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BACKGROUND: Emerging data from longitudinal studies suggest that preserved ratio impaired spirometry (PRISm), defined by proportionate reductions in FEV(1) and FVC, is a heterogeneous population with frequent transitions to other lung function categories relative to individuals with normal and obstructive spirometry. Controversy regarding the clinical significance of these transitions exists (eg, whether transitions merely reflect measurement variability or noise). RESEARCH QUESTION: Are individuals with PRISm enriched for transitions associated with substantial changes in lung function? STUDY DESIGN AND METHODS: Current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study with spirometry available in phases 1 through 3 (enrollment, 5-year follow-up, and 10-year follow-up) were analyzed. Postbronchodilator lung function categories were as follows: PRISm (FEV(1) < 80% predicted with FEV(1)/FVC ratio ≥ 0.7), Global Initiative for Chronic Obstructive Lung Disease grade 0 (FEV(1) ≥ 80% predicted and FEV(1)/FVC ≥ 0.7), and obstruction (FEV(1)/FVC < 0.7). Significant transition status was affirmative if a subject belonged to two or more spirometric categories and had > 10% change in FEV(1) % predicted and/or FVC % predicted between consecutive visits. Ever-PRISm was present if a subject had PRISm at any visit. Logistic regression examined the association between significant transitions and ever-PRISm status, adjusted for age, sex, race, FEV(1) % predicted, current smoking, pack-years, BMI, and ever-positive bronchodilator response. RESULTS: Among subjects with complete data (N = 1,775) over 10.1 ± 0.4 years of follow-up, the prevalence of PRISm remained consistent (10.4%-11.3%) between phases 1 through 3, but nearly one-half of subjects with PRISm transitioned into or out of PRISm at each visit. Among all subjects, 19.7% had a significant transition; ever-PRISm was a significant predictor of significant transitions (unadjusted OR, 10.3; 95% CI, 7.9-13.5; adjusted OR, 14.9; 95% CI, 10.9-20.7). Results were similar with additional adjustment for radiographic emphysema and gas trapping, when lower limit of normal criteria were used to define lung function categories, and when FEV(1) alone (regardless of change in FVC % predicted) was used to define significant transitions. INTERPRETATION: PRISm is an unstable group, with frequent significant transitions to both obstruction and normal spirometry over time. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT000608764; URL: www.clinicaltrials.gov

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.

Nicotine dependence is highly comorbid with schizophrenia, and the etiology of the comorbidity is unknown. To determine whether there is a genetic correlation of smoking behavior with schizophrenia, genome-wide association study (GWAS) meta-analysis results from five smoking phenotypes (ever/never smoker (N=74,035), age of onset of smoking (N=28,647), cigarettes smoked per day (CPD, N=38,860), nicotine dependence (N=10,666), and current/former smoker (N=40,562)) were compared to GWAS meta-analysis results from schizophrenia (N=79,845) using linkage disequilibrium (LD) score regression. First, the SNP heritability (h(2)(g)) of each of the smoking phenotypes was computed using LD score regression (ever/never smoker h(2)(g) =0.08, age of onset of smoking h(2)(g)=0.06, CPD h(2)(g)=0.06, nicotine dependence h(2)(g)=0.15, current/former smoker h(2)(g)=0.07, p

Background Previous investigations in adult smokers from the COPDGene Study have shown that early-life respiratory disease is associated with reduced lung function, COPD, and airway thickening. Using 5-year follow-up data, we assessed disease progression in subjects who had experienced early-life respiratory disease. We hypothesized that there are alternative pathways to reaching reduced FEV 1 and that subjects who had childhood pneumonia, childhood asthma, or asthma-COPD overlap (ACO) would have less lung function decline than subjects without these conditions. Methods Subjects returning for 5-year follow-up were assessed. Childhood pneumonia was defined by self-reported pneumonia at Results Follow-up data from 4,915 subjects were examined, including 407 subjects who had childhood pneumonia, 323 subjects who had childhood asthma, and 242 subjects with ACO. History of childhood asthma or ACO was associated with an increased exacerbation frequency (childhood asthma, P P = .006) and odds of severe exacerbations (childhood asthma, OR, 1.41; ACO, OR, 1.42). History of childhood pneumonia was associated with increased exacerbations in subjects with COPD (absolute difference [β], 0.17; P = .04). None of these early-life respiratory diseases were associated with an increased rate of lung function decline or progression on CT scans. Conclusions Subjects who had early-life asthma are at increased risk of developing COPD and of having more active disease with more frequent and severe respiratory exacerbations without an increased rate of lung function decline over a 5-year period. Trial Registry ClinicalTrials.gov; No. NCT00608764; https://clinicaltrials.gov.

Contains fulltext : 194255.pdf (Publisher’s version ) (Open Access) BACKGROUND: Emphysema has considerable variability in its regional distribution. Craniocaudal emphysema distribution is an important predictor of the response to lung volume reduction. However, there is little consensus regarding how to define upper lobe-predominant and lower lobe-predominant emphysema subtypes. Consequently, the clinical and genetic associations with these subtypes are poorly characterized. METHODS: We sought to identify subgroups characterized by upper-lobe or lower-lobe emphysema predominance and comparable amounts of total emphysema by analyzing data from 9,210 smokers without alpha-1-antitrypsin deficiency in the Genetic Epidemiology of COPD (COPDGene) cohort. CT densitometric emphysema was measured in each lung lobe. Random forest clustering was applied to lobar emphysema variables after regressing out the effects of total emphysema. Clusters were tested for association with clinical and imaging outcomes at baseline and at 5-year follow-up. Their associations with genetic variants were also compared. RESULTS: Three clusters were identified: minimal emphysema (n = 1,312), upper lobe-predominant emphysema (n = 905), and lower lobe-predominant emphysema (n = 796). Despite a similar amount of total emphysema, the lower-lobe group had more severe airflow obstruction at baseline and higher rates of metabolic syndrome compared with subjects with upper-lobe predominance. The group with upper-lobe predominance had greater 5-year progression of emphysema, gas trapping, and dyspnea. Differential associations with known COPD genetic risk variants were noted. CONCLUSIONS: Subgroups of smokers defined by upper-lobe or lower-lobe emphysema predominance exhibit different functional and radiological disease progression rates, and the upper-lobe predominant subtype shows evidence of association with known COPD genetic risk variants. These subgroups may be useful in the development of personalized treatments for COPD.

Rationale and Objective Emphysema is characterized by airspace dilation, inflammation, and irregular deposition of elastin and collagen in the interstitium. Computed tomographic studies have reported that lung mass (LM) may be increased in smokers, a finding attributed to inflammatory and parenchymal remodeling processes observed on histopathology. We sought to examine the epidemiologic and clinical associations of LM in smokers. Materials and Methods Baseline epidemiologic, clinical, and computed tomography (CT) data (n = 8156) from smokers enrolled into the COPDGene Study were analyzed. LM was calculated from the CT scan. Changes in lung function at 5 years' follow-up were available from 1623 subjects. Regression analysis was performed to assess for associations of LM with forced expiratory volume in 1 second (FEV1) and FEV1 decline. Results Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 chronic obstructive pulmonary disease had greater LM than either smokers with normal lung function or those with GOLD 2–4 chronic obstructive pulmonary disease (P

Background LpPLA 2 mass and activity have been variably related to cardiovascular disease risk, and the distribution of LpPLA 2 in patients with type 1 diabetes (T1D), wherein cardiovascular disease risk is high despite normal or higher levels of high-density lipoprotein (HDL) cholesterol, is unknown. Objective To determine whether there are differences in the distribution of LpPLA 2 mass and activity across lipoproteins and their association with coronary artery calcium (CAC) in patients with T1D. Methods Men with T1D (n = 19) not on statins, with and without CAC progression, and men without diabetes matched for HDL cholesterol (n = 25) had lipoproteins separated by fast protein liquid chromatography. Results Both LpPLA 2 mass and activity were found within low-density lipoprotein (LDL) and HDL pools with more LpPLA 2 mass being associated with HDL (54% vs 44%; P -value 2 activity being associated with LDL (56% vs 40%; P value = .02). In T1D, more LpPLA 2 activity was associated with large- or less-dense LDL compared to those without diabetes. However, no difference in LpPLA 2 activity or mass between lipoprotein subfractions was observed between all groups, and there was no relationship between LpPLA 2 activity or mass and its distribution and CAC score progression in healthy or T1D men. Conclusion LpPLA 2 is found in both LDL and HDL and is distributed differently in men with T1D without any relationship to CAC score progression.

People with type 1 diabetes mellitus manifest a greater burden of both periodontal disease and coronary artery disease (CAD); however, little is known about their interrelation. Coronary artery calcium (CAC) measures subclinical atherosclerosis and predicts major adverse coronary events. The relation between periodontal disease and CAC progression in individuals with type 1 diabetes has not been previously described. We determined the prevalence and progression of CAC in relation to self-reported periodontal disease. Multivariate logistic and tobit regression models were used to examine the relation between periodontal disease duration and CAC progression and whether this relation differs by diabetes status after controlling for age, gender, total and high-density lipoprotein cholesterol, hypertension, smoking, body mass index (BMI), duration of diabetes, and baseline CAC. A total of 473 patients with type 1 diabetes and 548 without diabetes were followed for a mean of 6.1 years. At baseline, the prevalence and duration of periodontal disease did not differ between subjects with and without diabetes (14.5% vs 13.4%, p = 0.60; 6 vs 9 years, p = 0.18). Duration of periodontal disease was not significantly associated with baseline CAC prevalence. In patients with type 1 diabetes, periodontal disease duration was significantly related to CAC progression (p = 0.004) but not in subjects without diabetes (p = 0.63). In conclusion, this study suggests that periodontal disease is an independent predictor of long-term progression of CAC in patients with type 1 diabetes.

BACKGROUND The risk factors for acute episodes of respiratory disease in current and former smokers who do not have COPD are unknown. METHODS Eight thousand two hundred forty-six non-Hispanic white and black current and former smokers in the Genetic Epidemiology of COPD (COPDGene) cohort had longitudinal follow-up (LFU) every 6 months to determine acute respiratory episodes requiring antibiotics or systemic corticosteroids, an ED visit, or hospitalization. Negative binomial regression was used to determine the factors associated with acute respiratory episodes. A Cox proportional hazards model was used to determine adjusted hazard ratios (HRs) for time to first episode and an acute episode of respiratory disease risk score. RESULTS At enrollment, 4,442 subjects did not have COPD, 658 had mild COPD, and 3,146 had moderate or worse COPD. Nine thousand three hundred three acute episodes of respiratory disease and 2,707 hospitalizations were reported in LFU (3,044 acute episodes of respiratory disease and 827 hospitalizations in those without COPD). Major predictors included acute episodes of respiratory disease in year prior to enrollment (HR, 1.20; 95% CI, 1.15-1.24 per exacerbation), airflow obstruction (HR, 0.94; 95% CI, 0.91-0.96 per 10% change in % predicted FEV 1 ), and poor health-related quality of life (HR, 1.07; 95% CI, 1.06-1.08 for each 4-unit increase in St. George's Respiratory Questionnaire score). Risks were similar for those with and without COPD. CONCLUSIONS Although acute episode of respiratory disease rates are higher in subjects with COPD, risk factors are similar, and at a population level, there are more episodes in smokers without COPD.

Rationale and Objectives Computed tomography (CT) of the chest can be used to assess pectoralis muscle area (PMA) and subcutaneous adipose tissue (SAT) area. Adipose tissue content is associated with inflammatory mediators in chronic obstructive pulmonary disease (COPD) subjects. Based on gender differences in body composition, we aimed to assess the hypothesis that in subjects with COPD, the relationships between PMA, SAT, and blood biomarkers of inflammation differ by gender. Materials and Methods We compared chest CT measures of PMA and SAT on a single slice at aortic arch and supraesternal notch levels from 73 subjects (28 women) with COPD between genders. The relationships of PMA and SAT area to biomarkers were assessed using within-gender regression models. Results Women had a lesser PMA and a greater SAT area than men (difference range for PMA, 13.3–22.8 cm2; for SAT, 11.8–12.4 cm2; P

Although the physiologic interrelationships between triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) are not fully understood, studies typically are adjusted for one when one is examining the role of the other. If the mechanism of coronary heart disease (CHD) risk is mediated through the other, then controlling for the second factor may mask the true effect of the first. We investigated the relationship between the combined effect of increased (↑) TG and decreased (↓) HDL-C compared with isolated ↑TG or isolated ↓HDL-C on CHD risk in men and women and compared these TG/HDL-C categories to non-HDL cholesterol (non-HDL-C).Subjects (936 women and 746 men) from the San Luis Valley Study were grouped on the basis of 4 sex-specific NCEP-ATP III cutpoints (↑TG ≥150 mg/dL, and ↓HDL-C,40 and50 mg/dL for men and women, respectively). Descriptive statistics and survival analyses were used. The reference group was ↓TG/↑HDL-C (TG150, and HDL-C50 and40 mg/dL for women and men, respectively). Non-HDL-C was analyzed as a continuous variable.Among women, all groups had greater risk of CHD compared with the ↓TG/↑HDL-C reference in univariate analysis: ↓TG/↓HDL-C HR = 2.82 [95% confidence interval 1.12-7.1], ↑TG/↑HDL-C HR = 3.82 [1.50-9.74], ↑TG/↓HDL-C HR= 4.32 [1.91-9.80]. The risk remained significant in the ↓TG/↓HDL-C group (HR= 3.27 [1.26-8.50] and marginally significant in other groups in multivariable analysis. Neither ↑TG nor ↓HDL-C was related to CHD risk in men. Non-HDL cholesterol was significantly related to CHD in men but not in women.The CHD risk associated with ↓HDL-C in women was2- to 4-fold elevated depending on TG levels. Non-HDL cholesterol was a significant predictor of CHD in men. Examining the combined effects of risk factors that share physiologic pathways may reveal important associations that can be otherwise obscured. Further dissection of gender specific pathways that affect HDL-C and TG and non-HDL cholesterol are important in understanding CHD risk.

Background Chronic bronchitis (CB) in patients with COPD is associated with an accelerated lung function decline and an increased risk of respiratory infections. Despite its clinical significance, the chronic bronchitic phenotype in COPD remains poorly defined. Methods We analyzed data from subjects enrolled in the Genetic Epidemiology of COPD (COPDGene) Study. A total of 1,061 subjects with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II to IV were divided into two groups: CB (CB+) if subjects noted chronic cough and phlegm production for ≥ 3 mo/y for 2 consecutive years, and no CB (CB−) if they did not. Results There were 290 and 771 subjects in the CB+ and CB− groups, respectively. Despite similar lung function, the CB+ group was younger (62.8 ± 8.4 vs 64.6 ± 8.4 years, P = .002), smoked more (57 ± 30 vs 52 ± 25 pack-years, P = .006), and had more current smokers (48% vs 27%, P Conclusions CB in patients with COPD is associated with worse respiratory symptoms and higher risk of exacerbations. This group may need more directed therapy targeting chronic mucus production and smoking cessation not only to improve symptoms but also to reduce risk, improve quality of life, and improve outcomes. Trial registry ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov

Studies have shown that family history is a risk factor for COPD, but have not accounted for family history of smoking. Therefore, we sought to identify the effects of family history of smoking and family history of COPD on COPD susceptibility.We compared 821 patients with COPD to 776 control smokers from the Genetic Epidemiology of COPD (COPDGene) Study. Questionnaires captured parental histories of smoking and COPD, as well as childhood environmental tobacco smoke (ETS) exposure. Socioeconomic status was defined by educational achievement.Parental history of smoking (85.5% case patients, 82.9% control subjects) was more common than parental history of COPD (43.0% case patients, 30.8% control subjects). In a logistic regression model, parental history of COPD (OR, 1.73; P.0001) and educational level (OR, 0.48 for some college vs no college; P.0001) were significant predictors of COPD, but parental history of smoking and childhood ETS exposure were not significant. The population-attributable risk from COPD family history was 18.6%. Patients with COPD with a parental history had more severe disease, with lower lung function, worse quality of life, and more frequent exacerbations. There were nonsignificant trends for more severe emphysema and airway disease on quantitative chest CT scans.Family history of COPD is a strong risk factor for COPD, independent of family history of smoking, personal lifetime smoking, or childhood ETS exposure. Although further studies are required to identify genetic variants that influence COPD susceptibility, clinicians should question all smokers, especially those with known or suspected COPD, regarding COPD family history.

Background Smoking ordinances have been associated with reduced acute myocardial infarction rates, but nearly all studies lack patient-level data. Objective We determined whether a smoking ordinance was associated with a reduction in hospitalizations for acute myocardial infarction, irrespective of smoking status and infarct presentation (ST elevation vs. non-ST elevation). Methods Detailed chart abstraction of biomarkers to confirm first acute myocardial infarction events was performed from the single community hospital serving Greeley, Colorado and adjacent zip codes, 17 months before and 31 months after implementing a public smoking ordinance. Poisson regression analysis, adjusted for population growth, was used to assess changes in mean incidence rates. Results A total of 706 hospitalizations were identified from July 2002 through June 2006: 482 among Greeley city residents and 224 within adjacent zip code areas. A postordinance reduction in hospitalizations was observed in Greeley (relative risk [RR] 0.73; 95% confidence interval [CI], 0.59-0.90). A smaller, nonsignificant decrease was noted in the area immediately surrounding Greeley (RR 0.83; 95% CI, 0.61-1.14). However, the comparison of relative risk reductions between Greeley and the surrounding area was not significant ( P =.48). The reduction in Greeley was more pronounced among smokers (RR 0.44; 95% CI, 0.29-0.65) than nonsmokers (RR 0.86; 95% CI, 0.67-1.09) and did not differ by acute myocardial infarction presentation ( P =.38). Conclusions A smoking ordinance was associated with a decrease in acute myocardial infarction hospitalizations of a magnitude similar to previous reports, but could not be distinguished from the adjacent geographic area. Reductions were greatest among smokers, despite previous studies suggesting that benefits accrue primarily among nonsmokers. Smoke-free policy may therefore exert a beneficial effect among smokers, who are disproportionately exposed to direct and sidestream smoke.

Background Although exercise treadmill testing (ETT) is less sensitive and specific for diagnosis of coronary disease in women, little is known about gender differences in the prognostic importance of ETT variables. Methods We studied 9,569 consecutive patients (46.8% women) referred for ETT between July 2001 and June 2004 in a community-based system. We assessed the association between ETT variables (exercise capacity, symptoms, ST-segment deviations, heart rate recovery, and chronotropic response) and time to all-cause death and myocardial infarction (MI), adjusting for patient and stress test characteristics. Models were stratified by gender to determine the relationship between ETT variables and outcomes. Results In the entire population, exercise capacity and heart rate recovery were significantly associated with all-cause death, whereas exercise capacity, chest pain, and ST-segment deviations were significantly associated with subsequent MI. The relationship between ETT variables and outcomes were similar between men and women, except for abnormal exercise capacity, which had a significantly stronger association with death in men (men: hazard ratio [HR] 2.89 and 95% CI 1.89-4.44, women: HR 0.99 and 95% CI 0.52-1.93, and interaction P = .01), and chronotropic incompetence, which had a significantly stronger relationship with MI in women (men: HR 1.29 and 95% CI 0.74-2.20, women: HR 2.79 and 95% CI 0.94-8.27, and interaction P = .04). Conclusions Although many traditional ETT variables had similar prognostic value in both men and women, exercise capacity was more prognostically important in men, and chronotropic incompetence was more important in women. Future studies should confirm these findings in additional populations.

To assess the relationship between mortality and impairment and decline in a specific executive cognitive function, the capacity for behavioral self-regulation.This study examined the association between mortality and baseline and 22-month decline in the capacity for behavioral self-regulation, as measured by the Behavioral Dyscontrol Scale, among 1,293 participants of the San Luis Valley Health and Aging Study (SLVHAS), a population-based longitudinal study. The Behavioral Dyscontrol Scale and a measure of overall mental status, the Mini-Mental State Examination, were administered at baseline and follow-up interviews. Cox regression was used to examine baseline and decline in capacity for behavioral self-regulation as possible predictors of mortality.Baseline Behavioral Dyscontrol Scale score was predictive of mortality, independent of demographics and comorbidity count (hazard ratio [HR]=1.07; 95% confidence interval [CI]: 1.04, 1.09). It remained a significant predictor with further adjustment for Mini-Mental State Examination score. Decline in this specific executive cognitive function was associated with mortality after adjustment for covariates and baseline cognitive scores (HR=1.09; 95% CI: 1.04, 1.13).Thus, both baseline capacity for behavioral self-regulation and its decline over time predicted mortality in the SLVHAS cohort. These associations may partly be attributed to maintaining the ability for self-care. Understanding how specific forms of impairment contribute to mortality may help identify patients who could benefit from early intervention.

Our aim was to identify an insulin response element (IRE) in the lipoprotein lipase (LPL) gene. We identified a 19 bp sequence as a putative IRE in LPL non-coding exon 10 using bioinformatics. Upon sequencing the IRE region, a novel 5 bp deletion was identified in Hispanics ( N = 406) with a carrier frequency of 4.2% but not in non-Hispanic whites ( N = 604) or Africans. Electrophoretic mobility shift assay revealed binding sites for regulatory factor(s) in muscle cell nuclear extracts with putative IRE sequence. Antibody supershift assay using human aorta smooth muscle cell nuclear extract revealed that Elk-1 specifically binds to putative IRE. TaqMan real-time RT-PCR of the 5 bp deletion, the mutant and wild type cDNA expressed in COS-1 and human muscle cells revealed that the 5 bp deletion was associated with modest reduction in LPL expression. There was also a slight reduction in LPL translation in the deletion mutant. Our data suggest the presence of an IRE in the 3′UTR of the LPL gene.

Background Controversy remains regarding whether gender differences exist in clinical management after exercise treadmill testing (ETT). Methods We studied 7,506 patients (49.8% women) without documented coronary heart disease referred for ETT from July 2001 to June 2004 in a community-based setting. We assessed the relationship between gender and subsequent diagnostic testing (secondary stress testing or coronary angiography) within 6 months after ETT. Secondary outcomes included subsequent stress testing, coronary angiography, and new cardiology visits in the 6-month interval. Multivariable analyses assessed the relationship between gender and these outcomes adjusting for demographic, clinical, and stress test characteristics. In subsequent analyses, patients were stratified by Duke Treadmill Scores (Duke University, Durham, NC). Results Compared with men, women referred for ETT were older, had a higher prevalence of some cardiac risk factors, achieved lower peak workloads, and, more often, experienced chest pain or ST-segment changes. After accounting for differences in clinical and ETT parameters, gender was not associated with any subsequent diagnostic testing in the 6 months after ETT (OR 1.0, 95% CI 0.85-1.18). In secondary analyses, women were less likely to undergo angiography (OR 0.63, 95% CI 0.47-0.83) with a trend toward more subsequent stress testing. Stratified analyses revealed less subsequent testing in high-to-intermediate Duke Treadmill Score women compared with men (OR 0.61, 95% CI 0.48-0.79). Women and men were equally likely to die (hazards ratio 0.93, 95% CI 0.61-1.44) in the adjusted survival analysis. Conclusions Overall, women and men equally underwent subsequent diagnostic testing after ETT. Although women were less likely to undergo angiography and higher-risk women were less likely to undergo subsequent testing, adverse events were not higher in women. Given these findings, assumptions regarding gender disparities in clinical management after ETT should be reevaluated in other settings.

Background: While coronary artery calcium (CAC) has extensive validation for predicting clinical events, most outcome studies of CAC have been performed in asymptomatic populations, and little is known about how CAC predicts mortality in patients with chronic obstructive pulmonary disease (COPD). We

An approach to diet and drug therapy to treat abnormal lipid levels was developed by the National Cholesterol Education Program (NCEP) based on low-density lipoprotein cholesterol (LDL-C) concentrations. This approach was subsequently modified to include high-density lipoprotein cholesterol (HDL-C) concentrations. Although drug therapy can be recommended for the primary prevention of coronary artery disease (CAD) in many patients with high LDL-C levels, the decision about when to treat borderline-high LDL-C concentrations in the absence of clinical atherosclerosis is more difficult. The NCEP developed a paradigm for the primary prevention of CAD with drug therapy in patients with borderline LDL-C levels of 130 –190 mg/dL, based on an individual patient’s risk factors for CAD and findings on physical examination. A patient with borderlinehigh LDL-C levels would be considered a candidate for lipid-lowering drug therapy in the presence of other risk factors for premature CAD, such as male sex, hypertension, diabetes, obesity, family history of early CAD, and smoking. In addition to recognizing elevated HDL-C levels as a major predisposing factor for CAD, the NCEP added menopause without estrogen-replacement therapy to its risk-factor guidelines. 2 Although these risk factors imply a greater relative risk for a subset of middleaged men and women, the absolute risk for CAD in older individuals is overwhelmed by the effect of age. Recent studies have shown the value of reducing LDL-C levels in the primary prevention of cardiovascular disease (CVD). In the West of Scotland Prevention Study, LDL-C lowering with pravastatin resulted in a 31% reduction in CVD in middle-aged men with LDL-C levels of 155–232 mg/dL. Interestingly, baseline LDL-C levels did not predict a reduction in events. The Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) 5 reported a 37% reduction in primary endpoints over 5 years with lovastatin therapy in middle-aged men and women with borderline-high LDL-C levels, as defined by the NCEP guidelines. This study confirmed that some high-risk patients with borderline-high LDL-C levels benefit from lipid-lowering therapy. However, clinicians are still faced with the challenge of identifying those patients with borderline-high LDL-C concentrations who are at increased risk for CVD and will respond to lipid-lowering therapy. Most atherosclerosis prevention trials have focused on total cholesterol levels or LDL-C levels as the primary target for intervention. It is clear, however, that not all the reductions in coronary events can be attributed to lowering LDL-C concentrations. Evidence indicates that various lipoprotein subspecies may enhance the clinician’s ability to identify patients at high risk for CAD prior to the development of clinical atherosclerosis. In particular, small, dense low-density lipoprotein (sdLDL), intermediate-density lipoprotein (IDL), high-density lipoprotein-2 (HDL2), lipoprotein(a) (Lp[a]), and apolipoprotein(CIII) (apo[CIII]) distribution among lipoproteins have been implicated in the etiology of CAD and may respond to lipid-lowering therapy. LDL-C comprises lipoproteins with hydrated densities of 1.006 –1.063 g/mL. Included in this density range are a number of lipoprotein subspecies, including IDL, sdLDL, and big, buoyant LDL (bbLDL). Indeed, further heterogeneity may exist within each of these major subspecies. IDLs are believed to be particularly atherogenic, and some investigators have attributed a greater atherogenic potential to sdLDL compared with bbLDL. The measurement of plasma lipoprotein apoprotein concentrations can be used to estimate the presence of atherogenic subspecies. A combination of elevated apolipoprotein(B) (apo[B]) levels and borderline-high LDL-C levels reflects an increase in both IDL and sdLDL concentrations. Lowdensity lipoprotein (LDL) compositional abnormalities, combined with decreased HDL2 cholesterol levels, can be estimated by the ratio of apo(B) to apolipoprotein(AI) (apo[AI]) or by the distribution of apo(CIII) between apo(B)-containing particles and high-density lipoprotein (HDL) particles. The association of apo(CIII) with apo(B) particles reflects the presence of increased concentrations of IDL and small very low-density lipoprotein (sVLDL) particles, and often accompanies elevated sdLDL levels. Many of these variations in lipoprotein subspecies occur in patients who have been characterized by the NCEP criteria used to identify individuals with borderline-high LDL-C concentrations at high risk for CAD (Table 1). Central obesity, which commonly occurs in middleFrom the Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington School of Medicine, Seattle, Washington. Supported in part by NIH grants HL-30086, DK-02456, RR-36 (GCRC), and DK-35816 (CNRU). Correspondence should be addressed to John D. Brunzell, MD, University of Washington School of Medicine, Department of Medicine, Box 356178, Seattle, Washington 98195-6178.