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Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

The use of a four-level questionnaire to assess leisure time physical activity (PA) and its validation is reviewed in this paper. This questionnaire was first published in 1968 and has then been used by more than 600 000 subjects, especially in different population studies in the Nordic countries. A number of modifications to the questionnaire have been published. These are mostly minor changes, such as adding practical examples of activities to illustrate the levels of PA. Some authors have also added duration requirements that were not included for all levels of PA in the original version. The concurrent validity, with respect to aerobic capacity and movement analysis using objective measurements has been shown to be good, as has the predictive validity with respect to various risk factors for health conditions and for morbidity and mortality.

BACKGROUND: Use of oral contraceptives with estrogen and hormone replacement therapy with estrogen or testosterone are associated with increased risk of venous thromboembolism (VTE). However, whether endogenous estradiol and testosterone concentrations are also associated with risk of VTE is unknown.OBJECTIVE: We tested the hypothesis that elevated endogenous total estradiol and total testosterone concentrations are associated with increased risk of VTE in the general population.METHODS: We studied 4658 women, not receiving exogenous estrogen, and 4673 men from the 1981-1983 Copenhagen City Heart Study, who had estradiol and testosterone concentrations measured. Of these, 636 developed VTE (deep venous thrombosis [DVT] and/or pulmonary embolism [PE]) during a follow-up of 21 years (range, 0.02-32 years). Associations between endogenous estradiol and testosterone concentrations and risk of VTE were estimated by Cox proportional hazards regression with time-dependent covariates and corrected for regression dilution bias.RESULTS: Multifactorially adjusted hazard ratios of VTE for individuals with estradiol levels >75th vs. ≤25th percentile were 0.84 (95%CI, 0.25-2.85), 1.05 (0.53-2.08) and 1.05 (0.03-35.13) for pre- and post-menopausal women and men, respectively. For testosterone, corresponding risk estimates were 0.64 (0.03-12.32), 1.11 (0.66-1.86) and 1.30 (0.62-2.73). In addition, no associations were observed between extreme hormone percentiles (>95th vs. ≤75th) and risk of DVT, PE or recurrent VTE.CONCLUSION: This prospective study suggests that high endogenous concentrations of estradiol and testosterone in women and men in the general population are not associated with increased risk of VTE, DVT or PE.

BACKGROUND: Use of oral contraceptives with estrogen and hormone replacement therapy with estrogen or testosterone are associated with increased risk of venous thromboembolism (VTE). However, whether endogenous estradiol and testosterone concentrations are also associated with risk of VTE is unknown.OBJECTIVE: We tested the hypothesis that elevated endogenous total estradiol and total testosterone concentrations are associated with increased risk of VTE in the general population.METHODS: We studied 4658 women, not receiving exogenous estrogen, and 4673 men from the 1981-1983 Copenhagen City Heart Study, who had estradiol and testosterone concentrations measured. Of these, 636 developed VTE (deep venous thrombosis [DVT] and/or pulmonary embolism [PE]) during a follow-up of 21 years (range, 0.02-32 years). Associations between endogenous estradiol and testosterone concentrations and risk of VTE were estimated by Cox proportional hazards regression with time-dependent covariates and corrected for regression dilution bias.RESULTS: Multifactorially adjusted hazard ratios of VTE for individuals with estradiol levels >75th vs. ≤25th percentile were 0.84 (95%CI, 0.25-2.85), 1.05 (0.53-2.08) and 1.05 (0.03-35.13) for pre- and post-menopausal women and men, respectively. For testosterone, corresponding risk estimates were 0.64 (0.03-12.32), 1.11 (0.66-1.86) and 1.30 (0.62-2.73). In addition, no associations were observed between extreme hormone percentiles (>95th vs. ≤75th) and risk of DVT, PE or recurrent VTE.CONCLUSION: This prospective study suggests that high endogenous concentrations of estradiol and testosterone in women and men in the general population are not associated with increased risk of VTE, DVT or PE.

Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases., Karl Michaëlsson (Department of Surgical Sciences, Orthopaedics, Uppsala University, Sweden) contributed to this study.

Hip circumference has been shown to be inversely associated with mortality. Muscle atrophy in the gluteofemoral region may be a possible explanation and thus physical activity is likely to play an important role. We aimed to estimate the combined effects of hip circumference and physical activity on mortality. From the Copenhagen City Heart Study, 3358 men and 4350 women aged 21 to 93 years without pre-existing diagnosis of diabetes, stroke, ischemic heart disease, or cancer in 1991-94 and with complete information on the variables of interest were included in the analyses. The participants were followed to 2009 in the Danish Civil Registration System, with 1.3% loss to follow-up and 2513 deaths. Hazard ratios (HR) were estimated for combinations of physical activity and hip circumference. Hip circumference was inversely associated with mortality irrespective of being physically active or not. However, being physically active seemed to counterbalance some of the adverse health effects of a small hip circumference; when comparing inactive to active, the excess mortality at the 25(th) percentile of hip circumference is 40% in men (HR= 1.40, 95% CI: 1.14-1.72) and 33% in women (HR= 1.33, CI: 1.10-1.62). These associations were observed after adjustment for waist circumference and weight change in the six months before the examination. Less effects of physical activity were found in individuals with greater hip circumferences. A small hip circumference appears hazardous to survival. However, being physically active may counterbalance some of the hazardous effects of a small hip circumference.

Hip circumference has been shown to be inversely associated with mortality. Muscle atrophy in the gluteofemoral region may be a possible explanation and thus physical activity is likely to play an important role. We aimed to estimate the combined effects of hip circumference and physical activity on mortality. From the Copenhagen City Heart Study, 3358 men and 4350 women aged 21 to 93 years without pre-existing diagnosis of diabetes, stroke, ischemic heart disease, or cancer in 1991-94 and with complete information on the variables of interest were included in the analyses. The participants were followed to 2009 in the Danish Civil Registration System, with 1.3% loss to follow-up and 2513 deaths. Hazard ratios (HR) were estimated for combinations of physical activity and hip circumference. Hip circumference was inversely associated with mortality irrespective of being physically active or not. However, being physically active seemed to counterbalance some of the adverse health effects of a small hip circumference; when comparing inactive to active, the excess mortality at the 25(th) percentile of hip circumference is 40% in men (HR= 1.40, 95% CI: 1.14-1.72) and 33% in women (HR= 1.33, CI: 1.10-1.62). These associations were observed after adjustment for waist circumference and weight change in the six months before the examination. Less effects of physical activity were found in individuals with greater hip circumferences. A small hip circumference appears hazardous to survival. However, being physically active may counterbalance some of the hazardous effects of a small hip circumference.

Langsted A, Freiberg JJ, Tybjaerg-Hansen A, Schnohr P, Jensen GB, Nordestgaard BG (Herlev Hospital, Herlev; University of Copenhagen; Bispebjerg Hospital; and Rigshospitalet, Copenhagen Ø, Denmark) Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med 2010; doi: 10.1111/j.1365-2796.2010.02333.x. Objectives. We compared the ability of very high levels of nonfasting cholesterol and triglycerides to predict risk of myocardial infarction and total mortality. Design. Prospective study from 1976 to 1978 until 2007. Setting. Danish general population. Participants. Randomly selected population of 7581 women and 6391 men, of whom 768 and 1151 developed myocardial infarction and 4398 and 4416 died, respectively. Participation rate was 72%, and follow-up was 100% complete. Less than 2% of participants were taking lipid-lowering therapy. Results. Compared to women with cholesterol

Langsted A, Freiberg JJ, Tybjaerg-Hansen A, Schnohr P, Jensen GB, Nordestgaard BG (Herlev Hospital, Herlev; University of Copenhagen; Bispebjerg Hospital; and Rigshospitalet, Copenhagen Ø, Denmark) Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med 2010; doi: 10.1111/j.1365-2796.2010.02333.x. Objectives. We compared the ability of very high levels of nonfasting cholesterol and triglycerides to predict risk of myocardial infarction and total mortality. Design. Prospective study from 1976 to 1978 until 2007. Setting. Danish general population. Participants. Randomly selected population of 7581 women and 6391 men, of whom 768 and 1151 developed myocardial infarction and 4398 and 4416 died, respectively. Participation rate was 72%, and follow-up was 100% complete. Less than 2% of participants were taking lipid-lowering therapy. Results. Compared to women with cholesterol

Langsted A, Freiberg JJ, Tybjaerg-Hansen A, Schnohr P, Jensen GB, Nordestgaard BG (Herlev Hospital, Herlev; University of Copenhagen; Bispebjerg Hospital; and Rigshospitalet, Copenhagen Ø, Denmark) Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med 2010; doi: 10.1111/j.1365-2796.2010.02333.x. Objectives. We compared the ability of very high levels of nonfasting cholesterol and triglycerides to predict risk of myocardial infarction and total mortality. Design. Prospective study from 1976 to 1978 until 2007. Setting. Danish general population. Participants. Randomly selected population of 7581 women and 6391 men, of whom 768 and 1151 developed myocardial infarction and 4398 and 4416 died, respectively. Participation rate was 72%, and follow-up was 100% complete. Less than 2% of participants were taking lipid-lowering therapy. Results. Compared to women with cholesterol

To estimate the excess deaths associated with weight loss in combination with leisure time physical activity among overweight or obese people.

To estimate the excess deaths associated with weight loss in combination with leisure time physical activity among overweight or obese people.

Udgivelsesdato: 2009/2

Udgivelsesdato: 2009/11, Objective. The aim of this study was to evaluate the long-term effects of stress on changes in health behaviour and cardiac risk profile in men and women. Design. A prospective cohort study. Setting. The Copenhagen City Heart Study, Denmark. Subjects. The analyses were based on 7066 women and men from the second (1981-1983) and third (1991-1993) wave of the Copenhagen City Heart Study. All participants were asked questions on stress and health behaviour and they had their weight, height, blood pressure and level of blood lipids measured by trained personnel. Main outcome measures. Changes in health behaviour (smoking, physical activity, alcohol consumption, overweight) and cardiac risk profile (cholesterol, HDL cholesterol, blood pressure, diabetes). Results. Individuals with high levels of stress compared to those with low levels of stress were less likely to quit smoking (OR = 0.58; 95% CI: 0.41-0.83), more likely to become physically inactive (1.90; 1.41-2.55), less likely to stop drinking above the sensible drinking limits (0.43; 0.24-0.79), and stressed women were more likely to become overweight (1.55; 1.12-2.15) during follow-up. Men and women with high stress were more likely to use antihypertensive medication (1.94; 1.63-2.30), and stressed men were more than two times as likely to develop diabetes during follow-up (2.36; 1.22-4.59). Conclusion. This longitudinal study supports a causal relation between stress and cardiovascular diseases mediated through unfavourable changes in health behaviour and cardiac risk profile

Udgivelsesdato: 2009/2

Udgivelsesdato: 2009/11, Objective. The aim of this study was to evaluate the long-term effects of stress on changes in health behaviour and cardiac risk profile in men and women. Design. A prospective cohort study. Setting. The Copenhagen City Heart Study, Denmark. Subjects. The analyses were based on 7066 women and men from the second (1981-1983) and third (1991-1993) wave of the Copenhagen City Heart Study. All participants were asked questions on stress and health behaviour and they had their weight, height, blood pressure and level of blood lipids measured by trained personnel. Main outcome measures. Changes in health behaviour (smoking, physical activity, alcohol consumption, overweight) and cardiac risk profile (cholesterol, HDL cholesterol, blood pressure, diabetes). Results. Individuals with high levels of stress compared to those with low levels of stress were less likely to quit smoking (OR = 0.58; 95% CI: 0.41-0.83), more likely to become physically inactive (1.90; 1.41-2.55), less likely to stop drinking above the sensible drinking limits (0.43; 0.24-0.79), and stressed women were more likely to become overweight (1.55; 1.12-2.15) during follow-up. Men and women with high stress were more likely to use antihypertensive medication (1.94; 1.63-2.30), and stressed men were more than two times as likely to develop diabetes during follow-up (2.36; 1.22-4.59). Conclusion. This longitudinal study supports a causal relation between stress and cardiovascular diseases mediated through unfavourable changes in health behaviour and cardiac risk profile

To examine whether physical activity (PA) is associated with changes in waist circumference (WC), and changes in WC given changes in body mass index (BMI). Longitudinal population-based study including 2026 men and 2782 women aged 21-81 years. Subjects were examined in 1991-1993 (baseline) and 2001-2003 (follow up), where height, weight and WC were measured. Information about overall PA in leisure-time (LTPA), walking, biking and sports activity was collected with self-administrated questionnaires at baseline. Outcomes were changes in WC and changes in WC given changes in BMI between baseline and follow up. The median increase in WC was 3.0 cm in men and 3.5 cm in women during follow-up, and with a considerable inter-individual variation. LTPA, walking and biking were not significantly associated with the outcomes. Inverse associations between sports activity and the outcomes were observed in both sexes, and these were significant in some analyses. Associations were not altered by adjustment for confounders or by exclusions of subjects with diseases and/or treatment by obesity-inducing medication. This study suggests that LTPA, walking and biking have no appreciable effects on changes in WC or changes in WC given changes in BMI, whereas sports activity may have small preventive effects Udgivelsesdato: 2008/12

Udgivelsesdato: 2008-Aug-15, PURPOSE: Results from longitudinal studies about the association between physical activity and chronic obstructive pulmonary disease (COPD) may have been biased because they did not properly adjust for time-dependent confounders. Marginal structural models (MSMs) have been proposed to address this type of confounding. We sought to assess the presence of time-dependent confounding in the association between physical activity and COPD development and course by comparing risk estimates between standard statistical methods and MSMs. METHODS: By using the population-based cohort Copenhagen City Heart Study, 6,568 subjects selected from the general population in 1976 were followed up until 2004 with three repeated examinations. RESULTS: Moderate to high compared with low physical activity was associated with a reduced risk of developing COPD both in the standard analysis (odds ratio [OR] 0.76, p = 0.007) and in the MSM analysis (OR 0.79, p = 0.025). In the subgroup with COPD (n = 2,226), high physical activity was associated with a reduced risk of COPD admissions during follow-up (standard, incidence rate ratio, 0.74; p = 0.096; MSM, 0.68, p = 0.044), and with a reduced risk of mortality (standard, hazard ratio 0.80, p = 0.001; MSM, 0.81, p = 0.008). CONCLUSION: These results support the previously reported associations between physical activity and reduced risk of COPD development, hospitalizations, and mortality, thereby suggesting they were not due to time-dependent confounding.

Udgivelsesdato: 2008/1

Context Low levels of high- density lipoprotein ( HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear. Objective To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss- of- function mutations in ABCA1 cause increased risk of ischemic heart disease ( IHD). Design, Setting, and Participants Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study ( CCHS), a 31-year prospective general population study ( n= 9022; 28 heterozygotes); the Copenhagen General Population Study ( CGPS), a cross- sectional general population study ( n= 31 241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study ( CIHDS), a case- control study ( n= 16 623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007. Main Outcome Measures Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype. Results Heterozygotes vs noncarriers for 4 ABCA1 mutations ( P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/ dL ( interquartile range, 31- 50 mg/ dL) vs 58 mg/ dL ( interquartile range, 46- 73 mg/ dL), corresponding to a reduction in HDL cholesterol of 17 mg/ dL ( P <. 001). A 17- mg/ dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 ( 95% confidence interval [ CI], 1.57- 1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 ( 95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 ( 95% CI, 0.34- 1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 ( 95% CI, 0.32- 2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined

Udgivelsesdato: 2008-Feb, OBJECTIVE: We aim to assess the relationship between stress and risk of primary colorectal cancer in men and women. DESIGN: A prospective cohort study. SETTING: The Copenhagen City Heart Study, Denmark. SUBJECTS: A total of 6488 women and 5426 men were included in the study. The participants were asked about intensity and frequency of stress at baseline in 1981-1983 and were followed until the end of 2000 in the Danish Cancer Registry. Less than 0.1% was lost to follow-up. MAIN OUTCOME MEASURES: First time incidence of primary colorectal cancer. RESULTS: During follow-up 162 women and 166 men were diagnosed with colorectal cancer. Women with moderate and high stress intensity had a hazard ratio of 0.60 (95% CI: 0.37-0.98) and 0.52 (0.23-1.14) for colorectal cancer, respectively, compared to women with no stress. For colon cancer, a one-unit increase on a seven-point stress-score was associated with an 11% lower incidence of the disease (HR = 0.89, 95% CI: 0.81-0.99) amongst women. There was no consistent evidence of an association between stress and colorectal cancer in men. CONCLUSION: Perceived stress was associated with lower risk of particularly colon cancer in women, whilst there was no clear relationship between stress and colorectal cancer in men.

To examine whether physical activity (PA) is associated with changes in waist circumference (WC), and changes in WC given changes in body mass index (BMI). Longitudinal population-based study including 2026 men and 2782 women aged 21-81 years. Subjects were examined in 1991-1993 (baseline) and 2001-2003 (follow up), where height, weight and WC were measured. Information about overall PA in leisure-time (LTPA), walking, biking and sports activity was collected with self-administrated questionnaires at baseline. Outcomes were changes in WC and changes in WC given changes in BMI between baseline and follow up. The median increase in WC was 3.0 cm in men and 3.5 cm in women during follow-up, and with a considerable inter-individual variation. LTPA, walking and biking were not significantly associated with the outcomes. Inverse associations between sports activity and the outcomes were observed in both sexes, and these were significant in some analyses. Associations were not altered by adjustment for confounders or by exclusions of subjects with diseases and/or treatment by obesity-inducing medication. This study suggests that LTPA, walking and biking have no appreciable effects on changes in WC or changes in WC given changes in BMI, whereas sports activity may have small preventive effects Udgivelsesdato: 2008/12

Udgivelsesdato: 2008-Aug-15, PURPOSE: Results from longitudinal studies about the association between physical activity and chronic obstructive pulmonary disease (COPD) may have been biased because they did not properly adjust for time-dependent confounders. Marginal structural models (MSMs) have been proposed to address this type of confounding. We sought to assess the presence of time-dependent confounding in the association between physical activity and COPD development and course by comparing risk estimates between standard statistical methods and MSMs. METHODS: By using the population-based cohort Copenhagen City Heart Study, 6,568 subjects selected from the general population in 1976 were followed up until 2004 with three repeated examinations. RESULTS: Moderate to high compared with low physical activity was associated with a reduced risk of developing COPD both in the standard analysis (odds ratio [OR] 0.76, p = 0.007) and in the MSM analysis (OR 0.79, p = 0.025). In the subgroup with COPD (n = 2,226), high physical activity was associated with a reduced risk of COPD admissions during follow-up (standard, incidence rate ratio, 0.74; p = 0.096; MSM, 0.68, p = 0.044), and with a reduced risk of mortality (standard, hazard ratio 0.80, p = 0.001; MSM, 0.81, p = 0.008). CONCLUSION: These results support the previously reported associations between physical activity and reduced risk of COPD development, hospitalizations, and mortality, thereby suggesting they were not due to time-dependent confounding.

Udgivelsesdato: 2008/1

Context Low levels of high- density lipoprotein ( HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear. Objective To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss- of- function mutations in ABCA1 cause increased risk of ischemic heart disease ( IHD). Design, Setting, and Participants Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study ( CCHS), a 31-year prospective general population study ( n= 9022; 28 heterozygotes); the Copenhagen General Population Study ( CGPS), a cross- sectional general population study ( n= 31 241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study ( CIHDS), a case- control study ( n= 16 623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007. Main Outcome Measures Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype. Results Heterozygotes vs noncarriers for 4 ABCA1 mutations ( P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/ dL ( interquartile range, 31- 50 mg/ dL) vs 58 mg/ dL ( interquartile range, 46- 73 mg/ dL), corresponding to a reduction in HDL cholesterol of 17 mg/ dL ( P <. 001). A 17- mg/ dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 ( 95% confidence interval [ CI], 1.57- 1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 ( 95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 ( 95% CI, 0.34- 1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 ( 95% CI, 0.32- 2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined

Udgivelsesdato: 2008-Feb, OBJECTIVE: We aim to assess the relationship between stress and risk of primary colorectal cancer in men and women. DESIGN: A prospective cohort study. SETTING: The Copenhagen City Heart Study, Denmark. SUBJECTS: A total of 6488 women and 5426 men were included in the study. The participants were asked about intensity and frequency of stress at baseline in 1981-1983 and were followed until the end of 2000 in the Danish Cancer Registry. Less than 0.1% was lost to follow-up. MAIN OUTCOME MEASURES: First time incidence of primary colorectal cancer. RESULTS: During follow-up 162 women and 166 men were diagnosed with colorectal cancer. Women with moderate and high stress intensity had a hazard ratio of 0.60 (95% CI: 0.37-0.98) and 0.52 (0.23-1.14) for colorectal cancer, respectively, compared to women with no stress. For colon cancer, a one-unit increase on a seven-point stress-score was associated with an 11% lower incidence of the disease (HR = 0.89, 95% CI: 0.81-0.99) amongst women. There was no consistent evidence of an association between stress and colorectal cancer in men. CONCLUSION: Perceived stress was associated with lower risk of particularly colon cancer in women, whilst there was no clear relationship between stress and colorectal cancer in men.

OBJECTIVES: This study was designed to determine whether measurement of plasma pro-B-type natriuretic peptide (proBNP) could be used in discriminating between cardiac and pulmonary dyspnea in the general population. BACKGROUND: Natriuretic peptides are useful markers in ruling out acute cardiac dyspnea in the emergency department, but their diagnostic significance in evaluating chronic dyspnea in the general population is unknown. METHODS: Within the Copenhagen City Heart Study, a large, community-based population study, dyspnea was evaluated by spirometry, oxygen saturation, echocardiography, and plasma proBNP. RESULTS: Of 2,929 participants, 959 reported dyspnea. The plasma proBNP concentration was higher in the group with dyspnea (mean 17.8 pmol/l; 95% confidence interval [CI] 16.3 to 19.4 pmol/l) than in the group without (10.6 pmol/l; 95% CI 10.0 to 11.4 pmol/l; p < 0.001). In the group with dyspnea, left ventricular hypertrophy and/or systolic dysfunction was associated with a 2.6-fold increase in plasma proBNP concentration (p < 0.001), whereas pulmonary dysfunction was not associated with increased plasma proBNP (p = 0.66). Using multivariable regression analysis, a model to estimate the expected concentration of plasma proBNP based on age and gender was established for dyspneic subjects: an actual plasma proBNP concentration below half of the expected value ruled out left ventricular systolic and diastolic dysfunction (sensitivity 100%, 95% CI 100% to 100%; specificity 15%, 95% CI 12% to 17%). CONCLUSIONS: In the general population with dyspnea, plasma proBNP concentrations are increased in left ventricular dilatation, hypertrophy, systolic dysfunction, or diastolic dysfunction, but are unaffected by pulmonary dysfunction. Udgivelsesdato: Oct 23, OBJECTIVES: This study was designed to determine whether measurement of plasma pro-B-type natriuretic peptide (proBNP) could be used in discriminating between cardiac and pulmonary dyspnea in the general population. BACKGROUND: Natriuretic peptides are useful markers in ruling out acute cardiac dyspnea in the emergency department, but their diagnostic significance in evaluating chronic dyspnea in the general population is unknown. METHODS: Within the Copenhagen City Heart Study, a large, community-based population study, dyspnea was evaluated by spirometry, oxygen saturation, echocardiography, and plasma proBNP. RESULTS: Of 2,929 participants, 959 reported dyspnea. The plasma proBNP concentration was higher in the group with dyspnea (mean 17.8 pmol/l; 95% confidence interval [CI] 16.3 to 19.4 pmol/l) than in the group without (10.6 pmol/l; 95% CI 10.0 to 11.4 pmol/l; p < 0.001). In the group with dyspnea, left ventricular hypertrophy and/or systolic dysfunction was associated with a 2.6-fold increase in plasma proBNP concentration (p < 0.001), whereas pulmonary dysfunction was not associated with increased plasma proBNP (p = 0.66). Using multivariable regression analysis, a model to estimate the expected concentration of plasma proBNP based on age and gender was established for dyspneic subjects: an actual plasma proBNP concentration below half of the expected value ruled out left ventricular systolic and diastolic dysfunction (sensitivity 100%, 95% CI 100% to 100%; specificity 15%, 95% CI 12% to 17%). CONCLUSIONS: In the general population with dyspnea, plasma proBNP concentrations are increased in left ventricular dilatation, hypertrophy, systolic dysfunction, or diastolic dysfunction, but are unaffected by pulmonary dysfunction.

RATIONALE: We have previously reported that regular physical activity reduces risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesized that higher levels of regular physical activity could reduce the risk of COPD by modifying smoking-related lung function decline. OBJECTIVE: To estimate the longitudinal association between regular physical activity and FEV(1) and FVC decline and COPD risk. METHODS: A population-based sample (n = 6,790) was recruited and assessed with respect to physical activity, smoking, lung function, and other covariates, in Copenhagen in 1981-1983, and followed until 1991-1994. Mean level of physical activity between baseline and follow-up was classified into "low," "moderate," and "high." FEV(1) and FVC decline rates were expressed as milliliters per year. COPD was defined as FEV(1)/FVC < or = 70%. Adjusted associations between physical activity and FEV(1) and FVC decline, and COPD incidence, were obtained using linear and logistic regression, respectively. RESULTS: Active smokers with moderate and high physical activity had a reduced FEV(1) and FVC decline compared with those with low physical activity (relative change of +2.6 and +4.8 ml/yr of FEV(1), P-for-trend = 0.006, and +2.6 and +7.7 ml/yr of FVC, P-for-trend < 0.0001, for the moderate and high physical activity group, respectively), after adjusting for all potential confounders and risk factors of lung function decline. Active smokers with moderate to high physical activity had a reduced risk of developing COPD as compared with the low physical activity group (odds ratio, 0.77; p = 0.027). CONCLUSIONS: This prospective study shows that moderate to high levels of regular physical activity are associated with reduced lung function decline and COPD risk among smokers. Udgivelsesdato: Mar 1

OBJECTIVES: This study was designed to determine whether measurement of plasma pro-B-type natriuretic peptide (proBNP) could be used in discriminating between cardiac and pulmonary dyspnea in the general population. BACKGROUND: Natriuretic peptides are useful markers in ruling out acute cardiac dyspnea in the emergency department, but their diagnostic significance in evaluating chronic dyspnea in the general population is unknown. METHODS: Within the Copenhagen City Heart Study, a large, community-based population study, dyspnea was evaluated by spirometry, oxygen saturation, echocardiography, and plasma proBNP. RESULTS: Of 2,929 participants, 959 reported dyspnea. The plasma proBNP concentration was higher in the group with dyspnea (mean 17.8 pmol/l; 95% confidence interval [CI] 16.3 to 19.4 pmol/l) than in the group without (10.6 pmol/l; 95% CI 10.0 to 11.4 pmol/l; p < 0.001). In the group with dyspnea, left ventricular hypertrophy and/or systolic dysfunction was associated with a 2.6-fold increase in plasma proBNP concentration (p < 0.001), whereas pulmonary dysfunction was not associated with increased plasma proBNP (p = 0.66). Using multivariable regression analysis, a model to estimate the expected concentration of plasma proBNP based on age and gender was established for dyspneic subjects: an actual plasma proBNP concentration below half of the expected value ruled out left ventricular systolic and diastolic dysfunction (sensitivity 100%, 95% CI 100% to 100%; specificity 15%, 95% CI 12% to 17%). CONCLUSIONS: In the general population with dyspnea, plasma proBNP concentrations are increased in left ventricular dilatation, hypertrophy, systolic dysfunction, or diastolic dysfunction, but are unaffected by pulmonary dysfunction. Udgivelsesdato: Oct 23, OBJECTIVES: This study was designed to determine whether measurement of plasma pro-B-type natriuretic peptide (proBNP) could be used in discriminating between cardiac and pulmonary dyspnea in the general population. BACKGROUND: Natriuretic peptides are useful markers in ruling out acute cardiac dyspnea in the emergency department, but their diagnostic significance in evaluating chronic dyspnea in the general population is unknown. METHODS: Within the Copenhagen City Heart Study, a large, community-based population study, dyspnea was evaluated by spirometry, oxygen saturation, echocardiography, and plasma proBNP. RESULTS: Of 2,929 participants, 959 reported dyspnea. The plasma proBNP concentration was higher in the group with dyspnea (mean 17.8 pmol/l; 95% confidence interval [CI] 16.3 to 19.4 pmol/l) than in the group without (10.6 pmol/l; 95% CI 10.0 to 11.4 pmol/l; p < 0.001). In the group with dyspnea, left ventricular hypertrophy and/or systolic dysfunction was associated with a 2.6-fold increase in plasma proBNP concentration (p < 0.001), whereas pulmonary dysfunction was not associated with increased plasma proBNP (p = 0.66). Using multivariable regression analysis, a model to estimate the expected concentration of plasma proBNP based on age and gender was established for dyspneic subjects: an actual plasma proBNP concentration below half of the expected value ruled out left ventricular systolic and diastolic dysfunction (sensitivity 100%, 95% CI 100% to 100%; specificity 15%, 95% CI 12% to 17%). CONCLUSIONS: In the general population with dyspnea, plasma proBNP concentrations are increased in left ventricular dilatation, hypertrophy, systolic dysfunction, or diastolic dysfunction, but are unaffected by pulmonary dysfunction.

RATIONALE: We have previously reported that regular physical activity reduces risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesized that higher levels of regular physical activity could reduce the risk of COPD by modifying smoking-related lung function decline. OBJECTIVE: To estimate the longitudinal association between regular physical activity and FEV(1) and FVC decline and COPD risk. METHODS: A population-based sample (n = 6,790) was recruited and assessed with respect to physical activity, smoking, lung function, and other covariates, in Copenhagen in 1981-1983, and followed until 1991-1994. Mean level of physical activity between baseline and follow-up was classified into "low," "moderate," and "high." FEV(1) and FVC decline rates were expressed as milliliters per year. COPD was defined as FEV(1)/FVC < or = 70%. Adjusted associations between physical activity and FEV(1) and FVC decline, and COPD incidence, were obtained using linear and logistic regression, respectively. RESULTS: Active smokers with moderate and high physical activity had a reduced FEV(1) and FVC decline compared with those with low physical activity (relative change of +2.6 and +4.8 ml/yr of FEV(1), P-for-trend = 0.006, and +2.6 and +7.7 ml/yr of FVC, P-for-trend < 0.0001, for the moderate and high physical activity group, respectively), after adjusting for all potential confounders and risk factors of lung function decline. Active smokers with moderate to high physical activity had a reduced risk of developing COPD as compared with the low physical activity group (odds ratio, 0.77; p = 0.027). CONCLUSIONS: This prospective study shows that moderate to high levels of regular physical activity are associated with reduced lung function decline and COPD risk among smokers. Udgivelsesdato: Mar 1

BACKGROUND: Information about the influence of regular physical activity on the course of chronic obstructive pulmonary disease (COPD) is scarce. A study was undertaken to examine the association between regular physical activity and both hospital admissions for COPD and all-cause and specific mortality in COPD subjects. METHODS: From a population-based sample recruited in Copenhagen in 1981-3 and 1991-4, 2386 individuals with COPD (according to lung function tests) were identified and followed until 2000. Self-reported regular physical activity at baseline was classified into four categories (very low, low, moderate, and high). Dates and causes of hospital admissions and mortality were obtained from Danish registers. Adjusted associations between physical activity and hospital admissions for COPD and mortality were obtained using negative binomial and Cox regression models, respectively. RESULTS: After adjustment for relevant confounders, subjects reporting low, moderate or high physical activity had a lower risk of hospital admission for COPD during the follow up period than those who reported very low physical activity (incidence rate ratio 0.72, 95% confidence interval (CI) 0.53 to 0.97). Low, moderate and high levels of regular physical activity were associated with an adjusted lower risk of all-cause mortality (hazard ratio (HR) 0.76, 95% CI 0.65 to 0.90) and respiratory mortality (HR 0.70, 95% CI 0.48 to 1.02). No effect modification was found for sex, age group, COPD severity, or a background of ischaemic heart disease. CONCLUSIONS: Subjects with COPD who perform some level of regular physical activity have a lower risk of both COPD admissions and mortality. The recommendation that COPD patients be encouraged to maintain or increase their levels of regular physical activity should be considered in future COPD guidelines, since it is likely to result in a relevant public health benefit.

BACKGROUND: Information about the influence of regular physical activity on the course of chronic obstructive pulmonary disease (COPD) is scarce. A study was undertaken to examine the association between regular physical activity and both hospital admissions for COPD and all-cause and specific mortality in COPD subjects. METHODS: From a population-based sample recruited in Copenhagen in 1981-3 and 1991-4, 2386 individuals with COPD (according to lung function tests) were identified and followed until 2000. Self-reported regular physical activity at baseline was classified into four categories (very low, low, moderate, and high). Dates and causes of hospital admissions and mortality were obtained from Danish registers. Adjusted associations between physical activity and hospital admissions for COPD and mortality were obtained using negative binomial and Cox regression models, respectively. RESULTS: After adjustment for relevant confounders, subjects reporting low, moderate or high physical activity had a lower risk of hospital admission for COPD during the follow up period than those who reported very low physical activity (incidence rate ratio 0.72, 95% confidence interval (CI) 0.53 to 0.97). Low, moderate and high levels of regular physical activity were associated with an adjusted lower risk of all-cause mortality (hazard ratio (HR) 0.76, 95% CI 0.65 to 0.90) and respiratory mortality (HR 0.70, 95% CI 0.48 to 1.02). No effect modification was found for sex, age group, COPD severity, or a background of ischaemic heart disease. CONCLUSIONS: Subjects with COPD who perform some level of regular physical activity have a lower risk of both COPD admissions and mortality. The recommendation that COPD patients be encouraged to maintain or increase their levels of regular physical activity should be considered in future COPD guidelines, since it is likely to result in a relevant public health benefit.

BACKGROUND: Information about the influence of regular physical activity on the course of chronic obstructive pulmonary disease (COPD) is scarce. A study was undertaken to examine the association between regular physical activity and both hospital admissions for COPD and all-cause and specific mortality in COPD subjects. METHODS: From a population-based sample recruited in Copenhagen in 1981-3 and 1991-4, 2386 individuals with COPD (according to lung function tests) were identified and followed until 2000. Self-reported regular physical activity at baseline was classified into four categories (very low, low, moderate, and high). Dates and causes of hospital admissions and mortality were obtained from Danish registers. Adjusted associations between physical activity and hospital admissions for COPD and mortality were obtained using negative binomial and Cox regression models, respectively. RESULTS: After adjustment for relevant confounders, subjects reporting low, moderate or high physical activity had a lower risk of hospital admission for COPD during the follow up period than those who reported very low physical activity (incidence rate ratio 0.72, 95% confidence interval (CI) 0.53 to 0.97). Low, moderate and high levels of regular physical activity were associated with an adjusted lower risk of all-cause mortality (hazard ratio (HR) 0.76, 95% CI 0.65 to 0.90) and respiratory mortality (HR 0.70, 95% CI 0.48 to 1.02). No effect modification was found for sex, age group, COPD severity, or a background of ischaemic heart disease. CONCLUSIONS: Subjects with COPD who perform some level of regular physical activity have a lower risk of both COPD admissions and mortality. The recommendation that COPD patients be encouraged to maintain or increase their levels of regular physical activity should be considered in future COPD guidelines, since it is likely to result in a relevant public health benefit.

Udgivelsesdato: 2005-null, BACKGROUND: Psychological stress and alcohol are both suggested as risk factors for stroke. Further, there appears to be a close relation between stress and alcohol consumption. Several experimental studies have found alcohol consumption to reduce the immediate effects of stress in a laboratory setting. We aimed to examine whether the association between alcohol and stroke depends on level of self-reported stress in a large prospective cohort. METHODS: The 5,373 men and 6,723 women participating in the second examination of the Copenhagen City Heart Study in 1981-1983 were asked at baseline about their self-reported level of stress and their weekly alcohol consumption. The participants were followed-up until 31st of December 1997 during which 880 first ever stroke events occurred. Data were analysed by means of Cox regression modelling. RESULTS: At a high stress level, weekly total consumption of 1-14 units of alcohol compared with no consumption seemed associated with a lower risk of stroke (adjusted RR: 0.57, 95% CI: 0.31-1.07). At lower stress levels, no clear associations were observed. Regarding subtypes, self-reported stress appeared only to modify the association between alcohol intake and ischaemic stroke events. Regarding specific types of alcoholic beverages, self-reported stress only modified the associations for intake of beer and wine. CONCLUSIONS: This study indicates that the apparent lower risk of stroke associated with moderate alcohol consumption is confined to a group of highly stressed persons. It is suggested that alcohol consumption may play a role in reducing the risk of stroke by modifying the physiological or psychological stress response.

Udgivelsesdato: 2005-null, BACKGROUND: Psychological stress and alcohol are both suggested as risk factors for stroke. Further, there appears to be a close relation between stress and alcohol consumption. Several experimental studies have found alcohol consumption to reduce the immediate effects of stress in a laboratory setting. We aimed to examine whether the association between alcohol and stroke depends on level of self-reported stress in a large prospective cohort. METHODS: The 5,373 men and 6,723 women participating in the second examination of the Copenhagen City Heart Study in 1981-1983 were asked at baseline about their self-reported level of stress and their weekly alcohol consumption. The participants were followed-up until 31st of December 1997 during which 880 first ever stroke events occurred. Data were analysed by means of Cox regression modelling. RESULTS: At a high stress level, weekly total consumption of 1-14 units of alcohol compared with no consumption seemed associated with a lower risk of stroke (adjusted RR: 0.57, 95% CI: 0.31-1.07). At lower stress levels, no clear associations were observed. Regarding subtypes, self-reported stress appeared only to modify the association between alcohol intake and ischaemic stroke events. Regarding specific types of alcoholic beverages, self-reported stress only modified the associations for intake of beer and wine. CONCLUSIONS: This study indicates that the apparent lower risk of stroke associated with moderate alcohol consumption is confined to a group of highly stressed persons. It is suggested that alcohol consumption may play a role in reducing the risk of stroke by modifying the physiological or psychological stress response.

Udgivelsesdato: 2004-Feb, OBJECTIVES: To assess the impact of socio-economic status on the relationship between type of alcohol and all-cause mortality. DESIGN: A prospective population study. SETTING: The Copenhagen City Heart Study, Denmark. SUBJECTS: A total of 14,223 men and women participated in the first examination of The Copenhagen City Heart Study in 1976-1978. The participants were followed up until 18th of September 2001 during which 7208 persons died. The effect of beer, wine and spirits on mortality was stratified according to levels of education, income and cohabitation, and the association was examined after controlling for intake of the other types of alcohol, and for sex, smoking, physical activity and body mass index. MAIN OUTCOME MEASURES: Number and time of death from all causes. RESULTS: Consumers of wine were better educated and wealthier compared with beer and spirits drinkers. The association between type of beverage and mortality was noticed to differ according to socio-economic level, especially where the apparent protective effect of wine consumption tended to be strongest in the lower income and educational groups. CONCLUSIONS: This study finds the specific effects of beer, wine or spirits to moderately diverge in the socio-economic groups. Future studies addressing the association between the type of beverage and mortality may need to more thoroughly take socio-economic factors into account.

There is a demand and need for healthy solid dietary fats. However, synthetic fats can be tailored to contain specific physiologic properties. Our goal was to design dietary solid test fats that would be both beneficial to the atherogenic lipid profile and stable against lipid peroxidation. Sixteen men (age 35-75 y) substituted 80 g of their normal dietary fat intake with test fat for two periods of 21 d each in a double-blind, randomized, crossover study. Although solid, both test fats were low in cholesterol-raising SFA. Test fat "F" contained 5 g/100 g long chain (n-3) fatty acids matched by oleic acid in test fat "O." Plasma total triacylglycerol (TAG), VLDL TAG, cholesterol in VLDL, and intermediate density lipoproteins (IDL) were lower (P <0.05), whereas apolipoprotein (apo) B of the large LDL-2 (d = 1031-1042 g/L) subclass, and cholesterol of HDL2b subclass, were higher after intake of F than O fat (P <0.05). There was no difference in the effect on in vivo oxidation measured as the ratio of plasma isoprostanes F-2 to arachidonic acid and urinary isoprostanes, whereas the vitamin E activity/plasma total lipids ratio was higher after intake of F than O (P = 0.008). In conclusion, a solid dietary fat containing (n-3) PUFA decreased plasma TAG, VLDL, and IDL cholesterol, and redistributed lipoprotein subclasses in LDL and HDL, with a higher concentration of the larger and less atherogenic subfractions. These changes took place without an increase in oxidative stress as measured by in vivo markers.

Udgivelsesdato: 2004-Feb, OBJECTIVES: To assess the impact of socio-economic status on the relationship between type of alcohol and all-cause mortality. DESIGN: A prospective population study. SETTING: The Copenhagen City Heart Study, Denmark. SUBJECTS: A total of 14,223 men and women participated in the first examination of The Copenhagen City Heart Study in 1976-1978. The participants were followed up until 18th of September 2001 during which 7208 persons died. The effect of beer, wine and spirits on mortality was stratified according to levels of education, income and cohabitation, and the association was examined after controlling for intake of the other types of alcohol, and for sex, smoking, physical activity and body mass index. MAIN OUTCOME MEASURES: Number and time of death from all causes. RESULTS: Consumers of wine were better educated and wealthier compared with beer and spirits drinkers. The association between type of beverage and mortality was noticed to differ according to socio-economic level, especially where the apparent protective effect of wine consumption tended to be strongest in the lower income and educational groups. CONCLUSIONS: This study finds the specific effects of beer, wine or spirits to moderately diverge in the socio-economic groups. Future studies addressing the association between the type of beverage and mortality may need to more thoroughly take socio-economic factors into account.