Hypercholesterolaemia and risk of coronary heart disease in the elderly: impact of age: the Copenhagen City Heart Study.

BACKGROUND: Population and interventional studies have shown that high plasma-cholesterol is a risk factor of coronary heart disease (CHD). However, in most of the studies elderly people were excluded. AIM: This paper assesses whether the effect of total plasma-cholesterol on the risk of incident CHD decreases with age in a healthy population. METHODS: Within the Copenhagen City Heart Study in 1981-1983, 4647 men and 5829 women, aged 40-93 years, underwent a cardiovascular health examination including measurement of plasma-cholesterol. The cohort was followed with respect to incident CHD until 1994, i.e. before statins were introduced in Denmark. RESULTS: In people below 60 years of age plasma-cholesterol levels on 5-6; 6-8; and >8 mmol/L were associated with relative risks of CHD on 2.0 (95% confidence interval (CI) 1.2-3.2, P=0.004); 3.1 (CI 2.0-5.0, P<0.001); and 5.1 (CI 2.8-9.3, P<0.001), respectively (reference group: plasma-cholesterol <5 mmol/L). In people aged 60-70 years a plasma-cholesterol level on 5-6 mmol/L was not associated with increased risk, whereas plasma-cholesterol on 6-8 mmol/L and >8 mmol/L was associated with relative risks on 1.3 (CI 1.0-1.8, P=0.03), and 2.3 (CI 1.6-3.4, P<0.001), respectively. In people aged 70-80 years only plasma-cholesterol >8 mmol/L conferred increased relative risk on 1.6 (CI 1.2-2.4, P=0.007). In people above 80 years of age increased plasma-cholesterol was not associated with increased risk of incident CHD. CONCLUSION: The risk of incident CHD associated with high plasma-cholesterol declines with age. This finding should be considered in future recommendations of plasma-cholesterol levels in elderly people without atherosclerotic cardiovascular disease.

Microalbuminuria and obesity: impact on cardiovascular disease and mortality.

OBJECTIVE: Microalbuminuria and obesity are both associated with cardiovascular disease (CVD). The aim of this study was to determine the association between obesity (measured by body mass index, waist-to-hip ratio, waist circumference) and different levels of microalbuminuria. We also aimed to determine the risk of death and CVD at different levels of microalbuminuria and obesity. DESIGN: Population-based observational study based on 2696 men and women, 30-70 years of age. Urinary albumin excretion (UAE), body mass index, waist-to-hip ratio, waist circumference and other cardiovascular risk factors were measured during the years 1992-1994 at the Copenhagen City Heart Study. End-points were registered until 1999-2000 with respect to CVD and until 2004 with respect to death. RESULTS: There was a strong association between microalbuminuria and obesity. Microalbuminuria and obesity had additive effects on the relative risk of death independently of other risk factors. In contrast there was no statistically significant association between microalbuminuria and risk of CVD when stratified by obesity. CONCLUSIONS: Microalbuminuria (UAE > 5 microg/min) confers increased risk of death and to a similar extent as obesity. This effect is independent of concomitant obesity. We suggest microalbuminuria to be included in health examinations besides measurements of obesity.

Higher prevalence of risk factors for type 2 diabetes mellitus and subsequent higher incidence in men.

BACKGROUND: This study investigates risk factors and the incidence of type 2 diabetes mellitus (type 2 DM) in both sexes of a northern European population. METHODS: A total of 14,223 randomly selected men and women were studied from 1976 to 1978. Patients with diabetes (self-reported type 2 DM or non-fasting plasma glucose >11.1 mmol/l) were excluded. Some 6154 women and 4733 men were studied and followed up in 1981-1983 or in 1991-1994. The significance of risk factors was examined by multiple logistic regression analysis. RESULTS: Initially, a higher proportion of men than women had high, non-fasting blood glucose and triglycerides. Significantly more men (242, 5.4%) than women (152, 2.5%) developed type 2 DM. The odds ratio (OR) for developing diabetes with a BMI above 30 kg/m(2) compared to a BMI of 20-25 kg/m(2) was 8.1 in women and 6.3 in men; for a non-fasting plasma glucose of 8.4-11.0 mmol/l compared to a plasma glucose of 5.5-6.4, the ORs were 7.8 in women and 4.7 in men. The OR for developing diabetes in persons with a non-fasting triglyceride level above 2.0 mmol/l compared to 1.0-2.0 mmol/l was 1.8 in both sexes; women with non -fasting triglycerides below 1.0 mmol/l had an OR of 0.4. CONCLUSION: In a randomly selected northern European population, significantly more men than women develop type 2 DM.

Intensity versus duration of walking, impact on mortality: the Copenhagen City Heart Study.

BACKGROUND: Current recommendations prescribe that every adult should accumulate 30 min or more of moderate-intensity physical activity in leisure time, preferably all days of the week. To further support these recommendations we examined the impact of walking intensity and walking duration on all-cause mortality. DESIGN: Relative intensity and duration of walking were recorded in 7308 healthy women and men aged 20-93 at the third examination (1991-1994) of the Copenhagen City Heart Study. During an average of 12 years of follow-up 1391 deaths were recorded. RESULTS: For both sexes we found a significant inverse association between walking intensity and risk of death, but only a weak inverse association to walking duration. For women walking with average intensity, the adjusted hazard ratio (HR) of death was 0.75 [95% confidence interval (CI) 0.61-0.92; P<0.01] and walking with fast intensity 0.48 (95% CI 0.35-0.66; P<0.001) compared to women walking with slow intensity. For men the relative risks were 0.54 (95% CI 0.45-0.67; P<0.001) and 0.43 (95% CI 0.32-0.59; P<0.001), respectively. CONCLUSION: Our findings indicate that the relative intensity and not the duration of walking is of most importance in relation to all-cause mortality. Thus our general recommendation to all adults would be that brisk walking is preferable to slow.

Exhaled CO, a predictor of lung function?

BACKGROUND: Smoking is associated with an accelerated loss of lung function and inhalation accelerates the decline further. Exhaled CO reflects the exposure of smoke to the lungs. AIM: To investigate whether self-reported inhalation and type of cigarette influenced the level of exhaled CO and whether CO could provide additional information to usual measures of smoking regarding prediction of present lung function and decline in lung function over an extended period of time. METHOD: Cigarette smokers from the Copenhagen City Heart Study with valid measures of lung function and exhaled CO; in total 3738 subjects, 2096 women and 1642 men. RESULTS: Subjects not inhaling had slightly lower exhaled CO values than those inhaling, but substantially higher values than non-smokers (P<0.001). Smokers of plain cigarettes had slightly lower CO values than smokers of filter cigarettes (P<0.001). Increasing CO levels were correlated to a lower FEV(1)%pred and to an accelerated decline in lung function. However, in multiple linear regression analyses these correlations were not significant. CONCLUSION: Inhalation and type of cigarette affects exhaled CO levels. CO measures have no predictive value regarding neither present lung function nor decline in lung function with time in a population survey setting.

Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction.

AIMS: B-type natriuretic peptide (BNP) measurement in screening for left ventricular hypertrophy (LVH) and left ventricular systolic dysfunction (LVSD) has been evaluated in the general population, but corresponding information on proBNP and the N-terminal proBNP fragment is still limited. We therefore examined whether proBNP measurement is useful for LVH and LVSD screening in the general population. METHODS AND RESULTS: In the 4th Copenhagen City Heart Study, 3497 participants underwent echocardiography with assessment of left ventricular ejection fraction (LVEF) and mass. The impact of gender and age was determined and the diagnostic performance of the plasma proBNP concentration was evaluated using receiver operating characteristic (ROC) curves. Of 1502 men and 1995 women, 4.1 and 2.6% had LVSD defined as an LVEF<60% whereas only 0.4% displayed LVEF<40%. The proBNP concentration was 1.7-fold higher in women compared with men (P<0.0001) and related to age in both genders. The mean proBNP plasma concentration was two-fold higher in subjects with LVSD than without LVSD (P<0.0001). Likewise, LVH imposed a 1.9-fold increase in the proBNP concentration (P<0.0001): Both differences persisted after adjusting for ischaemic heart disease, hypertension, diabetes, gender, and age. The diagnostic performance of proBNP in detecting LVEF<40% was high with an area under the ROC curves of 0.92 (95% CI 0.79-1.00) in women and 0.85 (95% CI 0.74-0.96) in men. CONCLUSION: We have established the impact of age and gender on the proBNP concentration in a large, community-based cohort. The diagnostic performance for proBNP measurement in screening for LVH and LVSD in the general population parallels the reported data for BNP.

Long-term physical activity in leisure time and mortality from coronary heart disease, stroke, respiratory diseases, and cancer. The Copenhagen City Heart Study.

BACKGROUND: The purpose of this study was to describe the associations between different levels of long-term physical activity in leisure time and subsequent causes of deaths. DESIGN: The Copenhagen City Heart Study is a prospective cardiovascular population study of 19 329 men and women aged 20-93 in 1976. Physical activity in leisure time was estimated at the examinations in 1976-78 and 1981-83. This analysis consists of 2136 healthy men and 2758 women aged 20-79 years, with unchanged physical activity at the two examinations, and with all covariates included in the multivariate analyses: smoking, total-cholesterol, high-density lipoprotein-cholesterol, systolic blood pressure, diabetes mellitus, alcohol consumption, body mass index, education, income, and forced expiratory volume in 10.78 (% predicted). RESULTS: Adjusted relative risks (95% confidence interval) for coronary heart disease were, for moderate physical activity 0.71 (0.51, 0.99) and for high 0.56 (0.38, 0.82). For cancer, moderate activity 0.77 (0.61, 0.97) and high activity 0.73 (0.56, 0.95) and for all-cause mortality, moderate 0.78 (0.68, 0.89) and high 0.75 (0.64, 0.87) for both sexes combined. Using Kaplan-Meier plots we calculated gained years of expected lifetime from age 50. Men with high physical activity survived 6.8 years longer, and men with moderate physical activity 4.9 years longer than sedentary men. For women the figures were 6.4 and 5.5 years, respectively. CONCLUSION: Long-term moderate or high physical activity was in both sexes associated with significantly lower mortality from coronary heart disease, cancer and all-causes. The same tendency was found for stroke and respiratory diseases, but the associations did not reach statistical significance.

New definition of microalbuminuria in hypertensive subjects: association with incident coronary heart disease and death.

Microalbuminuria has so far been defined as urinary albumin excretion between 20 and 200 microg/min (or 15 to 150 microg/min overnight). In a recent report, an overnight urinary albumin excretion >5 microg/min was strongly predictive of coronary heart disease and death in the general population. The aim of the present study was to confirm this observation in a population of hypertensive individuals. In The Third Copenhagen City Heart Study in 1992 to 1994, 1734 men and women aged 30 to 70 years with hypertension, but no history of coronary heat disease, delivered a timed overnight urine sample. They were followed-up prospectively by registers until 2000 with respect to coronary heart disease, and until 2004 with respect to death. During follow-up, 123 incident cases of coronary heart disease and 308 deaths were traced. Incident coronary heart disease occurred in 11% of subjects with urinary albumin excretion > or =5 microg/min compared with 5% in subjects with urinary albumin excretion <5 microg/min (P<0.001). Similarly, the cumulative mortality was 28% versus 13% (P<0.001). The relative risks of coronary heart disease and death associated with urinary albumin excretion > or =5 microg/min were 2.0 (1.4 to 2.9; P<0.001) and 1.9 (1.5 to 2.3; P<0.001), respectively, after adjustment for age, sex, blood pressure level, antihypertensive drugs, diabetes, creatinine clearance, smoking, lipoproteins, and body mass index. In conclusion, our study supports the new definition of microalbuminuria as urinary albumin excretion >5 microg/min. In future risk assessment in hypertensive individuals, measurement of microalbuminuria has to be included.

The ischemic electrocardiogram: a harbinger for ischemic heart disease independent of the blood pressure level. The Copenhagen City Heart Study.

Information is limited on the co-existence and prognostic association of the ischemic electrocardiogram (ECG) and blood pressure. Prospectively collected data sets from 28,118 examinations in the Copenhagen City Heart Study were analyzed for cardiac morbidity and mortality for a 5.9-year follow-up. The prognosis of the ECG, independently of blood pressure, was examined. The Cox proportional hazard model was employed to evaluate the prognostic implications of ECG findings and relative risk was adjusted for age and multivariately adjusted for traditional cardiovascular risk factors. End-points were (1) fatal and non-fatal ischemic heart disease (IHD) events and (2) cardiovascular disease (CVD) mortality. During a total follow-up period of 166,471 person years (mean: 5.9 years) 1.481 IHD events were recorded and 1.051 CVD deaths. The relative risk of an ischemic ECG was independent of the blood pressure level. The multivariately adjusted relative risk for fatal and non-fatal IHD for the ischemic ECG was 1.70 (95% CI: 1.39-2.09, p < 0.001) in women, and 1.96 (95% CI: 1.67-2.30, p < 0.001) in men, and for CVD mortality 1.71 (95% CI: 1.34-2.17, p < 0.001) in women and 2.08 (95% CI: 1.74-2.49, p < 0.001) in men. An ECG with left ventricular hypertrophy (LVH) and ST-depression was the finding with the highest risk for future events. LVH by ECG voltage-only was associated with no statistically increased risk, except for men treated for arterial hypertension.

Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death in women versus men (The Copenhagen City Heart Study).

The Copenhagen City Heart Study is a population-based cohort study. Using baseline data from 3 cohort examinations (1976 to 1978, 1981 to 1983, and 1991 to 1994), we analyzed the gender-specific effect of atrial fibrillation (AF) on the risk of stroke and cardiovascular death during 5 years of follow-up. Baseline data from 29,310 subjects were included. AF was documented in 276 subjects (110 women and 166 men). During a mean follow-up of 4.7 years, 635 strokes were identified, 35 of which occurred in subjects who had AF (22 women and 13 men). After adjustment for age and co-morbidity, the effect of AF on the risk of stroke was 4.6-fold greater in women (hazard ratio 7.8, 95% confidence interval 5.8 to 14.3) than in men (hazard ratio 1.7, 95% confidence interval 1.0 to 3.0). Cardiovascular death occurred in 1,122 subjects, 63 of whom had AF (28 in women and 35 in men). The independent effect of AF on cardiovascular mortality rate was 2.5-fold greater in women (hazard ratio 4.4, 95% confidence interval 2.9 to 6.5) than in men (hazard ratio 2.2, 95% confidence interval 1.6 to 3.1). Our results indicate that AF is a much more pronounced risk factor for stroke and cardiovascular death in women than in men.

The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up.

BACKGROUND: Epidemiological studies have reported that patients with type 2 diabetes mellitus (DM) have increased mortality and morbidity from cardiovascular diseases, independent of other risk factors. However, most of these studies have been performed in selected patient groups. The purpose of the present study was prospectively to assess the impact of type 2 DM on cardiovascular morbidity and mortality in an unselected population. METHODS: A total of 13,105 subjects from the Copenhagen City Heart Study were followed up prospectively for 20 years. Adjusted relative risks of first, incident, admission for, or death from ischemic heart disease, acute myocardial infarction, or stroke, as well as total mortality in persons with type 2 DM compared with healthy controls, were estimated. RESULTS: The relative risk of first, incident, and admission for myocardial infarction was increased 1.5- to 4.5-fold in women and 1.5- to 2-fold in men, with a significant difference between sexes. The relative risk of first, incident, and admission for stroke was increased 2- to 6.5-fold in women and 1.5- to 2-fold in men, with a significant difference between sexes. In both women and men the relative risk of death was increased 1.5 to 2 times. CONCLUSIONS: In persons with type 2 DM, the risk of having an incident myocardial infarction or stroke is increased 2- to 3-fold and the risk of death is increased 2-fold, independent of other known risk factors for cardiovascular diseases.

Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes.

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

Transendothelial lipoprotein exchange and microalbuminuria.

OBJECTIVE: Microalbuminuria associates with increased risk of atherosclerosis in individuals without diabetes. We hypothesized that transendothelial lipoprotein exchange is elevated among such individuals, possibly explaining increased intimal lipoprotein accumulation and thus atherosclerosis. METHODS: Using an in vivo isotope technique, transendothelial exchange of low density lipoprotein (LDL) was measured in 77 non-diabetic individuals. Autologous 131-iodinated LDL was reinjected intravenously, and the 1-h fractional escape rate was calculated as index of transendothelial exchange. RESULTS: There was no difference in transendothelial LDL exchange between subjects with microalbuminuria versus normoalbuminuria (mean (95% confidence interval) 3.8%/h (3.3-4.3%/h) versus 4.2%/h (3.7-4.7%/h); P=0.33). In contrast, there was a positive correlation between transendothelial LDL exchange and (logarithmically transformed) plasma insulin: beta=0.6 (95% CI: 0.1-1.1); R=0.22; P<0.05. This correlation was independent of age, sex, blood pressure, plasma concentration of lipoproteins, LDL size, body mass index, plasma volume, and use of medicine, and it was unlikely caused by altered hepatic LDL receptor expression, or glycosylation of LDL. CONCLUSION: In non-diabetic individuals, transendothelial LDL exchange is not associated with microalbuminuria, but possibly with hyperinsulinemia.

Sex-specific increase in the prevalence of atrial fibrillation (The Copenhagen City Heart Study).

Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia. It is a risk factor for stroke and premature death. We studied the temporal changes in the prevalence of AF from 1976 to 1994 in a random population aged 50 to 89 years. The prevalence of AF, diagnosed from electrocardiograms (ECGs), was determined in 8,606 patients examined in 1976 to 1978, in 8,943 patients examined in 1981 to 1983, and in 6,733 subjects examined in 1991 to 1994. Changes in prevalence of AF were estimated by logistic regression analysis. In men, the age-standardized prevalence of AF increased from 1.4% in 1976 to 1978 (odds ratio [OR] 1.0, reference) to 1.9% in 1981 to 1983 (OR 1.6, 95% confidence interval [CI] 1.1 to 2.1), and to 3.3% in 1991 to 1994 (OR 2.3, 95% CI 1.6 to 3.4, p<0.001, adjusted for age). In women, the prevalence of AF decreased from 1.5% in 1976 to 1978 (OR 1.0, reference) to 1.0% in 1981 to 1983 (OR 0.7, 95% CI 0.5 to 1.0), and to 1.1% in 1991 to 1994 (OR 0.7, 95% CI 0.5 to 1.0), although the overall decrease was not significant (p=0.11, adjusted for age). After adjusting for changes in comorbidity, body weight, and height, the increase in the prevalence of AF in men from 1976 to 1978 and from 1991 to 1994 remained significant (OR 1.9, 95% CI 1.3 to 2.8, p=0.002). Although unchanged in women, the prevalence of AF in men more than doubled from the 1970s to the 1990s. The factors responsible for this gender-specific increase in the prevalence of this common arrhythmia have yet to be identified.

Rising rates of hospital admissions for atrial fibrillation.

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

Changes in leisure-time physical activity and risk of death: an observational study of 7,000 men and women.

Associations of regular leisure-time physical activity and changes in leisure-time physical activity with risk of death were studied in 7,023 healthy men and women aged 20-79 years in Copenhagen, Denmark. Physical activity was estimated in both 1976-1978 and 1981-1983. Men consistently engaging in a moderate or high degree of physical activity, respectively reported at both examinations, had significantly lower risks of death than men reporting low activity at both examinations. Adjusted relative risks were 0.71 (95% confidence interval (CI): 0.57, 0.88; p = 0.002) and 0.61 (95% CI: 0.48, 0.76; p < 0.001), respectively. Similar relative risks were found in women: 0.64 (95% CI: 0.52, 0.79; p < 0.001) and 0.66 (95% CI: 0.51, 0.85; p = 0.001), respectively. Men who increased their leisure-time physical activity from low to moderate or high had a significantly lower risk of death than men reporting low physical activity at both examinations (relative risk = 0.64, 95% CI: 0.50, 0.81; p < 0.001). In this study, maintaining or adopting a moderate or high degree of physical activity was associated with lower risk of death across a wide range of ages in both sexes.

[Individual and population based risk factors of ischemic heart diseases. A 21-year follow-up of 12,000 men and women from the Osterbro study]. / Individuelle og populationsbaserede risikofaktorer for iskaemisk hjertesygdom. Enogtyve års opfølgning af 12.000 maend og kvinder fra ØsterbroundersØgelsen.

INTRODUCTION: The importance of coronary heart disease risk factors may differ between individuals and community and by sex and age. METHOD: The Copenhagen City Heart Study followed for 21 years a random sample of 5599 men and 6478 women aged 30 to 79 years at baseline. The importance of risk factors in individuals and the community were evaluated as relative and population attributable risks. RESULTS: We traced 2180 coronary events. In Cox regression analysis with ten risk factors entered simultaneously, relative risks for coronary heart disease in men ranged from 1.69 to 1.20 with the highest risks for diabetes, hypertension, smoking, and physical inactivity. In women, relative risks ranged from 2.74 to 1.19 with the highest risks for diabetes, smoking, hypertension, and physical inactivity. Population attributable risks in men ranged from 22 to 3% with the highest risks for smoking, hypertension, and no daily alcohol intake. In women, attributable risks ranged from 37 to 3% with the highest risks for smoking, hypertension, and hypercholesterolemia. Several of these rankings differed by age. DISCUSSION: The importance of coronary heart disease risk factors may differ for individuals, the community, and by sex and age. Consequently, prevention strategies should be tailored accordingly.