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1.  Coronary microvascular function, insulin sensitivity and body composition in predicting exercise capacity in overweight patients with coronary artery disease 
Coronary artery disease (CAD) has a negative impact on exercise capacity. The aim of this study was to determine how coronary microvascular function, glucose metabolism and body composition contribute to exercise capacity in overweight patients with CAD and without diabetes.
Sixty-five non-diabetic, overweight patients with stable CAD, BMI 28–40 kg/m2 and left ventricular ejection fraction (LVEF) above 35 % were recruited. A 3-hour oral glucose tolerance test was used to evaluate glucose metabolism. Peak aerobic exercise capacity (VO2peak) was assessed by a cardiopulmonary exercise test. Body composition was determined by whole body dual-energy X-ray absorptiometry scan and magnetic resonance imaging. Coronary flow reserve (CFR) assessed by transthoracic Doppler echocardiography was used as a measure of microvascular function.
Median BMI was 31.3 and 72 % had impaired glucose tolerance or impaired fasting glucose. VO2peak adjusted for fat free mass was correlated with CFR (r = 0.41, p = 0.0007), LVEF (r = 0.33, p = 0.008) and left ventricular end-diastolic volume (EDV) (r = 0.32, p = 0.01) while it was only weakly linked to measures of glucose metabolism and body composition. CFR, EDV and LVEF remained independent predictors of VO2peak in multivariable regression analysis.
The study established CFR, EDV and LVEF as independent predictors of VO2peak in overweight CAD patients with no or only mild functional symptoms and a LVEF > 35 %. Glucose metabolism and body composition had minor impact on VO2peak. The findings suggest that central hemodynamic factors are important in limiting exercise capacity in overweight non-diabetic CAD patients.
PMCID: PMC4661957  PMID: 26613591
Coronary flow reserve; Coronary artery disease; Exercise capacity; Insulin sensitivity; Body composition
2.  The Impact of Comorbid Depression on Educational Inequality in Survival after Acute Coronary Syndrome in a Cohort of 83 062 Patients and a Matched Reference Population 
PLoS ONE  2015;10(10):e0141598.
Patients with low socioeconomic position have higher rates of mortality after diagnosis of acute coronary syndrome (ACS), but little is known about the mechanisms behind this social inequality. The aim of the present study was to examine whether any educational inequality in survival after ACS was influenced by comorbid conditions including depression.
From 2001 to 2009 all first-time ACS patients were identified in the Danish National Patient Registry. This cohort of 83 062 ACS patients and a matched reference population were followed for incident depression and mortality until December 2012 by linkage to person, patients and prescription registries. Educational status was defined at study entry and the impact of potential confounders and mediators (age, gender, cohabitation status, somatic comorbidity and depression) on the relation between education and mortality were identified by drawing a directed acyclic graph and analysed using multiple Cox regression analyses.
During follow-up, 29 583(35.6%) of ACS patients and 19 105(22.9%) of the reference population died. Cox regression analyses showed an increased mortality in the lowest educated compared to those with high education in both ACS patients and the reference population. Adjustment for previous and incident depression or other covariables only attenuated the relations slightly. This pattern of associations was seen for mortality after 30 days, 1 year and during total follow-up.
In this study the relative excess mortality rate in lower educated ACS patients was comparable with the excess risk associated with low education in the background population. This educational inequality in survival remained after adjustment for somatic comorbidity and depression.
PMCID: PMC4626047  PMID: 26513652
3.  Accumulation of Major Life Events in Childhood and Adult Life and Risk of Type 2 Diabetes Mellitus 
PLoS ONE  2015;10(9):e0138654.
The aim of the study was to estimate the effect of the accumulation of major life events (MLE) in childhood and adulthood, in both the private and working domains, on risk of type 2 diabetes mellitus (T2DM). Furthermore, we aimed to test the possible interaction between childhood and adult MLE and to investigate modification of these associations by educational attainment.
The study was based on 4,761 participants from the Copenhagen City Heart Study free of diabetes at baseline and followed for 10 years. MLE were categorized as 0, 1, 2, 3 or more events. Multivariate logistic regression models adjusted for age, sex, education and family history of diabetes were used to estimate the association between MLE and T2DM.
In childhood, experiencing 3 or more MLE was associated with a 69% higher risk of developing T2DM (Odds Ratio (OR) 1.69; 95% Confidence Interval (CI) 1.60, 3.27). The accumulation of MLE in adult private (p-trend = 0.016) and work life (p-trend = 0.049) was associated with risk of T2DM in a dose response manner. There was no evidence that experiencing MLE in both childhood and adult life was more strongly associated with T2DM than experiencing events at only one time point. There was some evidence that being simultaneously exposed to childhood MLE and short education (OR 2.28; 95% C.I. 1.45, 3.59) and work MLE and short education (OR 2.86; 95% C.I. 1.62, 5.03) was associated with higher risk of T2DM, as the joint effects were greater than the sum of their individual effects.
Findings from this study suggest that the accumulation of MLE in childhood, private adult life and work life, respectively, are risk factors for developing T2DM.
PMCID: PMC4578856  PMID: 26394040
4.  Effect of the glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes – a randomized, single-blinded, cross-over pilot study 
Impaired coronary microcirculation is associated with a poor prognosis in patients with type 2 diabetes. In the absence of stenosis of major coronary arteries, coronary flow reserve (CFR) reflects coronary microcirculation. Studies have shown beneficial effects of glucagon-like peptide-1 (GLP-1) on the cardiovascular system. The aim of the study was to explore the short-term effect of GLP-1 treatment on coronary microcirculation estimated by CFR in patients with type 2 diabetes.
Patients with type 2 diabetes and no history of coronary artery disease were treated with either the GLP-1 analogue liraglutide or received no treatment for 10 weeks, in a randomized, single-blinded, cross-over setup with a 2 weeks wash-out period. The effect of liraglutide on coronary microcirculation was evaluated using non-invasive trans-thoracic Doppler-flow echocardiography during dipyridamole induced stress. Peripheral microvascular endothelial function was assessed by Endo-PAT2000®. Interventions were compared by two-sample t-test after ensuring no carry over effect.
A total of 24 patients were included. Twenty patients completed the study (15 male; mean age 57 ± 9; mean BMI 33.1 ± 4.4, mean baseline CFR 2.35 ± 0.45). There was a small increase in CFR following liraglutide treatment (change 0.18, CI95% [-0.01; 0.36], p = 0.06) but no difference in effect in comparison with no treatment (difference between treatment allocation 0.16, CI95% [-0.08; 0.40], p = 0.18). Liraglutide significantly reduced glycated haemoglobin (HbA1c) (-10.1 mmol/mol CI95% [-13.9; -6.4], p = 0.01), systolic blood pressure (-10 mmHg CI95% [-17; -3], p = 0.01) and weight (-1.9 kg CI95% [-3.6; -0.2], p = 0.03) compared to no treatment. There was no effect on peripheral microvascular endothelial function after either intervention.
In this short-term treatment study, 10 weeks of liraglutide treatment had no significant effect on neither coronary nor peripheral microvascular function in patients with type 2 diabetes. Further long-term studies, preferably in patients with more impaired microvascular function and using a higher dosage of GLP-1 analogues, are needed to confirm these findings.
Trial registration NCT01931982.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0206-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4407869  PMID: 25896352
Coronary microcirculation; Diabetes Mellitus; Type 2 diabetes; Glucagon-like peptide-1; Coronary flow reserve; Microvascular dysfunction; Endothelial function; Liraglutide; Intervention study; Cross-over design
5.  Self‐Reported Cardiorespiratory Fitness: Prediction and Classification of Risk of Cardiovascular Disease Mortality and Longevity—A Prospective Investigation in the Copenhagen City Heart Study 
The predictive value and improved risk classification of self‐reported cardiorespiratory fitness (SRCF), when added to traditional risk factors on cardiovascular disease (CVD) and longevity, are unknown.
Methods and Results
A total of 3843 males and 5093 females from the Copenhagen City Heart Study without CVD in 1991–1994 were analyzed using multivariate Cox hazards regression to assess the predictive value and survival benefit for CVD and all‐cause mortality from SRCF. The category‐free net reclassification improvement from SRCF was calculated at 15‐year follow‐up on CVD and all‐cause mortality. Overall, 1693 individuals died from CVD. In the fully adjusted Cox model, those reporting the same (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.04 to 1.32) and lower (HR, 1.91; 95% CI, 1.62 to 2.24) SRCF than peers had an increased risk of CVD mortality, compared with individuals with higher SRCF. Compared with individuals with higher SRCF, those with the same and lower SRCF had 1.8 (95% CI, 1.0 to 2.5) and 5.1 (95% CI, 4.1 to 6.2) years lower life expectancy, respectively. Individuals with lower SRCF had a significantly increased risk of CVD mortality, compared with individuals with higher SRCF, within each strata of leisure time physical activity and self‐rated health, and SRCF significantly predicted CVD mortality independently of self‐rated health and walking pace. A net reclassification improvement of 30.5% (95% CI, 22.1% to 38.9%) for CVD mortality was found when adding SRCF to traditional risk factors. Comparable findings were found for all‐cause mortality.
SRCF has independent predictive value, is related to a considerable survival benefit, and improves risk classification when added to traditional risk factors of CVD and all‐cause mortality. SRCF might prove useful in improved risk stratification in primary prevention.
PMCID: PMC4330073  PMID: 25628408
cardiovascular mortality; net reclassification improvement; self‐reported fitness
6.  Psychosocial risk factors, pre-motor symptoms, and first-time hospitalization with Parkinson’s Disease: a prospective cohort study 
Experimental studies support a link between stress and development of parkinsonian symptoms, but prospective population studies are lacking. The aim of the current study is to determine the effects of several psychosocial factors on risk of Parkinson’s disease (PD) as well as identify potential pre-motor symptoms for PD in a large prospective cohort study.
In 1991–1993, a total of 9955 women and men free of PD from the Copenhagen City Heart Study, were asked about major life events, economic hardship, social network, impaired sleep, and vital exhaustion. The participants were followed for first-time hospitalization with PD in nationwide registers until 2011.
Vital exhaustion was associated with a higher risk of PD hospitalization in an exposure dependent manner (ptrend=0.001), with high vs. low vital exhaustion being associated with a hazard ratio of 2.50 (95% CI: 1.28–4.89). A slightly higher risk of PD hospitalization (HR=1.49; 95% CI: 0.87–2.56) was suggested in participants with impaired sleep at baseline. No more than weak associations were observed for economic hardship, major life events or inadequate social network in the current study.
Overall, the hypothesis that psychosocial risk factors affect the risk of PD is not supported. The results, however, suggests that vital exhaustion may be a pre-motor marker of the neuro-degenerative process eventually leading to motor-symptoms and clinical PD. Vital exhaustion may be useful for screening aimed at early detection and when considering disease-modifying therapies in people at high risk of clinical PD.
PMCID: PMC3664243  PMID: 23433314
Burnout; family relations; life change events; prospective studies; Parkinson’s disease; sleep disorders; social support; stress; psychological
7.  Burden of Hospital Admission and Repeat Angiography in Angina Pectoris Patients with and without Coronary Artery Disease: A Registry-Based Cohort Study 
PLoS ONE  2014;9(4):e93170.
To evaluate risk of hospitalization due to cardiovascular disease (CVD) and repeat coronary angiography (CAG) in stable angina pectoris (SAP) with no obstructive coronary artery disease (CAD) versus obstructive CAD, and asymptomatic reference individuals.
Methods and Results
We followed 11,223 patients with no prior CVD having a first-time CAG in 1998–2009 due to SAP symptoms and 5,695 asymptomatic reference individuals from the Copenhagen City Heart Study through registry linkage for 7.8 years (median). In recurrent event survival analysis, patients with SAP had 3–4-fold higher risk of hospitalization for CVD irrespective of CAG findings and cardiovascular comorbidity. Multivariable adjusted hazard ratios(95%CI) for patients with angiographically normal coronary arteries was 3.0(2.5–3.5), for angiographically diffuse non-obstructive CAD 3.9(3.3–4.6) and for 1–3-vessel disease 3.6–4.1(range)(all P<0.001). Mean accumulated hospitalization time was 3.5(3.0–4.0)(days/10 years follow-up) in reference individuals and 4.5(3.8–5.2)/7.0(5.4–8.6)/6.7(5.2–8.1)/6.1(5.2–7.4)/8.6(6.6–10.7) in patients with angiographically normal coronary arteries/angiographically diffuse non-obstructive CAD/1-, 2-, and 3-vessel disease, respectively (all P<0.05, age-adjusted). SAP symptoms predicted repeat CAG with multivariable adjusted hazard ratios for patients with angiographically normal coronary arteries being 2.3(1.9–2.9), for angiographically diffuse non-obstructive CAD 5.5(4.4–6.8) and for obstructive CAD 6.6–9.4(range)(all P<0.001).
Patients with SAP symptoms and angiographically normal coronary arteries or angiographically diffuse non-obstructive CAD suffer from considerably greater CVD burdens in terms of hospitalization for CVD and repeat CAG compared with asymptomatic reference individuals even after adjustment for cardiac risk factors and exclusion of cardiovascular comorbidity as cause. Contrary to common perception, excluding obstructive CAD by CAG in such patients does not ensure a benign cardiovascular prognosis.
PMCID: PMC3976412  PMID: 24705387
8.  Speed and Duration of Walking and Other Leisure Time Physical Activity and the Risk of Heart Failure: A Prospective Cohort Study from the Copenhagen City Heart Study 
PLoS ONE  2014;9(3):e89909.
Physical activity (PA) confers some protection against development of heart failure (HF) but little is known of the role of intensity and duration of exercise.
Methods and Results
In a prospective cohort study of men and women free of previous MI, stroke or HF with one or more examinations in 1976–2003, we studied the association between updated self-assessed leisure-time PA, speed and duration of walking and subsequent hospitalization or death from HF. Light and moderate/high level of leisure-time PA and brisk walking were associated with reduced risk of HF in both genders whereas no consistent association with duration of walking was seen. In 18,209 subjects age 20–80 with 1580 cases of HF, using the lowest activity level as reference, the confounder-adjusted hazard ratios (HR) for light and moderate/high leisure-time physical activity were 0.75 (0.66–0.86) and 0.80 (0.69–0.93), respectively. In 9,937 subjects with information on walking available and 542 cases of HF, moderate and high walking speed were associated with adjusted HRs of 0.53 (0.43–0.66) and 0.30 (0.21–0.44), respectively, and daily walking of ½–1 hrs, 1–2 and >2 hrs with HR of 0.80 (0.61–1.06), 0.82 (0.62–1.06), and 0.96 (0.73–1.27), respectively. Results were similar for both genders and remained robust after exclusion of HF related to coronary heart disease and after a series of sensitivity analyses.
Speed rather than duration of walking was associated with reduced risk of HF. Walking is the most wide-spread PA and public health measures to curb the increase in HF may benefit from this information.
PMCID: PMC3951187  PMID: 24621514
9.  Impact of Gender, Co-Morbidity and Social Factors on Labour Market Affiliation after First Admission for Acute Coronary Syndrome. A Cohort Study of Danish Patients 2001–2009 
PLoS ONE  2014;9(1):e86758.
Over the last decades survival after acute coronary syndrome (ACS) has improved, leading to an increasing number of patients returning to work, but little is known about factors that may influence their labour market affiliation. This study examines the impact of gender, co-morbidity and socio-economic position on subsequent labour market affiliation and transition between various social services in patients admitted for the first time with ACS.
From 2001 to 2009 all first-time hospitalisations for ACS were identified in the Danish National Patient Registry (n = 79,714). For this population, data on sick leave, unemployment and retirement were obtained from an administrative register covering all citizens. The 21,926 patients, aged 18–63 years, who had survived 30 days and were part of the workforce at the time of diagnosis were included in the analyses where subsequent transition between the above labour market states was examined using Kaplan-Meier estimates and Cox proportional hazards models.
A total of 37% of patients were in work 30 days after first ACS diagnosis, while 55% were on sick leave and 8% were unemployed. Seventy-nine per cent returned to work once during follow-up. This probability was highest among males, those below 50 years, living with a partner, the highest educated, with higher occupations, having specific events (NSTEMI, and percutaneous coronary intervention) and with no co-morbidity. During five years follow-up, 43% retired due to disability or voluntary early pension. Female gender, low education, basic occupation, co-morbidity and having a severer event (invasive procedures) and receiving sickness benefits or being unemployed 30 days after admission were associated with increased probability of early retirement.
About half of patients with first-time ACS stay in or return to work shortly after the event. Women, the socially disadvantaged, those with presumed severer events and co-morbidity have lower rates of return.
PMCID: PMC3907569  PMID: 24497976
10.  Trends in time to invasive examination and treatment from 2001 to 2009 in patients admitted first time with non-ST elevation myocardial infarction or unstable angina in Denmark 
BMJ Open  2014;4(1):e004052.
To investigate trends in time to invasive examination and treatment for patient with first time diagnosis of non-ST elevation myocardial infarction (NSTEMI) and unstable angina during the period from 2001 to 2009 in Denmark.
From 1 January 2001 to 31 December 2009 all first time hospitalisations with NSTEMI and unstable angina were identified in the National Patient Registry (n=65 909). Time from admission to initiation of coronary angiography (CAG), percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) was calculated. We described the development in invasive examination and treatment probability (CAG, PCI and CABG at 3, 7, 10, 30 and 60 days) for the years 2001–2009, taking the competing risk of death into account using Aalen–Johansen estimators and a Fine-Gray model.
Nationwide Danish cohort.
The proportion of patients receiving a CAG and PCI increased substantially over time while the proportion receiving a CABG decreased for both NSTEMI and unstable angina. For both NSTEMI and unstable angina, a significant increase in invasive examination and treatment probability at 3 days for CAG and PCI were seen especially from 2007 through to 2009. For NSTEMI, the CAG examination probability at 3 days leaped from 20% in 2007 to 32% in 2008 and 39% in 2009, and for PCI the same was true with a leap in treatment probability from 19% to 28% from 2008 to 2009.
In Denmark the use of CAG and PCI in treatment of NSTEMI and unstable angina has increased from 2001 to 2009, while the use of CABG has decreased. During the same period, there was a marked increase in invasive examination and treatment probability at 3 days, that is, more patients were treated faster which is in line with the political aim of reducing time to treatment.
PMCID: PMC3902505  PMID: 24413349
11.  Copenhagen study of overweight patients with coronary artery disease undergoing low energy diet or interval training: the randomized CUT-IT trial protocol 
Coronary artery disease (CAD) is accountable for more than 7 million deaths each year according to the World Health Organization (WHO). In a European population 80% of patients diagnosed with CAD are overweight and 31% are obese. Physical inactivity and overweight are major risk factors in CAD, thus central strategies in secondary prevention are increased physical activity and weight loss.
In a randomized controlled trial 70 participants with stable CAD, age 45–75, body mass index 28–40 kg/m2 and no diabetes are randomized (1:1) to 12 weeks of intensive exercise or weight loss both succeeded by a 40-week follow-up. The exercise protocol consist of supervised aerobic interval training (AIT) at 85-90% of VO2peak 3 times weekly for 12 weeks followed by supervised AIT twice weekly for 40 weeks. In the weight loss arm dieticians instruct the participants in a low energy diet (800–1000 kcal/day) for 12 weeks, followed by 40 weeks of weight maintenance combined with supervised AIT twice weekly. The primary endpoint of the study is change in coronary flow reserve after the first 12 weeks’ intervention. Secondary endpoints include cardiovascular, metabolic, inflammatory and anthropometric measures.
The study will compare the short and long-term effects of a protocol consisting of AIT alone or a rapid weight loss followed by AIT. Additionally, it will provide new insight in mechanisms behind the benefits of exercise and weight loss. We wish to contribute to the creation of effective secondary prevention and sustainable rehabilitation strategies in the large population of overweight and obese patients diagnosed with CAD.
Trial registration NCT01724567
PMCID: PMC4225526  PMID: 24252596
Coronary artery disease; Secondary prevention; Rehabilitation; Exercise; Overweight; Obesity; Weight loss; Life style changes
12.  Educational Differences in Postmenopausal Breast Cancer – Quantifying Indirect Effects through Health Behaviors, Body Mass Index and Reproductive Patterns 
PLoS ONE  2013;8(10):e78690.
Studying mechanisms underlying social inequality in postmenopausal breast cancer is important in order to develop prevention strategies. Standard methods for investigating indirect effects, by comparing crude models to adjusted, are often biased. We applied a new method enabling the decomposition of the effect of educational level on breast cancer incidence into indirect effects through reproductive patterns (parity and age at first birth), body mass index and health behavior (alcohol consumption, physical inactivity, and hormone therapy use). The study was based on a pooled cohort of 6 studies from the Copenhagen area including 33,562 women (1,733 breast cancer cases) aged 50–70 years at baseline. The crude absolute rate of breast cancer was 399 cases per 100,000 person-years. A high educational level compared to low was associated with 74 (95% CI 22–125) extra breast cancer cases per 100,000 person-years at risk. Of these, 26% (95% CI 14%–69%) could be attributed to alcohol consumption. Similar effects were observed for age at first birth (32%; 95% CI 10%–257%), parity (19%; 95%CI 10%–45%), and hormone therapy use (10%; 95% CI 6%–18%). Educational level modified the effect of physical activity on breast cancer. In conclusion, this analysis suggests that a substantial number of the excess postmenopausal breast cancer events among women with a high educational level compared to a low can be attributed to differences in alcohol consumption, use of hormone therapy, and reproductive patterns. Women of high educational level may be more vulnerable to physical inactivity compared to women of low educational level.
PMCID: PMC3812044  PMID: 24205296
13.  Major life events increase the risk of stroke but not of myocardial infarction: results from the Copenhagen City Heart Study 
More attention has been paid to psychosocial conditions as possible risk factors for cardiovascular disease (CVD) and the impact of accumulated major life events (MLE) on the development of CVD has received little attention.
The aim of this study was to explore the influences of MLE on CVD risk in a large cohort study.
The study population consisted of 9542 randomly selected adults free of CVD examined in the Copenhagen City Heart Study in 1991–1994 and followed up for CVD defined as myocardial infarction or ischaemic stroke until 2001. MLE were analysed using an 11-item questionnaire and hazard ratios (HR) were calculated using the Cox proportional hazards model.
During follow-up there were 443 myocardial infarctions (MI) and 350 ischaemic strokes. Financial problems in both childhood and adulthood were associated with risk of stroke with an HR of 1.71 (95% CI: 1.29–2.26) and 1.60 (1.12–2.30), respectively. Accumulation of MLE was also associated with risk of stroke with HR reaching a maximum of 1.41 (95% CI: 1.06–1.90) for more than one event in childhood and 1.49 (95% CI: 1.09–2.04) for more than one event in adulthood. MLE accumulated over a life course showed a dose–response relationship with stroke. Associations were somewhat attenuated by adjustment for vital exhaustion suggesting a mediating role, but not by adjustment for behavioural risk factors. There were no associations between MLE and MI.
In this population-based cohort study, we found that MLE conveyed a moderately increased risk of stroke partly mediated through vital exhaustion. We found no association between MLE and the risk of MI.
PMCID: PMC3634577  PMID: 20038841
adulthood; childhood; ischaemic stroke; myocardial infarction; prospective study
14.  Does the Benefit on Survival from Leisure Time Physical Activity Depend on Physical Activity at Work? A Prospective Cohort Study 
PLoS ONE  2013;8(1):e54548.
To investigate if persons with high physical activity at work have the same benefits from leisure time physical activity as persons with sedentary work.
In the Copenhagen City Heart Study, a prospective cohort of 7,411 males and 8,916 females aged 25–66 years without known cardiovascular disease at entry in 1976–78, 1981–83, 1991–94, or 2001–03, the authors analyzed with sex-stratified multivariate Cox proportional hazards regression the association between leisure time physical activity and cardiovascular and all-cause mortality among individuals with different levels of occupational physical activity.
During a median follow-up of 22.4 years, 4,003 individuals died from cardiovascular disease and 8,935 from all-causes. Irrespective of level of occupational physical activity, a consistently lower risk with increasing leisure time physical activity was found for both cardiovascular and all-cause mortality among both men and women. Compared to low leisure time physical activity, the survival benefit ranged from 1.5–3.6 years for moderate and 2.6–4.7 years for high leisure time physical activity among the different levels of occupational physical activity.
Public campaigns and initiatives for increasing physical activity in the working population should target everybody, irrespective of physical activity at work.
PMCID: PMC3547911  PMID: 23349926
15.  Home-based cardiac rehabilitation is an attractive alternative to no cardiac rehabilitation for elderly patients with coronary heart disease: results from a randomised clinical trial 
BMJ Open  2012;2(6):e001820.
To compare home-based cardiac rehabilitation (CR) with usual care (control group with no rehabilitation) in elderly patients who declined participation in centre-based CR.
Randomised clinical trial with 12 months follow-up and mortality data after 5.5 years (mean follow-up 4½ years).
Rehabilitation unit, Department of Cardiology, Copenhagen, Denmark.
Elderly patients ≥65 years with coronary heart disease.
A physiotherapist made home visits in order to develop an individualised exercise programme that could be performed at home and surrounding outdoor area. Risk factor intervention, medical adjustment, physical and psychological assessments were offered at baseline and after 3, 6 and 12 months.
Main outcome measurements
The primary outcome was 6 min walk test (6MWT). Secondary outcomes were blood pressure, body composition, cholesterol profile, cessation of smoking, health-related quality of life (HRQoL), anxiety and depression.
40 patients participated. The study population was characterised by high age (median age 77 years, range 65–92 years) and high level of comorbidity. Patients receiving home-based CR had a significant increase in the primary outcome 6MWT of 33.5 m (95% CI: 6.2 to 60.8, p=0.02) at 3 months, whereas the usual care group did not significantly improve, but with no significant differences between the groups. At 12 months follow-up, there was a decline in 6MWT in both groups; −55.2 m (95% CI: 18.7 to 91.7, p<0.01) in the home group and −52.1 m (95% CI: −3.0 to 107.1, p=0.06) in the usual care group. There were no significant differences in blood pressure, body composition, cholesterol profile, cessation of smoking or HRQoL after 3, 6 and 12 months follow-up.
Participation in home-based CR improved exercise capacity among elderly patients with coronary heart disease, but there was no significant difference between the home intervention and the control group. In addition, no significant difference was found in the secondary outcomes. When intervention ceased, the initial increase in exercise capacity was rapidly lost.
PMCID: PMC3533030  PMID: 23253876
16.  Intensity versus duration of physical activity: implications for the metabolic syndrome. A prospective cohort study 
BMJ Open  2012;2(5):e001711.
To explore the relative importance of leisure time physical activity (LTPA), walking and jogging on risk of developing the metabolic syndrome (MS).
A prospective cohort study.
The Copenhagen City Heart Study.
10 135 men and women aged 21–98 years who attended an initial examination in 1991–1994 and were re-examined after 10 years.
Outcome measures
The association of LTPA, jogging, walking speed and walking volume with MS at baseline and at 10-year follow-up was investigated by multiple logistic regression analyses.
Baseline prevalence of MS was 20.7% in women and 27.3% in men. In both women and men, MS prevalence was associated with lower LTPA and walking speed and was lower in joggers compared to non-joggers. In subjects free of MS at baseline, 15.4% had developed MS at 10-year follow-up. Risk of developing MS was reduced in subjects with moderate or high LTPA, higher walking speed and in joggers whereas a higher volume of walking was not associated with reduced risk. After multiple adjustment, odds ratio (OR) of developing MS in moderate/high LTPA was 0.71 (95% CI 0.50 to 1.01), fast walking speed 0.51 (0.33 to 0.80) and joggers 0.60 (0.37 to 0.95) and walking >1 h daily 1.22 (0.91 to 1.65).
Our results confirm the role of physical activity in reducing MS risk and suggest that intensity more than volume of physical activity is important.
PMCID: PMC3488727  PMID: 23045359
Preventive Medicine; Epidemiology; Public Health; Sports Medicine
17.  Insulin resistance and exercise tolerance in heart failure patients: linkage to coronary flow reserve and peripheral vascular function 
Insulin resistance has been linked to exercise intolerance in heart failure patients. The aim of this study was to assess the potential role of coronary flow reserve (CFR), endothelial function and arterial stiffness in explaining this linkage.
39 patients with LVEF < 35% (median LV ejection fraction (LVEF) 31 (interquartile range (IQ) 26–34), 23/39 of ischemic origin) underwent echocardiography with measurement of CFR. Peak coronary flow velocity (CFV) was measured in the LAD and coronary flow reserve was calculated as the ratio between CFV at rest and during a 2 minutes adenosine infusion. All patients performed a maximal symptom limited exercise test with measurement of peak oxygen uptake (VO2peak), digital measurement of endothelial function and arterial stiffness (augmentation index), dual X-ray absorptiometry scan (DEXA) for body composition and insulin sensitivity by a 2 hr hyperinsulinemic (40 mU/min/m2) isoglycemic clamp.
Fat free mass adjusted insulin sensitivity was significantly correlated to VO2peak (r = 0.43, p = 0.007). Median CFR was 1.77 (IQ 1.26-2.42) and was correlated to insulin sensitivity (r 0.43, p = 0.008). CFR (r = 0.48, p = 0.002), and arterial stiffness (r = −0.35, p = 0.04) were correlated to VO2peak whereas endothelial function and LVEF were not (all p > 0.15). In multivariable linear regression adjusting for age, CFR remained independently associated with VO2peak (standardized coefficient (SC) 1.98, p = 0.05) whereas insulin sensitivity (SC 1.75, p = 0.09) and arterial stiffness (SC −1.17, p = 0.29) were no longer associated with VO2peak.
The study confirms that insulin resistance is associated with exercise intolerance in heart failure patients and suggests that this is partly through reduced CFR. This is the first study to our knowledge that shows an association between CFR and exercise capacity in heart failure patients and links the relationship between insulin resistance and exercise capacity to CFR.
PMCID: PMC3444364  PMID: 22889317
Coronary flow reserve; Heart failure; Exercise capacity; Insulin sensitivity; Arterial stiffness
18.  Cardiorespiratory fitness, cardiovascular workload and risk factors among cleaners; a cluster randomized worksite intervention 
BMC Public Health  2012;12:645.
Prevalence of cardiovascular risk factors is unevenly distributed among occupational groups. The working environment, as well as lifestyle and socioeconomic status contribute to the disparity and variation in prevalence of these risk factors. High physical work demands have been shown to increase the risk for cardiovascular disease and mortality, contrary to leisure time physical activity. High physical work demands in combination with a low cardiorespiratory fitness infer a high relative workload and an excessive risk for cardiovascular mortality. Therefore, the aim of this study is to examine whether a worksite aerobic exercise intervention will reduce the relative workload and cardiovascular risk factors by an increased cardiorespiratory fitness.
A cluster-randomized controlled trial is performed to evaluate the effect of the worksite aerobic exercise intervention on cardiorespiratory fitness and cardiovascular risk factors among cleaners. Cleaners are eligible if they are employed ≥ 20 hours/week, at one of the enrolled companies. In the randomization, strata are formed according to the manager the participant reports to. The clusters will be balanced on the following criteria: Geographical work location, gender, age and seniority. Cleaners are randomized to either I) a reference group, receiving lectures concerning healthy living, or II) an intervention group, performing worksite aerobic exercise “60 min per week”. Data collection will be conducted at baseline, four months and 12 months after baseline, at the worksite during working hours. The data collection will consist of a questionnaire-based interview, physiological testing of health and capacity-related measures, and objective diurnal measures of heart rate, physical activity and blood pressure. Primary outcome is cardiorespiratory fitness.
Information is lacking about whether an improved cardiorespiratory fitness will affect the cardiovascular health, and additionally decrease the objectively measured relative workload, in a population with high physical work demands. Previous intervention studies have lacked robust objective measurements of the relative workload and physical work demands. This study will monitor the relative workload and general physical activity before, during after the intervention, and contribute to the understanding of the previously observed opposing effects on cardiovascular health and mortality from occupational and leisure time physical activity.
Trial registration
The study is registered as ISRCTN86682076.
PMCID: PMC3490923  PMID: 22888833
Worksite intervention; Cleaners; Aerobic exercise; Work demands; Physical activity; Ambulatory blood pressure
19.  Occupational and leisure time physical activity: risk of all-cause mortality and myocardial infarction in the Copenhagen City Heart Study. A prospective cohort study 
BMJ Open  2012;2(1):e000556.
Men with low physical fitness and high occupational physical activity are recently shown to have an increased risk of cardiovascular disease and all-cause mortality. The association between occupational physical activity with cardiovascular disease and all-cause mortality may also depend on leisure time physical activity.
A prospective cohort study.
The Copenhagen City Heart Study.
7819 men and women aged 25–66 years without a history of cardiovascular disease who attended an initial examination in the Copenhagen City Heart Study in 1976–1978.
Outcome measures
Myocardial infarction and all-cause mortality. Occupational physical activity was defined by combining information from baseline (1976–1978) with reassessment in 1981–1983. Conventional risk factors were controlled for in Cox analyses.
During the follow-up from 1976 to 1978 until 2010, 2888 subjects died of all-cause mortality and 787 had a first event of myocardial infarction. Overall, occupational physical activity predicted all-cause mortality and myocardial infarction in men but not in women (test for interaction p=0.02). High occupational physical activity was associated with an increased risk of all-cause mortality among men with low (HR 1.56; 95% CI 1.11 to 2.18) and moderate (HR 1.31; 95% CI 1.05 to 1.63) leisure time physical activity but not among men with high leisure time physical activity (HR 1.00; 95% CI 0.78 to 1.26) (test for interaction p=0.04). Similar but weaker tendencies were found for myocardial infarction. Among women, occupational physical activity was not associated with subsequent all-cause mortality or myocardial infarction.
The findings suggest that high occupational physical activity imposes harmful effects particularly among men with low levels of leisure time physical activity.
Article summary
Article focus
Men with low physical fitness and high occupational physical activity are recently shown to have an increased risk of cardiovascular disease and all-cause mortality.
It is unknown if the association between occupational physical activity with cardiovascular disease and all-cause mortality also depends on leisure time physical activity.
Key messages
This study shows that men with high occupational physical activity have an increased risk of all-cause mortality.
Leisure time physical activity was found to modify the positive association between occupational physical activity and risk of all-cause mortality. High occupational physical activity imposes harmful effects particularly among men with low levels of leisure time physical activity.
Strengths and limitations of this study
Study strengths include the long follow-up time, repeated assessment of the occupational physical activity, objective measures of several covariates from clinical examinations, information on outcomes obtained from valid registers, and participation of both sexes. Some limitations are the lack of control for psychosocial work factors and the self-reported exposures.
PMCID: PMC3282285  PMID: 22331387
20.  Income inequality, individual income, and mortality in Danish adults: analysis of pooled data from two cohort studies 
BMJ : British Medical Journal  2002;324(7328):13.
To analyse the association between area income inequality and mortality after adjustment for individual income and other established risk factors.
Analysis of pooled data from two cohort studies. The relation between income inequality in small areas of residence (parishes) and individual mortality was examined with Cox proportional hazard analyses.
Two population studies conducted in Copenhagen, Denmark.
13 710 women and 12 018 men followed for a mean of 12.8 years.
Main outcome measure
All cause mortality.
Age standardised mortality was highest in the parishes with the least equal income distribution. After adjustment for individual risk factors, parish income inequality was not associated with mortality, whereas individual household income was. Thus, individuals in the highest income quarter had lower mortality than those in the lowest quarter (adjusted hazard ratio for men 0.51 (95% confidence interval 0.45 to 0.59) and for women 0.60 (0.54 to 0.68)).
Area income inequality is not in itself associated with all cause mortality in this Danish population. Adjustment for individual risk factors makes the apparent effect disappear. This may be the result of Denmark's welfare system, based on a Nordic model.
What is already known on this topicSeveral ecological studies have shown that higher levels of income inequality in countries, states, or smaller areas are associated with higher all cause mortalityA few prospective studies from the United States have examined this after controlling for individual risk factorsWhat this study addsInequality in the distribution of income in parishes in Copenhagen is as high as inequality reported from metropolitan areas in the United StatesArea based income inequality did not affect all cause mortality after adjustment for individual income and other risk factorsDenmark's welfare system (based on a Nordic model) may even out the effect of area inequality
PMCID: PMC61651  PMID: 11777797
21.  Smoking and risk of myocardial infarction in women and men: longitudinal population study 
BMJ : British Medical Journal  1998;316(7137):1043-1047.
Objective: To compare risk of myocardial infarction associated with smoking in men and women, taking into consideration differences in smoking behaviour and a number of potential confounding variables.
Design: Prospective cohort study with follow up of myocardial infarction.
Setting: Pooled data from three population studies conducted in Copenhagen.
Subjects: 11 472 women and 13 191 men followed for a mean of 12.3 years.
Main outcome measures: First admission to hospital or death caused by myocardial infarction.
Results: 1251 men and 512 women had a myocardial infarction during follow up. Compared with non-smokers, female current smokers had a relative risk of myocardial infarction of 2.24 (range 1.85-2.71) and male smokers 1.43 (1.26-1.62); ratio 1.57 (1.25-1.97). Relative risk of myocardial infarction increased with tobacco consumption in both men and women and was higher in inhalers than in non-inhalers. The risks associated with smoking, measured by both current and accumulated tobacco exposure, were consistently higher in women than in men and did not depend on age. This sex difference was not affected by adjustment for arterial blood pressure, total and high density lipoprotein cholesterol concentrations, triglyceride concentrations, diabetes, body mass index, height, alcohol intake, physical activity, and level of education.
Conclusion: Women may be more sensitive than men to some of the harmful effects of smoking. Interactions between components of smoke and hormonal factors that may be involved in development of ischaemic heart disease should be examined further.
PMCID: PMC28505  PMID: 9552903

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