Gorm Jensen

A 15-Year Follow-up Study of Ventilatory Function in Adults with Asthma

BACKGROUND Although the prevalence of asthma and morbidity related to asthma are increasing, little is known about the natural history of lung function in adults with this disease. METHODS We used data from a longitudinal epidemiologic study of the general population in a Danish city, the Copenhagen City Heart Study, to analyze changes over time in the forced expiratory volume in one second (FEV1) in adults with self-reported asthma and adults without asthma. The study was conducted between 1976 and 1994; for each patient, three measurements of lung function were obtained over a 15-year period. The final data set consisted of measurements from 17,506 subjects (8136 men and 9370 women), of whom 1095 had asthma. RESULTS Among subjects who participated in all three evaluations, the unadjusted decline in FEV1 among subjects with asthma was 38 ml per year, as compared with 22 ml per year in those without asthma. The decline in FEV1 normalized for height (FEV1 divided by the square of the height in meters) was greater among the subjects with asthma than among those without the disease (P<0.001). Among both men and women, and among both smokers and nonsmokers, subjects with asthma had greater declines in FEV1 over time than those without asthma (P<0.001). At the age of 60 years, a 175-cm-tall nonsmoking man without asthma had an average FEV1 of 3.05 liters, as compared with 1.99 liters for a man of similar age and height who smoked and had asthma. CONCLUSIONS In a sample of the general population, people who identified themselves as having asthma had substantially greater declines in FEV1 over time than those who did not.

Very Low Levels of Microalbuminuria Are Associated With Increased Risk of Coronary Heart Disease and Death Independently of Renal Function, Hypertension, and Diabetes

Background—The aim of this study was to assess the level of urinary albumin excretion (microalbuminuria), which is associated with increased risk of coronary heart disease and death, in the population. Microalbuminuria has been suggested as an atherosclerotic risk factor. However, the lower cutoff level of urinary albumin excretion is unknown. It is also unknown whether impaired renal function confounds the association. Methods and Results—In the Third Copenhagen City Heart Study in 1992 to 1994, 2762 men and women 30 to 70 years of age underwent a detailed cardiovascular investigation program, including a timed overnight urine sample. The participants were then followed up prospectively by registers until 1999 with respect to coronary heart disease and until 2001 with respect to death. During follow-up, 109 incident cases of coronary heart disease and 276 deaths were traced. A urinary albumin excretion above the upper quartile, ie, 4.8 μg/min, was associated with increased risk of coronary heart disease (RR, 2.0; 95% CI, 1.4 to 3.0; P <0.001) and death (RR, 1.9; 95% CI, 1.5 to 2.4; P <0.001) independently of age, sex, renal creatinine clearance, diabetes mellitus, hypertension, and plasma lipids. Lower levels of urinary albumin excretion were not associated with increased risk. Conclusions—Microalbuminuria, defined as urinary albumin excretion >4.8 μg/min (corresponding to ≈6.4 μg/min during daytime), is a strong and independent determinant of coronary heart disease and death. Our suggestion is to redefine microalbuminuria accordingly and perform intervention studies.

Type of Alcohol Consumed and Mortality from All Causes, Coronary Heart Disease, and Cancer

Several population studies from different countries have shown a J-shaped relation between intake of alcohol and mortality from all causes (1-6). Studies comparing different countries have found a strong inverse relation between incidence rates of coronary heart disease and wine consumption but a weak or nonexistent relation for consumption of beer or spirits (7-9). The findings that different types of alcoholic beverages have different effects on mortality are indirectly supported by several clinical and experimental studies (10-12). In contrast, prospective studies have shown that beer (13), spirits (14), and wine (15) may have protective effects. However, most of these investigations were based on populations with one predominant type of alcohol consumption; this precluded valid comparison of the effects of the three different types of alcohol. We sought to analyze the effect of intake of different types of alcohol on mortality from all causes, coronary heart disease, and cancer in several large Danish cohort studies. Methods The Copenhagen Centre for Prospective Population Studies is based on three study samples: that of the Copenhagen City Heart Study; that of the Copenhagen County Centre of Preventive Medicine (the former Glostrup Population Studies), which includes six cohorts; and that of the Copenhagen Male Study (16-18). The study samples of the Copenhagen City Heart Study, initiated in 1976, and the Copenhagen County Centre of Preventive Medicine, initiated in 1964, were randomly selected within age strata from the populations residing in defined areas in greater Copenhagen. For the Copenhagen Male Study, initiated in 1971, employees of 14 large companies in Copenhagen were invited to participate. The mean participation rate in all studies was 80% (range, 69% to 88%). The combined study sample comprises 13 064 men and 11 459 women for whom information on alcohol intake and lifestyle-related variables, described below, was complete. Alcohol Intake Participants of the Copenhagen City Heart Study and the studies in the Copenhagen County Centre of Preventive Medicine were asked about their current average weekly intake of beer, wine, and spirits. In the Copenhagen Male Study, participants were asked about their average daily intake of beer, wine, and spirits on weekdays (Monday through Thursday) and weekends (Friday through Sunday); these reports were combined to estimate weekly alcohol consumption. Persons in our study who did not drink alcohol because they were receiving disulfiram or other medication were excluded from the analysis. One bottle of beer contains 11.6 g of alcohol, and 12 g is an approximate average for one serving of wine or spirits. We grouped participants into five categories on the basis of total intake of alcohol: less than 1 drink/wk (nondrinkers), 1 to 7 drinks/wk, 8 to 21 drinks/wk, 22 to 35 drinks/wk, and more than 35 drinks/wk. Intake of beer, wine, and spirits was categorized similarly; however, because of the frequency of end point data, more than 21 drinks/wk is the highest intake category for the individual types of beverages. Smoking Status Participants reported whether they were never-smokers, former smokers, or current smokers. Current smokers reported grams of tobacco smoked per day in the form of cigarettes (1 g/d), small cigars (3 g/d), cigars (5 g/d), and pipe tobacco (50 g/package). Five groups were defined: never-smokers, former smokers, smokers of 1 to 14 g of tobacco daily, smokers of 15 to 24 g of tobacco daily, and smokers of more than 24 g of tobacco daily. Education Participants reported the number of years that they attended school. Three groups were defined: fewer than 8 years, 8 to 11 years, and 12 or more years of school education. Physical Activity Participants reported whether they were physically active during leisure time. Four groups were defined: sedentary (<2 h/wk), light activity (2 to 4 h/wk), moderate activity (>4 h/wk, noncompetitive) and heavy activity (>4 h/wk, competitive). Body Mass Index Body weight and height were measured while the participant was wearing light clothes and no shoes. Body mass index was calculated as weight in kg divided by height in meters squared. Five categories of body mass index were defined: less than 20.0 kg/m2, 20.0 to 24.9 kg/m2, 25.0 to 29.9 kg/m2, 30.0 to 34.9 kg/m2, and 35.0 kg/m2 or more. Changes in Lifestyle-Related Variables When participants were re-examined during follow-up, the newly obtained values for alcohol intake, smoking status, physical activity, and body mass index were used to replace the old values in the statistical analyses. Observation time and vital status were included in the modeling accordingly. Follow-up Participants were followed from date of entry into the study to date of death, loss to follow-up, emigration, or end of follow-up, whichever came first. The vital status of populations was followed by using each participants unique identification number in the national Central Person Register until 9 January 1995. Fewer than 1% of the participants were lost to follow-up. Causes of death were obtained from the National Board of Health and were defined by using codes from International Classifications of Diseases, Eighth Revision (codes 410.0 to 414.0 for coronary heart disease and codes 140.0 to 209.0 for cancer). According to a previous study, the reported diagnoses for these grouped codes have proven to be sufficiently valid (20). Statistical Analysis We performed Poisson regression (21) by using SAS/STAT software (22) to estimate the effect of alcohol intake on the risk for death. These models generate estimates of relative risk that are adjusted for confounders. Each model included the following potential confounders as categorical variables: age, cohort study, sex, education, body mass index, physical activity, and smoking status. Owing to collinearity, it was impossible to include both the amount by type of beverage (beer, wine, or spirits) consumed and total alcohol intake in the same regression. We therefore estimated the influence of alcohol according to number of drinks consumed per week [0, 1 to 7, 8 to 21, 22 to 35,>35] in three regressions: 1) total alcohol consumption in drinks per week, without considering beverage type; 2) alcohol consumption in drinks of each beverage per week, without considering the total intake; and 3) percentage of total alcohol intake consumed as wine (0%, 1% to 30%,>30%). Effects that were insignificant according to the likelihood ratio test (5% level) were removed by backward elimination. A term indicating interaction between total alcohol intake and percentage alcohol consumed as beer, wine, or spirits was included in the analyses to assess whether the effects of beer, wine, and spirits differed at different levels of total alcohol intake; no such effects were identified, as judged from the fit of the model. Likewise, no interaction was found between sex and intake of different types of beverage in terms of mortality. Results A total of 4275 women and 1635 men drank less than 1 drink per week; 64 women and 1032 men drank 35 or more drinks per week. Of 13 613 participants who drank alcohol, 12 846 (69%) included wine in their intake (Table 1). During 257 859 person-years of follow-up, 4833 participants died; of these, 1075 died of coronary heart disease and 1552 died of cancer. Table 1. Baseline Characteristics of the Study Participants Baseline Characteristics Compared with participants who drank alcohol but no wine, those for whom wine made up more than 30% of their total alcohol intake were more likely to be women and have a higher educational level but were less likely to be smokers (Table 1). Participants for whom wine made up more than 30% of their alcohol intake were similar to those who drank no alcohol in terms of smoking habits, body mass index, and physical activity. Across categories of total alcohol intake, mean alcohol intake within the different categories of wine drinking was similar; for example, among participants who drank 8 to 21 drinks/wk, those who drank no wine, those who drank 1% to 30% wine, and those who drank more than 30% wine had a mean alcohol intake of 13.3, 13.7, and 12.8 drinks/wk, respectively. However, among light drinkers (1 to 7 drinks/wk), those who drank 1% to 30% of their alcohol as wine had a slightly higher mean intake than did those who avoided wine and those who drank more than 30% of their alcohol intake as wine. Thus, assessment of the effects of wine intake may not be subject to residual confounding by total alcohol intake when controlled for as specified. Total Alcohol Intake and Mortality We found J-shaped relations between total alcohol intake and all-cause mortality in the three substudies. Pooled analyses also revealed J-shaped relations (Table 2). When nondrinkers were used as the reference group (relative risk, 1.00), intake of 1 to 7 drinks per week carried a relative risk of 0.82 (95% CI, 0.76 to 0.88) and intake of more than 35 drinks per week carried a relative risk of 1.10 (CI, 0.95 to 1.26). Alcohol intake was negatively related to death from coronary heart disease and positively related to death from cancer (Table 2). Table 2. Relative Risk for Death with Regard to Total Alcohol Intake and Intake of Beer, Wine, and Spirits Intake of Beer, Wine, and Spirits and Mortality Light to moderate intake of beer or spirits had a small effect on death from all causes (Table 2). This finding contrasted with the effect of wine intake on mortality: Participants who drank 8 to 21 glasses of wine per week had a relative risk for death from all causes of 0.76 (CI, 0.67 to 0.86). Intake of fewer than 22 drinks of beer, wine, and spirits per week all carried lower risk for death from coronary heart disease; the reduction in risk was of the same magnitude for beer and wine drinking but was smaller and not statistically significant for spirits drinking. Furthermore, light to moderate drinkers of wine had

Effect of perioperative β blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial

Abstract Objectives To evaluate the long term effects of perioperative β blockade on mortality and cardiac morbidity in patients with diabetes undergoing major non-cardiac surgery. Design Randomised placebo controlled and blinded multicentre trial. Analyses were by intention to treat. Setting University anaesthesia and surgical centres and one coordinating centre. Participants 921 patients aged > 39 scheduled for major non-cardiac surgery. Interventions 100 mg metoprolol controlled and extended release or placebo administered from the day before surgery to a maximum of eight perioperative days. Main outcome measures The composite primary outcome measure was time to all cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure. Secondary outcome measures were time to all cause mortality, cardiac mortality, and non-fatal cardiac morbidity. Results Mean duration of intervention was 4.6 days in the metoprolol group and 4.9 days in the placebo group. Metoprolol significantly reduced the mean heart rate by 11% (95% confidence interval 9% to 13%) and mean blood pressure by 3% (1% to 5%). The primary outcome occurred in 99 of 462 patients in the metoprolol group (21%) and 93 of 459 patients in the placebo group (20%) (hazard ratio 1.06, 0.80 to 1.41) during a median follow-up of 18 months (range 6-30). All cause mortality was 16% (74/462) in the metoprolol group and 16% (72/459) in the placebo group (1.03, 0.74 to 1.42). The difference in risk for the proportion of patients with serious adverse events was 2.4% (− 0.8% to 5.6%). Conclusions Perioperative metoprolol did not significantly affect mortality and cardiac morbidity in these patients with diabetes. Confidence intervals, however, were wide, and the issue needs reassessment. Trial registration Current Controlled Trials ISRCTN58485613 [controlled-trials.com.

Rising rates of hospital admissions for atrial fibrillation.

Background: Atrial fibrillation is a common arrhythmia associated with excess morbidity and mortality. We studied temporal changes in hospital admission rates for atrial fibrillation using data from a prospective population-based cohort study spanning 2 decades (the Copenhagen City Heart Study). Methods: The study included baseline data collected in 1981 through 1983 on 10,955 persons age 40 to 79 years and baseline data collected in 1991 through 1994 on 7212 persons age 40 to 79 years. We used hospital diagnosis data from the Danish National Hospital Discharge Register to determine the rate of first hospital admission for atrial fibrillation during 7 years following each of the 2 baseline data collecting periods. Changes in admission rates were analyzed using Cox proportional hazard models. Results: During the 2 7-year periods, 379 subjects were admitted with a hospital diagnosis of atrial fibrillation. The rate of hospital admissions for atrial fibrillation increased among both men and women from the first to the second period (relative risk = 1.6; 95% confidence interval = 1.3–1.9 [adjusted for age, sex, prior myocardial infarction, arterial hypertension, diabetes mellitus, electrocardiographic left ventricular hypertrophy, decreased lung function, smoking, height, and weight]). Conclusion: During the latest 10 to 20 years, there has been a 60% increase in hospital admissions for atrial fibrillation independent of changes in known risk factors. This increase could result from changes in admission threshold or coding practices, or it could reflect a genuine increase in the population incidence of atrial fibrillation.

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.).

Risk Factors for Venous Thromboembolism Results From the Copenhagen City Heart Study

Background— Studies have suggested a link between risk factors for atherosclerotic disease and venous thromboembolism (VTE), but results are heterogeneous. We sought to identify risk factors for VTE with a focus on risk factors for atherosclerotic disease. Methods and Results— Data were taken from the Copenhagen City Heart Study, a prospective cohort study of a random, age-stratified sample of people living in a defined area in Copenhagen, Denmark, started in 1976 with follow-up until 2007. First VTE (deep vein thrombosis and pulmonary embolism) diagnosis was retrieved from electronic national registries from study baseline to 2007. Of 18 954 subjects (median follow-up, 19.5 years) representing 360 399 person-years of follow-up, 969 subjects experienced at least 1 VTE, corresponding to a crude incidence rate of 2.69 (95% confidence interval [CI], 2.52 to 2.86) per 1000 person-years. The variables found to be significantly associated with VTE in a multivariable model adjusted for age and calendar time were as follows: body mass index (hazard ratio [HR] for ≥35 versus <20=2.10 [95% CI, 1.39 to 3.16]); smoking (HR for ≥25 g tobacco per day versus never smoker=1.52 [95% CI, 1.15 to 2.01]); gender (HR for men versus women=1.24 [95% CI, 1.08 to 1.42]); household income (HR for medium versus low=0.82 [95% CI, 0.70 to 0.95]); and diastolic blood pressure (HR for >100 versus <80 mm Hg=1.34 [95% CI, 1.08 to 1.66]). Other cardiovascular risk factors including total/high-density lipoprotein/low-density lipoprotein cholesterol levels, triglyceride levels, and diabetes mellitus were not associated with VTE. Conclusions— Obesity and smoking were both found to be important risk factors for VTE whereas total/high-density lipoprotein/low-density lipoprotein cholesterol levels, triglyceride levels, and diabetes mellitus were not.

Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population

Homozygosity for mutations in ABC transporter A1 (ABCA1) causes Tangier disease, a rare HDL-deficiency syndrome. Whether heterozygosity for genetic variation in ABCA1 also contributes to HDL cholesterol (HDL-C) levels in the general population is presently unclear. We determined whether mutations or single-nucleotide polymorphisms (SNPs) in ABCA1 were overrepresented in individuals with the lowest 1% (n=95) or highest 1% (n=95) HDL-C levels in the general population by screening the core promoter and coding region of ABCA1. For all nonsynonymous SNPs identified, we determined the effect of genotype on lipid traits in 9,259 individuals from the general population. Heterozygosity for ABCA1 mutations was identified in 10% of individuals with low HDL-C only. Three of 6 nonsynonymous SNPs (V771M, V825I, and R1587K) were associated with increases or decreases in HDL-C in women in the general population and some with consistent trends in men, determined as isolated single-site effects varying only at the relevant SNP. Finally, these results were consistent over time. In conclusion, we show that at least 10% of individuals with low HDL-C in the general population are heterozygous for mutations in ABCA1 and that both mutations and SNPs in ABCA1 contribute to HDL-C levels in the general population.

Elevated urinary albumin excretion is associated with impaired arterial dilatory capacity in clinically healthy subjects.

BackgroundElevated urinary albumin excretion (UAE) predicts atherosclerotic cardiovascular disease. It is hypothesized that elevated UAE is associated with a generalized vascular dysfunction. This study tested this hypothesis for conduit arteries. Methods and ResultsClinically healthy subjects were selected: 19 with UAE >90th percentile in the background population (6.6 &mgr;g/min<UAE<150 &mgr;g/min) and 41 with normoalbuminuria (UAE <6.6 &mgr;g/min). External ultrasound was used to measure the dilatory response of the brachial artery to postischemic increased blood flow (endothelium-dependent, flow-associated dilation) and to nitroglycerin (endothelium-independent, nitroglycerin-induced dilation). Plasma concentrations of the endothelial markers nitrate/nitrite, thrombomodulin, and von Willebrand factor antigen were also measured. Both flow-associated and nitroglycerin-induced dilations were significantly impaired in subjects with elevated UAE as compared with normoalbuminuric control subjects: 102.0±1.0% (mean±SEM) versus 104.3±0.6% (P <0.05) and 120.1±1.5% versus 123.8±1.0% (P <0.05). No differences in the plasma concentrations of endothelial markers were found. ConclusionsSlightly elevated UAE is associated with impaired conduit arterial dilatory capacity in clinically healthy subjects, and this impairment may be explained by a reduced dilatory response to nitric oxide of both endogenous and exogenous origin. Impaired arterial dilatory capacity may contribute to the increased cardiovascular risk in subjects with elevated UAE.

Alcohol Consumption and Risk of Atrial Fibrillation in Men and Women The Copenhagen City Heart Study

Background—The relationship of the full range of alcohol consumption with risk of incident atrial fibrillation has been inconsistent in previous, mainly case-control studies. Methods and Results—In a prospective cohort study, we studied the association between self-reported alcohol use and incident atrial fibrillation among 16 415 women and men enrolled in the Copenhagen City Heart Study. We ascertained use of beer, wine, and spirits individually at up to 3 study visits with a structured questionnaire. We identified cases of atrial fibrillation by routine study ECGs and a validated nationwide registry of all hospitalizations. A total of 1071 cases occurred during follow-up. Among both women and men, alcohol consumption throughout the moderate range was not associated with risk of atrial fibrillation. However, consumption of 35 or more drinks per week among men was associated with a hazard ratio of 1.45 (95% CI 1.02 to 2.04); few women consumed this amount of alcohol. Approximately 5% of cases of atrial fibrillation among men were attributable to heavy alcohol use. Further adjustment for blood pressure and incident coronary heart disease and congestive heart failure did not attenuate the association (hazard ratio 1.63; 95% CI 1.15 to 2.31). Conclusions—Heavy alcohol consumption is associated with a higher risk of atrial fibrillation, at least among men. This relationship does not appear to be related to the adverse effects of heavy drinking on coronary heart disease or blood pressure.