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.

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.

Trajectory of Preserved Ratio Impaired Spirometry: Natural History and Long-Term Prognosis.

Rationale: Natural history of preserved ratio impaired spirometry (PRISm), often defined as FEV1/FVC ⩾lower limit of normal and FEV1 <80% of predicted value, is not well described. Objectives: To investigate the natural history and long-term prognosis of the following PRISm trajectories: persistent PRISm trajectory (individuals with PRISm both young and middle-aged), normal to PRISm trajectory (individuals developing PRISm from normal spirometry in young adulthood), and PRISm to normal trajectory (individuals recovering from PRISm in young adulthood by normalizing spirometry while middle-aged). Methods: We followed 1,160 individuals aged 20-40 years from the Copenhagen City Heart Study from 1976 to 1983 until 2001 to 2003 to determine their lung function trajectory; 72 had persistent PRISm trajectory, 76 had normal to PRISm trajectory, 155 had PRISm to normal trajectory, and 857 had normal trajectory. From 2001-2003 until 2018, we determined the risk of cardiopulmonary disease and death. Measurements and Main Results: We recorded 198 admissions for heart disease, 143 for pneumonia, and 64 for chronic obstructive pulmonary disease as well as 171 deaths. Compared with individuals with normal trajectory, hazard ratios for individuals with persistent PRISm trajectory were 1.55 (95% confidence interval, 0.91-2.65) for heart disease admission, 2.86 (1.70-4.83) for pneumonia admission, 6.57 (3.41-12.66) for chronic obstructive pulmonary disease admission, and 3.68 (2.38-5.68) for all-cause mortality. Corresponding hazard ratios for individuals with normal to PRISm trajectory were 1.91 (1.24-2.95), 2.74 (1.70-4.42), 7.61 (4.21-13.72), and 2.96 (1.94-4.51), respectively. Prognosis of individuals with PRISm to normal trajectory did not differ from those with normal trajectory. Conclusions: PRISm in middle-aged individuals is associated with increased risk of cardiopulmonary disease and all-cause mortality, but individuals who recover from PRISm during their adult life are no longer at increased risk.

The physical activity paradox in cardiovascular disease and all-cause mortality: the contemporary Copenhagen General Population Study with 104 046 adults.

AIMS: Leisure time physical activity associates with reduced risk of cardiovascular disease and all-cause mortality, while these relationships for occupational physical activity are unclear. We tested the hypothesis that leisure time physical activity associates with reduced major adverse cardiovascular events (MACE) and all-cause mortality risk, while occupational physical activity associates with increased risks. METHODS AND RESULTS: We studied 104 046 women and men aged 20-100 years in the Copenhagen General Population Study with baseline measurements in 2003-2014 and median 10-year follow-up. Both leisure and occupational physical activity were based on self-report with four response categories. We observed 7913 (7.6%) MACE and 9846 (9.5%) deaths from all causes. Compared to low leisure time physical activity, multivariable adjusted (for lifestyle, health, living conditions, and socioeconomic factors) hazard ratios for MACE were 0.86 (0.78-0.96) for moderate, 0.77 (0.69-0.86) for high, and 0.85 (0.73-0.98) for very high activity; corresponding values for higher occupational physical activity were 1.04 (0.95-1.14), 1.15 (1.04-1.28), and 1.35 (1.14-1.59), respectively. For all-cause mortality, corresponding hazard ratios for higher leisure time physical activity were 0.74 (0.68-0.81), 0.59 (0.54-0.64), and 0.60 (0.52-0.69), and for higher occupational physical activity 1.06 (0.96-1.16), 1.13 (1.01-1.27), and 1.27 (1.05-1.54), respectively. Similar results were found within strata on lifestyle, health, living conditions, and socioeconomic factors, and when excluding individuals dying within the first 5 years of follow-up. Levels of the two domains of physical activity did not interact on risk of MACE (P = 0.40) or all-cause mortality (P = 0.31). CONCLUSION: Higher leisure time physical activity associates with reduced MACE and all-cause mortality risk, while higher occupational physical activity associates with increased risks, independent of each other.

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.

Impaired neck motor control in chronic whiplash and tension-type headache.

OBJECTIVES: The purpose of this study is twofold, first to present a new method based on head laser tracking designed to measure head or hand movements and second to further investigate if patients suffering from chronic whiplash or tension-type headache have impaired motor control of neck muscles. MATERIAL AND METHODS: A new laser tracking instrument was designed to measure the ability of a test person to track a reference point moving on the wall by a laser fixed to the forehead or held in the hand. The reference point to be tracked moves in runs of a circle or a square at three different speeds 10, 20, or 30 cm/s. We used a 1 × 1 ×1 m setup geometry to provide head movements well below pain release. Groups of 22 patients diagnosed with chronic whiplash-associated disorder grade 2, 19 patients diagnosed with chronic tension-type headache, and 37 control persons were compared. RESULTS: A small but highly significant dyscoordination of head movements was observed in both patient groups and in whiplash also of the hand. CONCLUSIONS: Our study presents a new method based on laser tracking for precision quantitative measurements of head or hand movements during standardized conditions. The results confirm that motor control of head movements is impaired in both chronic whiplash and tension-type headache, and in whiplash also of the hand. This suggests involvement of the central nervous system in the pathology of these diseases.

Lung Function Trajectories Leading to Chronic Obstructive Pulmonary Disease as Predictors of Exacerbations and Mortality.

Rationale: Chronic obstructive pulmonary disease (COPD) can develop not only through a lung function trajectory dominated by an accelerated decline of FEV1 from normal maximally attained FEV1 in early adulthood (normal maximally attained FEV1 trajectory) but also through a trajectory with FEV1 below normal in early adulthood (low maximally attained FEV1 trajectory).Objectives: To test whether the long-term risk of exacerbations and mortality differs between these two subtypes of COPD.Methods: The cohort included 1,170 young adults enrolled in the Copenhagen City Heart Study during the 1970s and 1980s. In 2001-2003, which served as the baseline for the present analyses, 79 participants had developed COPD through normal maximally attained FEV1 trajectory, 65 had developed COPD through low maximally attained FEV1 trajectory, and 1,026 did not have COPD.Measurements and Main Results: From 2001 until 2018, we observed 139 severe exacerbations of COPD and 215 deaths, of which 55 were due to nonmalignant respiratory disease. In Cox models, there was no difference with regard to risk of severe exacerbations between the two trajectories, but individuals with normal maximally attained FEV1 had an increased risk of nonmalignant respiratory disease mortality (using inverse probability of censoring weighting with adjusted hazard ratio [HR], 6.20; 95% confidence interval [CI], 2.09-18.37; P = 0.001) and all-cause mortality (adjusted HR, 1.93; 95% CI, 1.14-3.26; P = 0.01) compared with individuals with low maximally attained FEV1.Conclusions: COPD developed through normal maximally attained FEV1 trajectory is associated with an increased risk of respiratory and all-cause mortality compared with COPD developed through low maximally attained FEV1 trajectory.

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.

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.

Can we walk away from cardiovascular disease risk or do we have to 'huff and puff'? A cross-sectional compositional accelerometer data analysis among adults and older adults in the Copenhagen City Heart Study.

BACKGROUND: It is unclear whether walking can decrease cardiovascular disease (CVD) risk or if high intensity physical activity (HIPA) is needed, and whether the association is modified by age. We investigated how sedentary behaviour, walking, and HIPA, were associated with systolic blood pressure (SBP), waist circumference (WC), and low-density lipoprotein cholesterol (LDL-C) among adults and older adults in a general population sample using compositional data analysis. Specifically, the measure of association was quantified by reallocating time between sedentary behaviour and 1) walking, and 2) HIPA. METHODS: Cross-sectional data from the fifth examination of the Copenhagen City Heart Study was used. Using the software Acti4, we estimated daily time spent in physical behaviours from accelerometer data worn 24 h/day for 7 days (i.e., right frontal thigh and iliac crest; median wear time: 6 days, 23.8 h/day). SBP, WC, and LDL-C were measured during a physical examination. Inclusion criteria were ≥ 5 days with ≥16 h of accelerometer recordings per day, and no use of antihypertensives, diuretics or cholesterol lowering medicine. The 24-h physical behaviour composition consisted of sedentary behaviour, standing, moving, walking, HIPA (i.e., sum of climbing stairs, running, cycling, and rowing), and time in bed. We used fitted values from linear regression models to predict the difference in outcome given the investigated time reallocations relative to the group-specific mean composition. RESULTS: Among 1053 eligible participants, we found an interaction between the physical behaviour composition and age. Age-stratified analyses (i.e.,

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.

ß2-Adrenergic genotypes and risk of severe exacerbations in COPD: a prospective cohort study.

BACKGROUND: Individual susceptibility to exacerbations in chronic obstructive pulmonary disease (COPD) is likely influenced by genetic factors; however, most such variance is unexplained. We hypothesised that ß2-adrenergic receptor genotypes, Gly16Arg (rs1042713, c.46G>A) and Gln27Glu (rs1042714, c.79C>G) influence risk of severe exacerbations in COPD. METHODS: Among 96 762 individuals in the Copenhagen General Population Study, we identified 5262 with COPD (forced expiratory volume in one second divided by forced vital capacity, FEV1/FVC, below 0.7, FEV1 less than 80% of predicted value, age above 40 years and no asthma) who had genotyping performed. Severe exacerbations were defined as acute admissions due to COPD during 5 years of follow-up (mean 3.4 years). 923 individuals with COPD diagnosed similarly in the Copenhagen City Heart Study (CCHS) were used for replication analyses. RESULTS: We recorded 461 severe exacerbations in 5262 subjects. The HRs for severe exacerbations were 1.62 (95% CI 1.30 to 2.03, p=0.00002) for 16Gly/Arg heterozygotes and 1.41 (1.04 to 1.91, p=0.03) for 16Arg homozygotes, compared with 16Gly homozygotes. HRs were 1.35 (1.03 to 1.76, p=0.03) for 27Gln/Glu heterozygotes and 1.49 (1.12 to 1.98, p=0.006) for 27Gln homozygotes, compared with 27Glu homozygotes. Similar trends were observed in the CCHS. Among 27Gln homozygotes only, HRs were 5.20 (1.81 to 14.9, p=0.002) for 16Gly/Arg heterozygotes and 4.03 (1.40 to 11.6, p=0.01) for 16Arg homozygotes, compared with 16Gly homozygotes. CONCLUSION: Common ß2-adrenergic receptor genotypes influence risk of severe exacerbations in COPD, potentially mainly by genetic influence of the 16Arg allele in rs1042713.

Midlife cardiorespiratory fitness and the long-term risk of chronic obstructive pulmonary disease.

BACKGROUND: Good midlife cardiorespiratory fitness (CRF) may reduce the risk of chronic obstructive pulmonary disease (COPD). Reverse causation may play a role if follow-up time is short. We examined the association between CRF and both incident COPD and COPD mortality in employed men with up to 46 years follow-up, which allowed us to account for reverse causality. METHODS: Middle-aged men (n=4730) were recruited in 1970-1971. CRF was determined as VO2max by ergometer test. Categories of CRF (low, normal, high) were defined as ± 1 Z-score (± 1 SD) above or below the age-adjusted mean. Endpoints were identified through national registers and defined as incident COPD, and death from COPD. Multi-adjusted Cox models and restricted mean survival times (RMST) were performed. RESULTS: Compared with low CRF, the estimated risk of incident COPD was 21% lower in participants with normal CRF (HR 0.79, 95% CI 0.63 to 0.99) and 31 % lower with high CRF (HR 0.69, 95% CI 0.52 to 0.91). Compared with low CRF, the risk of death from COPD was 35% lower in participants with normal CRF (HR 0.65, 95% CI 0.46 to 0.91) and 62% lower in participants with high CRF (HR 0.38, 95% CI 0.23 to 0.61). RMST showed a delay to incident COPD and death from COPD in the magnitude of 1.3-1.8 years in normal and high CRF vs low CRF. Test for reverse causation did not alter the results. CONCLUSION: In a population of healthy, middle-aged men, higher levels of CRF were associated with a lower long-term risk of incident COPD and death from COPD.

Time spent cycling, walking, running, standing and sedentary: a cross-sectional analysis of accelerometer-data from 1670 adults in the Copenhagen City Heart Study : Physical behaviours among 1670 Copenhageners.

BACKGROUND: Information about how much time adults spend cycling, walking and running can be used for planning and evaluating initiatives for active, healthy societies. The objectives of this study were to describe how much time adult Copenhageners cycle, walk, run, stand and spend sedentary using accelerometers, and to describe differences between population groups. METHODS: In the fifth examination of the Copenhagen City Heart Study, 2335 individuals gave consent to wear accelerometers (skin-attached; right thigh and iliac crest; 24 h/day, 7 consecutive days) of which 1670 fulfilled our inclusion criteria (≥16 h/day for ≥5 days; median wear time: 23.8 h/day). Daily time spent cycling, walking, running, standing and sedentary was derived from accelerometer-based data using the Acti4 software, and differences between sex, age groups, level of education and BMI were investigated using Kruskal-Wallis rank sum tests. RESULTS: Among those cycling (61%), the median cycling time was 8.3 min/day. The median time walking, running, standing and sedentary was 82.6, 0.1, 182.5 and 579.1 min/day, respectively. About 88% walked fast (i.e., ≥100 steps/min) ≥30 min/day. The shortest duration and lowest prevalence of cycling, walking and running were found among older individuals, those with a low level of education, and individuals being overweight or obese. CONCLUSIONS: We found a long duration and high prevalence of cycling and walking, but also that many adult Copenhageners spent much time sedentary. Population groups with low participation in physical activities such as cycling and walking should be targeted in future initiatives towards an active, healthy society.

Increasing population height and risk of incident atrial fibrillation: the Copenhagen City Heart Study.

Aims: The incidence of atrial fibrillation (AF) has increased significantly over the last decades. Population height is changing in many countries. Height is an important risk factor for AF. The aim of the present study was to assess the role of changes in population height in the increased risk of AF. Methods and results: The Copenhagen City Heart Study comprises 18 852 randomly selected men and women aged 20-93 years, studied in four separate cross-sectional surveys in 1976-78, 1981-83, 1991-94, and 2001-03, including physical examination, electrocardiogram (ECG), and standard questionnaires. Hospitalization and mortality data were collected from public registers. Prevalent AF was determined from ECGs and incident AF from register diagnoses. During follow-up, age-standardized prevalence of AF increased significantly from 1.35% to 2.11% in men and from 0.67% to 1.07% in women (P < 0.001). Incident AF increased four-fold in both men and women [hazard ratio (HR) 4.16, 95% confidence interval (CI) 3.27-5.29; P < 0.001]. In multivariable Fine and Gray subdistribution hazards regression analyses, height was consistently an important risk factor for incident AF with HRs between 1.35 (95% CI 1.10-1.66; P = 0.004) and 1.65 (95% CI 1.40-1.93; P < 0.001). Population height increased with 3.3 cm for men and 2.1 cm for women, and population attributable risks for height was 20-30%. Conclusion: Height is a powerful risk factor for AF. Adult height is attained at age 20, while AF incidence occurs 50 years later. Given a causal relationship between height and AF incidence, increased population height in Denmark will contribute to an increase in AF occurrence for at least 25 more years.

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.).

Reference equations for pulmonary diffusing capacity of carbon monoxide and nitric oxide in adult Caucasians.

The aim of this study was to determine reference equations for the combined measurement of diffusing capacity of the lung for carbon monoxide (CO) and nitric oxide (NO) (DLCONO). In addition, we wanted to appeal for consensus regarding methodology of the measurement including calculation of diffusing capacity of the alveolo-capillary membrane (Dm) and pulmonary capillary volume (Vc).DLCONO was measured in 282 healthy individuals aged 18-97 years using the single-breath technique and a breath-hold time of 5 s (true apnoea period). The following values were used: 1) specific conductance of nitric oxide (θNO)=4.5 mLNO·mLblood-1·min-1·mmHg-1; 2) ratio of diffusing capacity of the membrane for NO and CO (DmNO/DmCO)=1.97; and 3) 1/red cell CO conductance (1/θCO)=(1.30+0.0041·mean capillary oxygen pressure)·(14.6/Hb concentration in g·dL-1).Reference equations were established for the outcomes of DLCONO, including DLCO and DLNO and the calculated values Dm and Vc Independent variables were age, sex, height and age squared.By providing new reference equations and by appealing for consensus regarding the methodology, we hope to provide a basis for future studies and clinical use of this novel and interesting method.

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.

Prevalence of night-time dyspnoea in COPD and its implications for prognosis.

The information on night-time symptoms in chronic obstructive pulmonary disease (COPD) is sparse. We investigated the prevalence of night-time dyspnoea in 6616 individuals with COPD recruited from the general population in the Copenhagen area, Denmark, and described characteristics and prognosis of subjects with this symptom. The prevalence of night-time dyspnoea was 4.3%: 2.1% in Global Initiative for Chronic Obstructive Lung Disease (GOLD) group A, 12.9% in GOLD B, 2.6% in GOLD C and 16.3% in GOLD D. Compared with individuals without night-time dyspnoea, those with night time dyspnoea had lower forced expiratory volume in 1 s, higher daytime dyspnoea scores (modified Medical Research Council scale) and more wheezing, more often had chronic mucus hypersecretion, ischaemic heart disease and atrial fibrillation, and more often reported stress, nervousness and tiredness. After adjustment for age and sex, the presence of night-time dyspnoea was associated with future COPD exacerbations (hazard ratio (HR) 2.3, 95% CI 1.7-3.0), hospital admissions due to COPD (HR 3.2, 95% CI 2.3-4.4) and mortality (HR 1.7, 95% CI 1.2-2.3). Prevalence of night-time dyspnoea in COPD increases with disease severity according to both spirometric and clinical GOLD classification, and is associated with presence of daytime respiratory symptoms and cardiac comorbidities. Night-time dyspnoea is a significant predictor of poor prognosis in individuals with COPD.

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.