)

Objectives Occupation has been linked to cardiovascular disease (CVD) incidence and mortality, but few studies have investigated occupation in relation to early atherosclerotic disease. This study examined associations between various occupational characteristics and carotid artery intima-media thickness (IMT) in a multi-ethnic sample. Methods The Multi-Ethnic Study of Atherosclerosis (MESA) recruited 6814 adults aged 45–84 years and free of clinical CVD (response rate 60%, 51% female). Questionnaire data were used to determine occupational group (managerial/professional, sales/office, service, blue-collar), psychosocial job characteristics (ie, job demands, job control) and other sociodemographic information. Results Common carotid artery (CCA)-IMT was greater for blue-collar jobs than for management/professional jobs (mean difference=0.012 mm, p=0.049) after adjustment for age, sex, race, place of birth (US or foreign born) and CVD risk factors. Compared to management/professional jobs, internal carotid artery (ICA)-IMT was greater for sales/office, service and blue-collar jobs (mean difference=0.071 mm, p<0.001; 0.057 mm, p=0.009; and 0.110 mm, p<0.001, respectively) after adjustment for age, sex, race and place of birth. The difference between blue-collar jobs and management/professional jobs remained significant after additional adjustment for CVD risk factors, income and education (mean difference=0.048 mm, p=0.045). Higher levels of control at work were associated with thinner CCA-IMT (mean difference=−0.009 mm, p=0.016, adjusted for age, sex, race and place of birth) but not with ICA-IMT. Job demands had no significant association with IMT. Conclusions Blue-collar jobs and low levels of job control were associated with the development of subclinical atherosclerosis.

High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. Increased lung attenuation on CT may identify subclinical lung injury and inflammation in community-dwelling adults http://ow.ly/97k3300tvKX

Angiotensin-Converting Inhibitors and Angiotensin II Receptor Blockers and Longitudinal Change in Percent Emphysema on Computed Tomography. The Multi-Ethnic Study of Atherosclerosis Lung Study

Rationale: Although emphysema on computed tomography (CT) is associated with increased morbidity and mortality in patients with and without spirometrically defined chronic obstructive pulmonary disease, no available medications target emphysema outside of alpha‐1 antitrypsin deficiency. Transforming growth factor‐&bgr; and endothelial dysfunction are implicated in emphysema pathogenesis, and angiotensin II receptor blockers (ARBs) inhibit transforming growth factor‐&bgr;, improve endothelial function, and restore airspace architecture in murine models. Evidence in humans is, however, lacking. Objectives: To determine whether angiotensin‐converting enzyme (ACE) inhibitor and ARB dose is associated with slowed progression of percent emphysema by CT. Methods: The Multi‐Ethnic Study of Atherosclerosis researchers recruited participants ages 45‐84 years from the general population from 2000 to 2002. Medication use was assessed by medication inventory. Percent emphysema was defined as the percentage of lung regions less than −950 Hounsfield units on CTs. Mixed‐effects regression models were used to adjust for confounders. Results: Among 4,472 participants, 12% used an ACE inhibitor and 6% used an ARB at baseline. The median percent emphysema was 3.0% at baseline, and the rate of progression was 0.64 percentage points over a median of 9.3 years. Higher doses of ACE or ARB were independently associated with a slower change in percent emphysema (P = 0.03). Over 10 years, in contrast to a predicted mean increase in percent emphysema of 0.66 percentage points in those who did not take ARBs or ACE inhibitors, the predicted mean increase in participants who used maximum doses of ARBs or ACE inhibitors was 0.06 percentage points (P = 0.01). The findings were of greatest magnitude among former smokers (P < 0.001). Indications for ACE inhibitor or ARB drugs (hypertension and diabetes) and other medications for hypertension and diabetes were not associated independently with change in percent emphysema. There was no evidence that ACE inhibitor or ARB dose was associated with decline in lung function. Conclusions: In a large population‐based study, ACE inhibitors and ARBs were associated with slowed progression of percent emphysema by chest CT, particularly among former smokers. Randomized clinical trials of ACE and ARB agents are warranted for the prevention and treatment of emphysema.

Time–location patterns of a diverse population of older adults: the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air)

The primary aim of this analysis was to present and describe questionnaire data characterizing time–location patterns of an older, multiethnic population from six American cities. We evaluated the consistency of results from repeated administration of this questionnaire and between this questionnaire and other questionnaires collected from participants of the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). Participants reported spending most of their time inside their homes (average: 121 h/week or 72%). More than 50% of the participants reported spending no time in several of the location options, including at home outdoors, at work/volunteer/school locations indoors or outdoors, or in “other” locations outdoors. We observed consistency between self-reported time–location patterns from repeated administration of the time–location questionnaire and compared with other survey instruments. Comparisons with national cohorts demonstrated the differences in time–location patterns in the MESA Air cohort due to differences in demographics, but the data showed similar trends in patterns by age, gender, season, and employment status. This study was the first to explicitly examine the time–location patterns in an older, multiethnic population and the first to add data on Chinese participants. These data can be used to inform future epidemiological research of MESA Air and other studies that include diverse populations.