Predicting exacerbations in COPD in the Danish general population.

BACKGROUND: Risk of exacerbations in individuals with mild chronic obstructive pulmonary disease (COPD) in the general population is less well described than in more advanced disease. We hypothesized that in addition to history of previous exacerbation also other clinical characteristics predict future moderate exacerbations. METHODS: In 96,462 individuals in the Copenhagen General Population Study, we identified 3175 with clinical COPD defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.70 and FEV1 <80% predicted in symptomatic individuals without asthma. We estimated the importance of age, sex, FEV1, modified Medical Research Council (mMRC) dyspnea scale, chronic bronchitis, exacerbation history, comorbidities, cohabitation, body mass index, smoking, and blood eosinophils for the 1-year and 3-year future risk of moderate COPD exacerbations and developed a prediction tool for future exacerbations in COPD in the general population based on easily available clinical information. RESULTS: We observed 265 exacerbations in 2543 maintenance treatment naïve individuals with COPD and 197 exacerbations in 632 individuals with COPD on maintenance treatment. In the maintenance treatment naïve group, exacerbation history (hazard ratio (HR): 8.53), low FEV1 (HR: 4.82 for <30% predicted versus 50-79% predicted), and higher age (HR: 1.46 for ≥75 years versus <65 years) were significant predictors of future exacerbations. In the group on maintenance treatment, male sex and mMRC ≥2 also predicted higher risk with borderline significance. CONCLUSIONS: In addition to exacerbation history also higher age and lower FEV1 predict future exacerbation risk in COPD in the general population.

Type-2 inflammation and lung function decline in chronic airway disease in the general population.

BACKGROUND: It is unclear if type-2 inflammation is associated with accelerated lung function decline in individuals with asthma and chronic obstructive pulmonary disease (COPD). We tested the hypothesis that type-2 inflammation indicated by elevated blood eosinophils (BE) and fraction of exhaled nitric oxide (FeNO) is associated with accelerated lung function decline in the general population. METHODS: We included adults from the Copenhagen General Population Study with measurements of BE (N=15 605) and FeNO (N=2583) from a follow-up examination and assessed forced expiratory volume in 1 s (FEV1) decline in the preceding 10 years. Based on pre- and post-bronchodilator lung function, smoking history and asthma at follow-up examination, participants were assigned as not having airway disease, asthma with full reversibility (AR), asthma with persistent obstruction (APO), COPD, and not classifiable airflow limitation (NAL). RESULTS: FEV1 decline in mL/year increased with 1.0 (95% CI 0.6 to 1.4, p<0.0001) per 100 cells/µL higher BE and with 3.2 (95% CI 2.0 to 4.5, p<0.0001) per 10 ppb higher FeNO. Adjusted FEV1 decline in mL/year was 18 (95% CI 17 to 20) in those with BE<300 cells/µL and FeNO<20 ppb, 22 (19-25) in BE≥300 cells/µL or FeNO≥20 ppb, and 27 (21-33) in those with BE≥300 cells/µL and FeNO≥20 ppb (p for trend<0.0001). Corresponding FEV1 declines were 24 (19-29), 33 (25-40) and 44 (31-56) in AR (0.002), 26 (14-37), 36 (12-60) and 56 (24-89) in APO (0.07), 32 (27-36), 31 (24-38) and 44 (24-65) in COPD (0.46), and 27 (21-33), 35 (26-45), and 37 (25-49) in NAL (0.10), respectively. CONCLUSIONS: Type-2 inflammation indicated by elevated BE and FeNO is associated with accelerated FEV1 decline in individuals with chronic airway disease in the general population, and this association was most pronounced in an asthma-like phenotype.

Impact of the metabolic syndrome on cardiopulmonary morbidity and mortality in individuals with lung function impairment: a prospective cohort study of the Danish general population.

Background: Whether the metabolic syndrome plays a role for the prognosis of individuals with lung function impairment (preserved ratio impaired spirometry (PRISm) or airflow limitation) is unclear. We hypothesised that the metabolic syndrome in individuals with lung function impairment is associated with increased cardiopulmonary morbidity and mortality. Methods: The Copenhagen General Population Study was initiated in 2003 based on a random sample of white men and women aged 20-100 years drawn from the Danish general population. The risk of ischemic heart disease/heart failure, respiratory disease, and all-cause mortality was analysed with Cox models adjusted for age, sex, current smoking, and asthma during 15 years of follow-up. Findings: Among 106,845 adults, 86,159 had normal lung function, 6126 had PRISm, and 14,560 had airflow limitation. We observed 10,448 hospital admissions for ischemic heart disease/heart failure, 21,140 for respiratory disease, and 11,125 deaths. Individuals with versus individuals without the metabolic syndrome generally had higher 5-year absolute risk of all outcomes, including within those with normal lung function, mild-moderate-severe PRISm, and very mild-mild-moderate-severe airflow limitation alike. Compared to individuals without the metabolic syndrome and with normal lung function, those with both the metabolic syndrome and severe PRISm had hazard ratios of 3.74 (95% CI: 2.53-5.55; p < 0.0001) for ischemic heart disease/heart failure, 5.02 (3.85-6.55; p < 0.0001) for respiratory disease, and 5.32 (3.76-7.54; p < 0.0001) for all-cause mortality. Corresponding hazard ratios in those with both the metabolic syndrome and severe airflow limitation were 2.89 (2.34-3.58; p < 0.0001) for ischemic heart disease/heart failure, 5.98 (5.28-6.78; p < 0.0001) for respiratory disease, and 4.16 (3.50-4.95; p < 0.0001) for all-cause mortality, respectively. The metabolic syndrome explained 13% and 27% of the influence of PRISm or airflow limitation on ischemic heart disease/heart failure and all-cause mortality. Interpretation: The metabolic syndrome conferred increased risk of cardiopulmonary morbidity and mortality at all levels of lung function impairment. Funding: Danish Lung Foundation, Danish Heart Foundation, Capital Region of Copenhagen, and Boehringer Ingelheim. JV is supported by the NIHR Manchester BRC.

Cohort study of postural sway and low back pain: the Copenhagen City Heart Study.

PURPOSE: Low back pain is a significant health problem with a high prevalence. Studies of smaller cohorts of low back pain patients have indicated increased body sway. The present paper tests the hypothesis of an association between low back pain and postural sway in a large randomly selected population. METHODS: The current study used the fifth examination (2011-2015) of The Copenhagen City Heart Study where 4543 participated. The participants answered a self-administered questionnaire regarding pain, physical activity, smoking, alcohol consumption, education, and other lifestyle factors. Measurement of postural body sway was performed using the CATSYS system. RESULTS: Totally 1134 participants (25%) reported to have low back pain. Subjects with low back pain had higher sway area and sway velocity than subjects without. CONCLUSION: When using multivariate statistical analysis, confounding factors such as male gender, higher age, larger body height, low education level, smoking, and low activity level explained the association between low back pain and postural sway.

Changes in cardiac time intervals over a decade and the risk of incident heart failure: The Copenhagen City Heart Study.

BACKGROUND: The cardiac time intervals include the isovolumic contraction time (IVCT), the left ventricular ejection time (LVET), the isovolumic relaxation time (IVRT) and the combination of all the cardiac time intervals in the myocardial performance index (MPI) (defined as [(IVCT+IVRT)/LVET)]. Whether the cardiac time intervals change over time and which clinical factors that accelerate these changes is not well-established. Additionally, whether these changes are associated with subsequent heart failure (HF), remains unknown. METHODS: We investigated participants from the general population (n = 1064) who had an echocardiographic examination including color tissue Doppler imaging performed in both the 4th and 5th Copenhagen City Heart Study. The examinations were performed 10.5 years apart. RESULTS: The IVCT, LVET, IVRT and MPI increased significantly over time. None of the investigated clinical factors were associated with increase in IVCT. Systolic blood pressure (standardized ß= - 0.09) and male sex (standardized ß= - 0.08) were associated with an accelerated decrease in LVET. Age (standardized ß=0.26), male sex (standardized ß=0.06), diastolic blood pressure (standardized ß=0.08), and smoking (standardized ß=0.08) were associated with an increase in IVRT, while HbA1c (standardized ß= - 0.06) was associated with a decrease in IVRT. Increasing IVRT over a decade was associated with an increased risk of subsequent HF in participants aged <65 years (per 10 ms increase: HR 1.33; 95%CI (1.02-1.72), p = 0.034). CONCLUSION: The cardiac time increased significantly over time. Several clinical factors accelerated these changes. An increase in IVRT was associated with an increased risk of subsequent HF in participants aged <65 years.

Association between exposure to heavy occupational lifting and cardiac structure and function: a cross-sectional analysis from the Copenhagen City Heart Study.

To investigate cross-sectional associations between heavy occupational lifting and cardiac structure and function. Participants from the 5th round of the Copenhagen City Heart Study, aged < 65 years old, answering a questionnaire regarding occupational physical activity, heavy occupational lifting, use of anti-hypertensive and heart medication, and data on blood pressure, cardiac structure and function, from an echocardiographic examination, were included. Adjusted linear regressions and logistic regressions were applied to estimate the cross-sectional association between heavy occupational lifting and cardiac structure and function across all included participants and in groups stratified by hypertension status, and the risk for having abnormal values of cardiac structure and function. 2511 participants were included. The cross-sectional standardized associations between heavy occupational lifting and measures of cardiac structure and function showed a trends for raised left ventricular mass index (LVMi) (ß 0.14, 99% CI - 0.03 to 0.31). The standardized associations stratified by hypertensive status showed significant associations between exposure to heavy occupational lifting and LVMi (ß 0.20, 99% CI - 0.002 to 0.40) and a trend of a raised end-diastolic interventricular septal thickness (IVSd) (ß 0.15, 99% CI - 0.03 to 0.33) among normotensives. Exposure to heavy occupational lifting increased the odds for an abnormal IVSd (OR 1.42, 99% CI 1.07-1.89). This cross-sectional study shows heavy occupational lifting to associate with indices of abnormal cardiac structure and function among normotensives, indicating an increased risk for cardiovascular disease.

U-Shaped Association Between Duration of Sports Activities and Mortality: Copenhagen City Heart Study.

OBJECTIVE: To investigate the association between the duration of weekly leisure-time sports activity and all-cause mortality. METHODS: As part of the prospective Copenhagen City Heart Study, 8697 healthy adults completed a comprehensive questionnaire about leisure-time sports activities. Duration (minutes per week) of leisure-time sports activities was recorded for tennis, badminton, soccer, handball, cycling, swimming, jogging, calisthenics, health club activities, weightlifting, and other sports. The primary end point was all-cause mortality, and the median follow-up was 25.6 years. The association between duration of leisure-time sports activities and all-cause mortality was studied using multivariable Cox proportional hazards regression analysis. RESULTS: Compared with the reference group of 2.6 to 4.5 hours of weekly leisure-time sports activities, we found an increased risk for all-cause mortality for those with 0 hours (hazard ratio [HR], 1.51; 95% CI, 1.29 to 1.76), for those with 0.1 to 2.5 hours (HR, 1.24; 95% CI, 1.05 to 1.46), and for those with more than 10 hours (HR, 1.18; 95% CI, 1.00 to 1.39) of weekly leisure-time sports activities. These relationships were generally consistent with additional adjustments for potential confounders among subgroups of age, sex, education, smoking, alcohol intake, and body mass index, when the first 5 years of follow-up were excluded, and for cardiovascular disease mortality. CONCLUSION: We observed a U-shaped association between weekly duration of leisure sports activities and cardiovascular and all-cause mortality, with lowest risk for those participating in 2.6 to 4.5 weekly hours, being consistent across subgroups. Participation in sport activities should be promoted, but the potential risk of very high weekly hours of sport participation should be considered for inclusion in guidelines and recommendations.

Diastolic function assessed with speckle tracking over a decade and its prognostic value: The Copenhagen City Heart Study.

BACKGROUND: The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) may be a more accurate measure of LV filling pressure then ratio of early filling pressure to early tissue velocity. The aim of the study was to investigate the impact of age, sex, obesity, smoking, hypertension, hypercholesterolemia, diabetes, physical activity level, socioeconomic, and psychosocial status on E/e'sr over a decade. Additionally, the predictive value of ΔE/e'sr on future major adverse cardiovascular events (MACE) has never been explored. METHOD: The study included 623 participants from the general population, who participated in the 4th and 5th Copenhagen City Heart Study (CCHS4 and CCHS5). Examinations were median 10 years apart. MACE was the composite endpoint of heart failure, myocardial infarction, and all-cause death. RESULTS: Follow-up time was median 5.7 years, and 43 (7%) experienced MACE. Mean age was 51 ± 14 years, and 43% were male. Mean ΔE/e'sr was 2.1 ± 23.0 cm. After multivariable adjustment for demographic, clinical, and biochemistry variables, high age (stand. ß-coef. = .24, P < .001) and mean arterial blood pressure (MAP) (stand. ß-coef. = .17, P < .001) were significantly associated with an accelerated increase in E/e'sr In multivariable Cox regression, E/e'sr at CCHS5 and ΔE/e'sr were independent predictors of MACE (HR = 1.20, 95% CI [1.01; 1.42] per 10 cm increase for both). ΔE/e'sr did only provide incremental prognostic value to change in left atrial volume index of the conventional diastolic measurements. CONCLUSION: In the general population, age and MAP were predictors of an accelerated increase in E/e'sr over a decade. E/e'sr at CCHS5 and ΔE/e'sr were independent predictors of future MACE.

Occupational inhalant exposures and longitudinal lung function decline.

BACKGROUND: Airborne exposures at the workplace are believed to be associated with lung function decline. However, longitudinal studies are few, and results are conflicting. METHODS: Participants from two general population-based cohorts, the Copenhagen City Heart Study and the Copenhagen General Population Study, with at least two lung function measurements were followed for a mean of 9 years (range 3-27 years). Occupational exposure was assigned to each year of follow-up between the two lung function measurements by a job exposure matrix. Associations between mean occupational exposure per year and mean annual decline in forced expiratory volume in 1 s (FEV1) were investigated using linear mixed-effects models according to cohort and time period (1976-1983 and 2003-2015). We adjusted for sex, height, weight, education, baseline FEV1 and pack-years of smoking per year during follow-up. RESULTS: A total of 16 144 individuals were included (mean age 48 years and 43% male). Occupational exposure to mineral dusts, biological dusts, gases and fumes and a composite category was not associated with FEV1 decline in analyses with dichotomised exposure. In analyses with an indexed measure of exposure, gases and fumes were associated with an FEV1 change of -5.8 mL per unit per year (95% CI -10.8- -0.7 mL per unit per year) during 1976-1983, but not during 2001-2015. CONCLUSION: In two cohorts from the Danish general population, occupational exposure to dusts, gases and fumes was not associated with excess lung function decline in recent years but might have been of importance decades ago.

Chronic productive cough and inhalant occupational exposure-a study of the general population.

PURPOSE: Occupational inhalant exposures have been linked with a higher occurrence of chronic productive cough, but recent studies question the association. METHODS: We included participants from two general population studies, the Copenhagen City General Population Study and the Copenhagen City Heart Study, to assess contemporary (year 2003-2017) and historical (1976-1983) occupational inhalant hazards. Job titles one year prior to study inclusion and an airborne chemical job-exposure matrix (ACE JEM) were used to estimate occupational exposure. The association between occupational exposures and self-reported chronic productive cough was studied using generalized estimating equations stratified by smoking status and cohort. RESULTS: The population consisted of 5210 working individuals aged 20-65 from 1976 to 1983 and 64,279 from 2003 to 2017. In smokers, exposure to high levels of mineral dust, biological dust, gases & fumes and the composite variable vapours, gases, dusts or fumes (VGDF) were associated with chronic productive cough in both cohorts with odds ratios in the range of 1.2 (95% confidence interval, 1.0;1.4) to 1.6 (1.2;2.1). High levels of biological dust were only associated with an increased risk of a chronic productive cough in the 2003-2017 cohort (OR 1.5 (1.1;2.0)). In non-smokers, high levels of VGDF (OR 1.5 (1.0;2.3)) and low levels of mineral dust (OR 1.7 (1.1;2.4)) were associated with chronic productive cough in the 1976-1983 cohort, while no associations were seen in non-smokers in the 2003-2017 cohort. CONCLUSION: Occupational inhalant exposure remains associated with a modestly increased risk of a chronic productive cough in smokers, despite declining exposure levels during the past four decades.

The impact of cardiovascular risk factors on global longitudinal strain over a decade in the general population: the copenhagen city heart study.

Global longitudinal strain (GLS) declines throughout adult-life as the LV remodels and adapts. Information on the impact of cardiac risk factors such as male sex, obesity, smoking status, hypertension, hypercholesterolemia, and diabetes on GLS. over time has not yet been investigated. The present prospective longitudinal study included 689 participants of the 4th and 5th Copenhagen City Heart Study who had GLS measured at both timepoints. Mean age was 51 years and 45% were male. All participants underwent two echocardiographic examinations median 10.4 (IQR: 10.2, 10.9) years apart. Average decline in GLS during follow-up was -0.7%. High age, male sex, high body mass index, and mean arterial blood pressure (MAP) proved to be significantly associated with an accelerated decline in GLS. In a multivariable regression model including all the investigated cardiovascular risk factors, age (stand. ß-coef. = -0.10, P = 0.005), male sex (stand. ß-coef. = -0.16, P < 0.001), and MAP (stand. ß-coef. = -0.07, P = 0.009) were independent predictors of an accelerated decline in GLS during a 10-year period. Finally, the investigated risk factors had different regional impact after the same multivariable adjustments. Male sex had a significant impact on changes in longitudinal strain at the apical, mid-wall and basal segments, meanwhile MAP and age only accelerated changes in the mid-wall and basal longitudinal strain. In the general population age, male sex, and MAP are independent predictors of an accelerated decline in GLS over a 10-year period. Furthermore, MAP, male sex and age had different regional impact.

Rubidium-82 positron emission tomography for detection of acute doxorubicin-induced cardiac effects in lymphoma patients.

BACKGROUND: Doxorubicin is a cornerstone in lymphoma treatment, but is limited by dose-dependent cardiotoxicity. Rubidium-82 positron emission tomography (82Rb PET) assesses coronary microvascular function through absolute quantification of myocardial perfusion and myocardial perfusion reserve (MPR). Doxorubicin-induced microvascular injury represents a potential early marker of cardiotoxicity. METHODS AND RESULTS: We included 70 lymphoma patients scheduled for doxorubicin-based treatment. Cardiotoxicity was evaluated with 82Rb PET myocardial perfusion imaging during rest and adenosine stress before chemotherapy and shortly after the first doxorubicin exposure. Patients with a MPR decline > 20% were defined as having a low threshold for cardiotoxicity. In the 54 patients with complete data sets, MPR was significantly lower after the initial doxorubicin exposure (2.69 vs 2.51, P = .03). We registered a non-significant decline in stress perfusion (3.18 vs 3.02 ml/g/min, P = .08), but no change in resting myocardial perfusion. There were 13 patients with a low cardiotoxic threshold. These patients had a significantly higher age, but were otherwise similar to the remaining part of the study population. CONCLUSION: Decreases in MPR after initial doxorubicin exposure in lymphoma patients may represent an early marker of doxorubicin-induced cardiotoxicity. The prognostic value of acute doxorubicin-induced changes in MPR remains to be investigated.

Dose-Response Association Between Level of Physical Activity and Mortality in Normal, Elevated, and High Blood Pressure.

It has been a challenge to verify the dose of exercise that will produce the maximum health benefits in hypertension. This study aimed to explore the association between level of daily physical activity, all-cause mortality and cardiovascular outcome at different blood pressure levels. A random sample of 18 974 white men and women aged 20 to 98 years were examined in a prospective cardiovascular population study. Self-reported activity level in leisure-time was drawn from the Physical Activity Questionnaire (level I: inactivity; II: light activity; and III: moderate/high-level activity). Blood pressure was defined as normal blood pressure: <120/<80 mm Hg; Prehypertension: 120-139/80-89 mm Hg; Stage I hypertension: 140-159/90-99 mm Hg; Stage II hypertension ≥160/≥100 mm Hg. The mean follow-up time was 23.4±11.7 years. At all levels of blood pressure, higher levels of physical activity were associated with lower all-cause mortality in a dose-response pattern. The pattern remained unchanged after adjustment for following confounders: sex, age, smoking status, education, diabetes mellitus, previous cardiovascular disease, body mass index, and calendar time. Compared with inactivity, following hazard ratios were found for stage I hypertension: light activity, hazard ratio 0.78 (0.72-0.84; P<0.001), moderate/high-level activity, hazard ratio 0.69 (0.63-0.75; P<0.001). At all levels of blood pressure, the risk of cardiovascular events was significantly reduced independent of the level of physical activity. In conclusion, the association between physical activity and all-cause mortality was present in an inverse dose-response pattern at all levels of blood pressure. Physical activity was associated with reduction in cardiovascular events independent of the level of physical activity.

Variability of monthly nitrogen multiple-breath washout during one year in children with cystic fibrosis.

BACKGROUND: Knowledge of between-session variability of nitrogen multiple-breath washout (N2MBW) indices is crucial when designing longitudinal interventional studies and in disease monitoring using N2MBW as end-point. Such information is currently sparse. METHODS: Monthly triplets of N2MBW were prospectively obtained from 14 children with CF during one year. Linear mixed models were used to analyze variability. Our aim was to assess between-session variability of N2MBW indices from repeated measurements and compare LCI derived from different software packages currently in use (TestPoint® vs. Spiroware®). RESULTS: Baseline LCI (median; range) was 9.37 (6.82; 12.08). Between-session differences in LCI measurements were up to 25%. Intra Class Correlation-Coefficient was 0.82. There was no systematic difference between LCI measurements derived from the two software packages (p=0.18); however, variability was significantly higher using Spiroware®. CONCLUSIONS: We report between-session variability of LCI using N2MBW in school-age children and adolescents with CF. LCI changes exceeding 25% may be considered clinically relevant. TestPoint® and Spiroware® can be used interchangeably in longitudinal studies.

Long-term prognosis of asthma, chronic obstructive pulmonary disease, and asthma-chronic obstructive pulmonary disease overlap in the Copenhagen City Heart study: a prospective population-based analysis.

BACKGROUND: Long-term prognosis of patients with characteristics of both chronic obstructive pulmonary disease (COPD) and asthma, named asthma-COPD overlap, is poorly described. We investigated the long-term prognosis of individuals with different types of chronic airway disease, with a special focus on individuals with asthma-COPD overlap. METHODS: We assigned participants from the Copenhagen City Heart Study into six subgroups: healthy never-smokers, ever-smokers without asthma and COPD, those with asthma with low cumulated smoking exposure and no airflow limitation, those with COPD, those with asthma-COPD overlap with asthma onset before the age of 40 years, and those with asthma-COPD overlap with asthma onset after the age of 40 years. We defined asthma-COPD overlap as current self-reported asthma and a postbronchodilatatory forced expiratory volume in 1 s (FEV1) to forced vital capacity ratio of less than 0·7, without any restrictions regarding smoking. We investigated the course of FEV1 decline for 18 years and risk of admission to hospital due to exacerbations or pneumonias and respiratory and all-cause mortality for 22 years. We analysed FEV1 decline in the six groups using a linear mixed-effects model. FINDINGS: We included 8382 participants from the Copenhagen City Heart Study in our study: 2199 never-smokers, 5435 ever-smokers, 158 with asthma, 320 with COPD, 68 with asthma-COPD overlap with early-onset asthma, and 202 with asthma-COPD overlap with late-onset asthma. The multivariable-adjusted decline in FEV1 in asthma-COPD overlap with early-onset asthma was 27·3 mL (standard error 5·0) per year, which did not differ significantly from the decline of 20·9 mL (1·2) per year in healthy never-smokers (p=0·19). FEV1 decline in individuals with asthma-COPD overlap with late-onset asthma was 49·6 mL (3·0) per year, higher than the decline in asthma-COPD overlap with early-onset asthma (p=0·0001), the decline of 39·5 mL (2·5) per year in COPD (p=0·003), and the decline in healthy never-smokers (p<0·0001). Hazard ratios for hospital admissions due to exacerbations of asthma or COPD were 39·48 (95% CI 25·93-60·11) in asthma-COPD overlap with early-onset asthma, 83·47 (61·67-112·98) in asthma-COPD overlap with late-onset asthma, 23·80 (17·43-33·50) in COPD, and 14·74 (10·06-21·59) in asthma compared with never-smokers without lung disease (all p<0·0001). Life expectancy was 9·3 years (5·4-13·1) shorter in participants with asthma-COPD overlap with early-onset asthma, 12·8 years (11·1-14·6) shorter in those with asthma-COPD overlap with late-onset asthma, 10·1 years (8·6-11·5) shorter in those with COPD (all p<0·0001), and 3·3 years (1·0-5·5) shorter in those with asthma (p=0·004) than in healthy never-smokers. INTERPRETATION: Prognosis of individuals with asthma-COPD overlap is poor and seems to be affected by the age of recognition of asthma, being worst in those with late asthma onset (after 40 years of age). Such patients should be followed up closely to prevent fast lung function decline and exacerbations. FUNDING: Capital Region of Copenhagen, Danish Heart Foundation, Danish Lung Foundation, Velux Foundation, AstraZeneca.

Self-reported occupational physical activity and cardiorespiratory fitness: Importance for cardiovascular disease and all-cause mortality.

OBJECTIVES: This study aimed to investigate whether workers with the combination of high occupational physical activity (OPA) and low cardiorespiratory fitness have an increased risk of cardiovascular disease (CVD) and all-cause mortality. METHODS: Using multivariable Cox proportional hazards regression, we analyzed 2190 males and 2534 females from the Copenhagen City Heart Study, aged 20-67 years and with no known CVD at study entry in 1991-1994, for the risk of CVD and all-cause mortality from independent, stratified and combinations of self-reported OPA (ie, low, moderate and high) and cardiorespiratory fitness (low, same and higher as peers) at baseline. RESULTS: During a median follow-up of 18.5 years, 257 and 852 individuals died from CVD and any cause, respectively. In the fully-adjusted model, an increased risk for CVD mortality was found for those with low compared to high self-reported cardiorespiratory fitness [hazard ratio (HR) 2.17, 95% confidence interval (95% CI) 1.40-3.38), for those with high compared to low OPA (HR 1.45, 95% CI 1.05-2.00), and for those with high compared to low OPA within the strata of low self-reported cardiorespiratory fitness (HR 2.83, 95% CI 1.24-6.46). Moreover, those with the combination of high OPA and low self-reported cardiorespiratory fitness had an increased risk for CVD mortality compared to those with the combination of low OPA and high self-reported cardiorespiratory fitness (HR 6.22, 95% CI 2.67-14.49). Rather similar, but lower risk estimates were found for all-cause mortality. CONCLUSION: These findings may have important implications for CVD prevention among workers with excessive cardiovascular strain at work.

Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. METHODS: We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. RESULTS: Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. CONCLUSIONS: Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).

Overweight and obesity may lead to under-diagnosis of airflow limitation: findings from the Copenhagen City Heart Study.

BACKGROUND: The prevalence of obesity has increased during the last decades and varies from 10-20% in most European countries to approximately 32% in the United States. However, data on how obesity affects the presence of airflow limitation (AFL) defined as a reduced ratio between forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) are scarce. METHODS: Data was derived from the third examination of the Copenhagen City Heart Study from 1991 until 1994 (n = 10,135). We examine the impact of different adiposity markers (weight, body mass index (BMI), waist circumference, waist-hip ratio, and abdominal height) on AFL. AFL was defined in four ways: FEV1/FVC ratio < 0.70, FEV1/FVC ratio < lower limit of normal (LLN), FEV1/FVC ratio <0.70 including at least one respiratory symptom, and FEV1/FVC ratio < LLN and FEV1% of predicted < LLN. RESULTS: All adiposity markers were positively and significantly associated with FEV1/FVC independent of age, sex, height, smoking status, and cumulative tobacco consumption. Among all adiposity markers, BMI was the strongest predictor of FEV1/FVC. FEV1/FVC increased with 0.04 in men and 0.03 in women, as BMI increased with 10 units (kg · m-2). Consequently, diagnosis of AFL was significantly less likely in subjects with BMI ≥ 25 kg · m-2 with odds ratios 0.63 or less compared to subjects with BMI between 18.5-24.9 kg · m-2 when AFL was defined as FEV1/FVC < 0.70. CONCLUSION: High BMI reduces the probability of AFL. Ultimately, this may result in under-diagnosis and under-treatment of COPD among individuals with overweight and obesity.

Total and cause-specific mortality by moderately and markedly increased ferritin concentrations: general population study and metaanalysis.

BACKGROUND: Previous population-based studies of plasma ferritin concentration have not revealed a relationship with total mortality. We tested the possible association of increased ferritin concentrations with increased risk of total and cause-specific mortality in the general population. METHODS: We examined total and cause-specific mortality according to baseline plasma ferritin concentrations in a Danish population-based study (the Copenhagen City Heart Study) of 8988 individuals, 6364 of whom died (median follow-up 23 years). We also included a metaanalysis of total mortality comprising population-based studies according to ferritin quartiles or tertiles. RESULTS: Multifactorially adjusted hazard ratios (HRs) for total mortality for individuals with ferritin ≥200 vs <200 µg/L were 1.1 (95% CI 1.1-1.2; P = 0.0008) overall, 1.1 (1.0-1.2; P = 0.02) in men, and 1.2 (1.0-1.3; P = 0.03) in women. Stepwise increasing concentrations of ferritin were associated with a stepwise increased risk of premature death overall (log rank, P = 2 × 10(-22)), with median survival of 55 years at ferritin concentrations ≥600 µg/L, 72 years at 400-599 µg/L, 76 years at 200-399 µg/L, and 79 years at ferritin <200 µg/L. The corresponding HR for total overall mortality for ferritin ≥600 vs <200 µg/L was 1.5 (1.2-1.8; P = 0.00008). Corresponding adjusted HRs for ferritin ≥600 vs <200 µg/L were 1.6 (1.1-2.3; P = 0.01) for cancer mortality, 2.9 (1.7-5.0; P = 0.0001) for endocrinological mortality, and 1.5 (1.1-2.0; P = 0.01) for cardiovascular mortality. The metaanalysis random effects odds ratio for total mortality for ferritin upper vs reference quartile or tertile was 1.0 (0.9-1.1; P = 0.3) (P heterogeneity = 0.5). CONCLUSIONS: Moderately to markedly increased ferritin concentrations represent a biological biomarker predictive of early death in a dose-dependent linear manner in the general population.

Socioeconomic status and prognosis of COPD in Denmark.

We investigated the association between length of school education and 5-year prognosis of chronic obstructive lung disease (COPD), including exacerbations, hospital admissions and survival. We used sample of general population from two independent population studies: The Copenhagen City Heart Study and Copenhagen General Population Study. A total of 6,590 individuals from general population of Copenhagen with COPD defined by the Global initiative for obstructive lung disease criteria were subdivided into 4 groups based on the length of school education: 1,590 with education < 8 years; 3,131 with education 8-10 years, 1,244 with more than 10 years, but no college/university education and 625 with college/university education. Compared with long education, short education was associated with current smoking (p < 0.001), higher prevalence of respiratory symptoms (p < 0.001) and lower forced expiratory volume in the first second in percent of predicted value (FEV1%pred) (p < 0.001). Adjusting for sex, age, FEV1%pred, dyspnea, frequency of previous exacerbations and smoking we observed that shortest school education (in comparison with university education), was associated with a higher risk of COPD exacerbations (hazards ratio 1.65, 95% CI 1.15-2.37) and higher risk of all-cause mortality (hazards ratio 1.96, 95% CI 1.28-2.99). We conclude that even in an economically well-developed country with a health care system (which is largely free of charge), low socioeconomic status, assessed as the length of school education, is associated with a poorer clinical prognosis of COPD.