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Although smoking is a risk factor for ischemic heart disease (heart tissue damage from oxygen deprivation, usually a result of reduced blood flow), it is not clear how this occurs. The risk increases with the amount of smoking, whether of cigarettes, pipe, or cigar. It has not been determined if a decrease in risk occurs if one quits smoking, especially once ischemic heart disease has developed. The role of smoking as a risk factor for first acute myocardial infarction (AMI), or heart attack, was examined according to the amount, type, and method of smoking in a study of almost 20,000 men and women. Tobacco smoking was substantiated as a risk factor, and the risk increased with the amount smoked. Smokers who inhaled tobacco had a much higher risk of AMI, but those who did not inhale had only a moderately increased risk. Filtered cigarettes and pipes did not reduce the risk, and no differences in risk were associated with different types of tobacco. Female nonsmokers were at lower risk than male nonsmokers, but women who smoked were at higher risk than men who smoked. There has been an increase in smoking among young women, and a decrease among young men, suggesting that heart disease may be affecting women more in the future. Ex-smokers, regardless of length of nonsmoking period, faced a risk of first AMI similar to that of the habitual smoker. The most probable mechanism by which smoking affects heart disease is by altering clotting factors and endothelium (heart and blood vessel lining) function. The authors have previously reported a 'protective' effect of alcohol against AMI, which upon further analysis seems to be limited to heavy smokers. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: Body fat distribution is a marker of metabolic health independent of body size. Visceral fat accumulation has been suggested to result from a decreased expandability of the subcutaneous fat depots. Furthermore, the visceral fat may be easier to mobilize than the peripheral fat. We examined whether differences in abdominal obesity at baseline influenced prospective body-weight changes. Objective: In this study we examined whether body-fat distribution at baseline was associated with long-term and short-term weight changes. Design: We included 3 observational studies (ntotal = 7271) with mean follow-up times of 5-9 y and two 8-10-wk weight loss intervention studies (ntotal = 1091). We examined the association between baseline waist circumference and weight changes in a substitution regression model, where body weight, height, and fatfree mass were fixed so that a difference in waist circumference would reflect a difference in body fat distribution alone. The results were summarized in meta-analyses. Results: In the observational studies, we found no associations between baseline waist circumference and subsequent weight change in men (β: 0.03 kg; 95% CI: -0.01, 0.08 kg; P = 0.19), but a negligible inverse association in women (β: -0.05 kg; 95% CI: -0.08, -0.01 kg; P = 0.01). There was no association between baseline waist circumference and weight loss in the intervention studies (men: β: -0.05 kg; 95% CI: -0.13, 0.03 kg; P = 0.25; women: β: -0.00 kg; 95% CI: -0.03, 0.03 kg; P = 0.84). However, in all studies, the SDs of the weight change residuals were greater, the greater the waist circumference at baseline. This trend was statistically significant in women in most studies as well as in men in 1 of the studies. Conclusions: With narrow CIs in 3 observational studies and 2 weight loss interventions, we did not find any clinically or epidemiologically relevant association between baseline abdominal obesity and weight change. However, the present study suggests that a greater baseline abdominal obesity is a marker for greater weight fluctuations. The CCHS trial was registered at www.clinical trials.gov as NCT02993172. The Health2006 trial was registered at www.clinicaltrials.gov as NCT00316667. The ORG study was conducted before trial registration was required. The NUGENOB trial was registered at www.isrctn.com as ISRCTN25867281. The DiOGenes trial was registered at www.clinicaltrials.gov as NCT00390637. [ABSTRACT FROM AUTHOR]

Background People who are physically active have at least a 30% lower risk of death during follow-up compared with those who are inactive. However, the ideal dose of exercise for improving longevity is uncertain. Objectives The aim of this study was to investigate the association between jogging and long-term, all-cause mortality by focusing specifically on the effects of pace, quantity, and frequency of jogging. Methods As part of the Copenhagen City Heart Study, 1,098 healthy joggers and 3,950 healthy nonjoggers have been prospectively followed up since 2001. Cox proportional hazards regression analysis was performed with age as the underlying time scale and delayed entry. Results Compared with sedentary nonjoggers, 1 to 2.4 h of jogging per week was associated with the lowest mortality (multivariable hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.11 to 0.80). The optimal frequency of jogging was 2 to 3 times per week (HR: 0.32; 95% CI: 0.15 to 0.69) or ≤1 time per week (HR: 0.29; 95% CI: 0.12 to 0.72). The optimal pace was slow (HR: 0.51; 95% CI: 0.24 to 1.10) or average (HR: 0.38; 95% CI: 0.22 to 0.66). The joggers were divided into light, moderate, and strenuous joggers. The lowest HR for mortality was found in light joggers (HR: 0.22; 95% CI: 0.10 to 0.47), followed by moderate joggers (HR: 0.66; 95% CI: 0.32 to 1.38) and strenuous joggers (HR: 1.97; 95% CI: 0.48 to 8.14). Conclusions The findings suggest a U-shaped association between all-cause mortality and dose of jogging as calibrated by pace, quantity, and frequency of jogging. Light and moderate joggers have lower mortality than sedentary nonjoggers, whereas strenuous joggers have a mortality rate not statistically different from that of the sedentary group. [ABSTRACT FROM AUTHOR]

Abstract: Background: Heart failure is a major public health problem. To improve its grave prognosis, early identification of cardiac dysfunction is mandatory. Conventional echocardiography is not suitable for this. Tissue Doppler imaging (TDI), however, could be so. Methods and Results: Within a large community-based population-study (n = 1012), cardiac function was evaluated by conventional echocardiography (left ventricular hypertrophy, dilatation, systolic, and severe diastolic dysfunction), TDI, and plasma proBNP. Averages of peak systolic (s′), early diastolic (e′), and late diastolic (a′) velocities from 6 mitral annular sites were used. TDI was furthermore quantified by a combined index (eas-index) of diastolic and systolic performance: e′/(a′ × s′). Compared with controls, persons with elevated plasma proBNP concentrations (n = 100) displayed lower systolic and diastolic performance by TDI, in terms of lower s′ (P = 0.017) and a′ (P < .001), and higher e′/a′ (P = .002) and eas-index (P < .001). This pattern remained significant after multivariable adjustment for age, sex, body mass index, heart rate, estimated glomerular filtration rate, hypertension, diabetes, ischemic heart disease, and conventional echocardiography. Furthermore, TDI provided incremental information over conventional echocardiography in predicting elevated plasma proBNP concentrations. Conclusions: Preclinical systolic and diastolic dysfunction by TDI is associated with elevated plasma proBNP levels, even when conventional echocardiography is normal. [Copyright &y& Elsevier]

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 HDL(2b) 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. [ABSTRACT FROM AUTHOR]

Color Tissue Doppler imaging (TDI) M-mode through the mitral leaflet is a novel method to obtain the cardiac time intervals including the isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT) and ejection time (ET). The myocardial performance index (MPI) is defined as [(IVCT+IVRT)/ET]. Our aim was to investigate if the cardiac time intervals can be used to predict heart failure (HF) in the general population. A total of 1915 participants (mean age 58 ± 16 years, 42% male) from the general population (The Copenhagen City Heart Study) underwent a health examination including TDI-echocardiography. The primary endpoint was incident HF. Participants with a history of HF were excluded (n = 23). During a median follow-up time of 16 years, 172 (9%) participants were diagnosed with incident HF. The risk of HF increased with 24% per 10 ms increase in IVCT (per 10 ms increase: HR 1.24; 95%CI (1.14–1.36), p < 0.001). The association remained significant after adjusting for age, sex, hypertension, diabetes, previous ischemic heart disease, diastolic blood pressure, heart rate, body mass index, eGFR, proBNP, LVEF <50%, s′, LAVI, and E/e′ (per 10 ms increase: HR 1.13; 95% CI (1.00–1.27), p = 0.045). A significant association was found between MPI and HF both in unadjusted and adjusted models (per 0.1 increase: HR 6.93; 95% CI (1.63–29.31), p = 0.009). No associations between the IVRT or ET and HF remained significant after multivariable adjustment. In the general population the IVCT provides novel and independent prognostic information on the long-term risk of incident HF. • Color TDI M-mode is a novel method to obtain cardiac time intervals including IVCT. • The IVCT is a novel and independent predictor of HF in the general population. • The association remained significant even after multivariable adjustment. [ABSTRACT FROM AUTHOR]

Up to 40% of all dementia cases may be preventable, primarily by treating or acting on well-established cardiovascular risk factors such as diabetes, hypertension, smoking, and physical inactivity. Whether physical inactivity is associated with risk of non-Alzheimer's dementia – a disease influenced by cardiovascular risk factors – and whether a given association differs for physical activity in leisure time and at work remains unknown. We conducted a prospective cohort study including 117,616 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study with up to 43 years of follow-up. Multifactorially adjusted hazard ratios for low versus high physical activity at leisure time was 1.60 (95% confidence interval 1.40–1.83) for non-Alzheimer's dementia and 0.94 (0.80–1.11) for Alzheimer's disease. Corresponding values for non-Alzheimer's dementia after additional adjustment for physical activity at work or apolipoprotein E (APOE) genotype were 1.60 (1.40–1.83) and 1.82 (1.34–2.15). Multifactorially and APOE adjusted hazard ratios for high versus low physical activity at work were 1.50 (1.10–2.05) for non-Alzheimer's dementia and 1.62 (1.14–2.31) for Alzheimer's disease. When combining the two types of physical activity, physical activity in leisure time had the strongest relationship with risk of non-Alzheimer's dementia. Physical inactivity in leisure time was associated with increased risk of non-Alzheimer's dementia, independent of modifiable risk factors and physical activity at work. The present study thus provides evidence for public health advice on physical activity in leisure time for the vascular part of dementia. [Display omitted] • Prospective study including 117,616 individuals from the general Danish population. • Up to 43 years of follow-up with no losses to follow-up. • Low leisure physical activity associates with high risk of non-Alzheimer's dementia. • Leisure versus work physical activity is superior in predicting risk. • Public health advice on physical activity may prevent non-Alzheimer's dementia. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To compare the new Patient Rule Induction Method (PRIM) Score and common clinical practice with the Framingham Point Score for classification of individuals with respect to coronary heart disease (CHD) risk. Methods and results: PRIM Score and the Framingham Point Score were estimated for 11,444 participants from the Copenhagen City Heart Study. Gender specific cumulative incidences and 10 year absolute CHD risks were estimated for subsets defined by age, total cholesterol, high-density lipoprotein (HDL) cholesterol, blood pressure, diabetes and smoking categories. PRIM defined seven mutually exclusive subsets in women and men, with cumulative incidences of CHD from 0.01 to 0.22 in women, and from 0.03 to 0.26 in men. PRIM versus Framingham Point Score found 11% versus 4% of all women, and 31% versus 35% of all men to have 10 year CHD risks>20%. Among women≥65 years with hypertension and/or with diabetes, 10 year CHD risk>20% was found for 100% with PRIM scoring but for only 18% with the Framingham Point Score. Conclusion: Compared to the PRIM Score, common clinical practice with the Framingham Point Score underestimates CHD risk in women, especially in women≥65 years with hypertension and/or with diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Background: Several studies have indicated an association between depression and the development of stroke, but few studies have focused on gender differences, although both depression and stroke are more common in women than in men. The aim of the present study was to describe whether vital exhaustion, a measure of fatigue and depression, prospectively predicts ischemic and hemorrhagic strokes in a large cohort, with particular focus on gender differences. Methods: The cohort was composed of 5219 women and 3967 men without cardiovascular disease who were examined in the Copenhagen City Heart Study in 1991–1994. Subjects were followed for 6–9 years. Fatal and nonfatal strokes were ascertained from the Danish National Register of Patients. Cox proportional hazards model was used to describe vital exhaustion as a potential risk factor for stroke. Results: Four hundred nine validated strokes occurred. A dose–response relationship between vital exhaustion score and the risk of stroke was found in women reaching a hazard ratio (HR) of 2.27 (95% confidence interval: 1.42–3.62) for the group with the highest score. HR was only slightly attenuated by multivariate adjustment. There was no association between vital exhaustion score and stroke in men. HR was strongest for ischemic stroke, whereas no association was seen for hemorrhagic stroke. Conclusion: Vital exhaustion, a measure of fatigue, conveyed an increased risk of ischemic stroke in women, but not in men, in this study sample. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Objectives: We tested whether heterozygosity for the K776N mutation (frequency: 0.4%) in ATP-binding cassette transporter A1 (ABCA1) predicted ischemic heart disease (IHD) in the Copenhagen City Heart Study population. Background: In a complex trait like IHD, genetic variation is considered to be conferred by common DNA polymorphisms, although rare mutations may have a larger impact. Tangier disease, a rare high-density lipoprotein cholesterol (HDL-C) deficiency syndrome with IHD, is caused by homozygous ABCA1 mutations. Methods: We analyzed blood samples from a large cohort study of 9,076 Danish individuals followed for 24 years (167,287 person-years), during which 1,033 incident IHD events occurred. The hypothesis was retested in an independent case-control study comparing 562 IHD patients with 3,103 controls. Results: The cumulative incidence of IHD as a function of age was increased in K776N heterozygotes compared with non-carriers (log-rank test: p = 0.005). At the age of 80 years, 48% of heterozygotes and 23% of non-carriers had IHD. Incidence rates in non-carriers and K776N heterozygotes were 61 and 157 per 10,000 person-years. The age-adjusted hazard ratio for IHD in K776N heterozygotes versus non-carriers was 2.4 (95% confidence interval 1.3 to 4.5). Adjusting for HDL-C, or for smoking, diabetes, and hypertension did not change the result, suggesting that genotype predicted risk of IHD beyond that offered by HDL-C, and by other conventional risk factors. Similar trends were obtained in an independent case-control study. Conclusions: Heterozygosity for an ABCA1 mutation (K776N) conferred two- to three-fold risk of IHD in 37 participants in the Copenhagen City Heart study. [Copyright &y& Elsevier]

: ObjectivesWe tested the hypothesis that platelet glycoprotein (GP) IIb/IIIa PlA2/PlA2 homozygotes or PlA1/PlA2 heterozygotes versus PlA1/PlA1 noncarriers have increased risk of ischemic cardiovascular disease and myocardial infarction (MI), stratified for age and gender.: BackgroundThe GP IIb/IIIa PlA1/PlA2 polymorphism influences aggregation of platelets; however, an association between ischemic cardiovascular disease and heterozygosity remains controversial, and association with homozygosity is largely unexplored.: MethodsWe genotyped the participants of the Copenhagen City Heart Study, a prospective cardiovascular investigation of the Danish general population (n = 9,149, 22-year follow-up) and assessed the risk of ischemic cardiovascular disease in heterozygotes or homozygotes versus noncarriers.: ResultsOf the participants, 70.0%, 27.3%, and 2.7% were noncarriers, heterozygotes, or homozygotes, respectively. Incidence of ischemic cardiovascular disease was 167 and 103 per 10,000 person-years in homozygous and noncarrier men (log-rank: p = 0.006), whereas this difference was not observed in women (p = 0.33) (genotype·gender interaction: p = 0.03). In homozygous versus noncarrier men <40 years of age, 40 to 50 years, and >50 years at entry, age-adjusted relative risks (RRs) of ischemic cardiovascular disease were 3.6 (1.4 to 9.0), 2.4 (1.3 to 4.6), and 1.0 (0.6 to 1.8), respectively (age·genotype interaction in men: p = 0.04); equivalent multifactorially adjusted RRs were 3.0 (1.1 to 8.0), 2.0 (1.0 to 3.9), and 1.0 (0.6 to 1.8), respectively. The corresponding age-adjusted RR values of MI in men were 5.2 (1.5 to 18), 3.5 (1.6 to 7.5), and 0.5 (0.1 to 1.5), respectively (age·genotype interaction in men: p = 0.002); equivalent multifactorially adjusted RRs were 3.8 (1.0 to 15), 3.1 (1.4 to 6.9), and 0.5 (0.2 to 1.5), respectively.: ConclusionsPlA2/PlA2 homozygosity is associated with a three-fold and four-fold risk of ischemic cardiovascular disease and MI in young men. [Copyright &y& Elsevier]

Abstract: Background: It is largely unknown whether prostate-specific antigen (PSA) level at first date of testing predicts long-term risk of prostate cancer (PCa) incidence and mortality in the general population. Objective: Determine whether baseline PSA levels predict long-term risk of PCa incidence and mortality. Design, setting, and participants: We examined 4383 men aged 20–94 yr from the Danish general population in the prospective Copenhagen City Heart Study. PSA was measured in plasma samples obtained in 1981–1983. Measurements: PCa incidence and mortality as a function of baseline PSA was assessed using Kaplan-Meier plots of cumulative incidence and competing risk subhazard ratios. Results and limitations: During 28 yr of follow-up, 170 men developed PCa, and 94 men died from PCa. Median follow-up was 18 yr (range: 0.5–28 yr). For PCa incidence, the subhazard ratio was 3.0 (95% confidence interval [CI], 1.9–4.6) for a PSA level of 1.01–2.00 ng/ml, 6.8 (95% CI, 4.2–11) for PSA 2.01–3.00 ng/ml, 6.6 (95% CI, 3.4–13) for PSA 3.01–4.00 ng/ml, 16 (95% CI, 10.4–25) for PSA 4.01–10.00 ng/ml, and 57 (95% CI, 32–104) for PSA >10.00 ng/ml versus 0.01–1.00 ng/ml. For PCa mortality, corresponding subhazard ratios were 2.2 (95% CI, 1.3–3.9), 5.1 (95% CI, 2.8–9.0), 4.2 (95% CI, 1.8–10), 7.0 (95% CI, 3.8–14), and 14 (95% CI, 6.0–32). For men with PSA levels of 0.01–1.00 ng/ml, the absolute 10-yr risk of PCa was 0.6% for ages <45 yr, 0.7% for ages 45–49 yr, 1.1% for ages 50–54 yr, 1.2% for ages 55–59 yr, 1.3% for ages 60–64 yr, 1.1% for ages 65–69 yr, 1.3% for ages 70–74 yr, and 1.5% for ages ≥75 yr; corresponding values for PSA levels >10.00 ng/ml were 35%, 41%, 63%, 71%, 77%, 69%, 75%, and 88%, respectively. Conclusions: Stepwise increases in PSA at first date of testing predicted a 3–57-fold increased risk of PCa, a 2–16-fold increased risk of PCa mortality, and a 35–88% absolute 10-yr risk of PCa in men with PSA levels >10.00 ng/ml. Equally important, the absolute 10-yr risk of PCa in men with PSA levels 0.01–1.00 ng/ml was only 0.6–1.5%. [Copyright &y& Elsevier]

The objective of this study was to evaluate the prognostic value of the myocardial performance index (MPI), assessed by color-coded tissue Doppler imaging (TDI) M-mode through the anterior mitral leaflet. Color TDI M-mode through the mitral leaflet is an easy, very fast, and precise method to estimate cardiac intervals and thus obtain the MPI, but the diagnostic and prognostic values of this parameter are unknown. In a large population study, cardiac function was evaluated in 1,100 participants by conventional echocardiography and TDI. MPI was calculated from pulse-wave Doppler analyses of left ventricular in- and outflow using standard procedures (MPIconv) and by color-coded TDI M-mode through the mitral leaflet in the apical 4-chamber view (MPITDI). MPITDI was increased in subjects with coronary heart disease (CHD) compared to controls, even after multivariable adjustment (p <0.002). During follow-up (median 5.3 years), 90 participants died. MPITDI was significantly associated with overall mortality, and risk of dying increased by 31% per 0.1 increase in MPITDI. In contrast to MPIconv, MPITDI provided independent prognostic information in a multivariable Cox proportional hazard model (adjusting for age, gender, body mass index, heart rate, mean arterial blood pressure, and CHD), with a hazard ratio of 1.18 (p = 0.01) per 0.1 increase in MPITDI. In conclusion, MPITDI is a quick, simple, and reproducible measurement, which is increased in subjects with CHD and provides independent prognostic information in a low-risk population. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to examine the effect of PCSK9 R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality. Background: The 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies. Methods: We determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698). Results: In carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values <0.0001). Observed risk reductions for IHD in 46L allele carriers were: 6% in the CCHS study (hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.68 to 1.31), 46% in the CGPS study (odds ratio [OR]: 0.54; 95% CI: 0.39 to 0.77), 18% in the CIHDS study (OR: 0.82; 95% CI: 0.55 to 1.21), and 30% in the studies combined (OR: 0.70; 95% CI: 0.58 to 0.86). In the CCHS study, HR for mortality was 1.18 (95% CI: 0.93 to 1.50). In meta-analyses, 46L allele carriers had a 12% (0.43 mmol/l) reduction in LDL-C and a 28% reduction in risk of IHD (HR: 0.72; 95% CI: 0.62 to 0.84), similar to results in the CCHS, CGPS, and CIHDS studies combined. However, the observed 12% (0.43 mmol/l) reduction in LDL-C theoretically predicted an only 5% reduction in risk of IHD (HR: 0.95; 95% CI: 0.92 to 0.97). Conclusions: The PCSK9 46L allele was associated with reductions in LDL-C from 20 to 80+ years in the general population. The reduction in risk of IHD was larger than predicted by the observed reduction in LDL-C alone. This could be because genotype is a better predictor of lifelong exposure to LDL-C than LDL-C measured in adult life. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Objectives: This study was designed to test the hypotheses that single nucleotide polymorphisms (SNPs), in zinc finger protein 202 (ZNF202), predict severe atherosclerosis and ischemic heart disease (IHD). Background: ZNF202 is a transcriptional repressor controlling promoter elements in genes involved in vascular maintenance and lipid metabolism. Methods: We first determined genotype association for 9 ZNF202 SNPs with severe atherosclerosis (ankle brachial index >0.7 vs. ≤0.7) in a cross-sectional study of 5,355 individuals from the Danish general population. We then determined genotype association with IHD in 10,431 individuals from the Danish general population, the CCHS (Copenhagen City Heart Study), including 1,511 incident IHD events during 28 years of follow-up. Results were verified in 2 independent case-control studies including, respectively, 942 and 1,549 cases with IHD and 8,998 controls. Finally, we determined whether g.−660A>G altered transcriptional activity of the ZNF202 promoter in vitro. Results: Cross-sectionally, ZNF202 g.−660 GG versus AA homozygosity predicted an odds ratio for severe atherosclerosis of 2.01 (95% confidence interval [CI]: 1.34 to 3.01). Prospectively, GG versus AA homozygosity predicted a hazard ratio for IHD of 1.21 (95% CI: 1.02 to 1.43). In the 2 case-control studies, the equivalent odds ratios for IHD were 1.29 (95% CI: 1.02 to 1.62) and 1.60 (95% CI: 1.34 to 1.92), confirming the results from the prospective study. Only 2 other SNPs, which were highly correlated with g.−660A>G, also predicted risk of severe atherosclerosis and IHD. Finally, ZNF202 g.−660G versus g.−660A was associated with a 60% reduction in transcriptional activity in vitro, whereas none of the 2 correlated SNPs were predicted to be functional. Conclusions: Homozygosity for a common functional promoter variant in ZNF202 predicts severe atherosclerosis and an increased risk of IHD. [Copyright &y& Elsevier]

Purpose: The social gradient in prostate cancer incidence observed in several studies may be a result of differential access to prostate cancer screening. We aim to assess if socioeconomic status, stress, and marital status are associated with prostate cancer risk in a population with free access to health care. Methods: The 5,496 men who participated in the Copenhagen City Heart Study were asked about their income, educational level, stress level, and marital status during 1981–1983. These men were prospectively followed up in the Danish Cancer Registry until the end of 2002 and fewer than 0.1 % were lost to follow-up. Results: During follow-up, 157 men were diagnosed with prostate cancer. Neither high income (HR = 1.17, 95% confidence interval [CI]: 0.78–1.76) nor high education (HR = 1.22; 95% CI: 0.76–1.96) were associated with risk of prostate cancer. There were also no differences in prostate cancer risk according to stress (HR = 0.99; 95% CI: 0.90–1.09) or marital status. Conclusion: In a racially homogeneous population of Caucasians with free access to health care, we found no evidence of a relation between sociodemographic variables or stress and subsequent risk of prostate cancer. [Copyright &y& Elsevier]

Abstract: Objective: Zinc Finger Protein 202 (ZNF202) is a transcriptional repressor of genes affecting the vascular endothelium as well as lipid metabolism. A phenotype associated with genetic variation in ZNF202 is presently unknown. We tested the hypothesis that a common variant in ZNF202, A154V, predicts risk of ischemic heart disease (IHD), myocardial infarction (MI), and ischemic cerebrovascular disease (ICVD). Methods and results: We conducted a prospective study of more than 9000 individuals from the general population with 24 years follow-up. In women, age-adjusted hazard ratios in heterozygotes and homozygotes versus non-carriers were 1.2 (95% CI: 1.0–1.5, P =0.04) and 1.5 (1.1–2.1, P =0.007) for IHD, 1.5 (1.1–2.1; P =0.01) and 1.7 (1.1–2.8, P =0.02) for MI, and 1.3 (1.0–1.8, P =0.07) and 1.3 (0.8–2.1; P =0.33) for ICVD. Adjustments for lipids and lipoproteins did not alter these hazard ratios substantially. Genotype did not predict risk in men. Finally, results for IHD were borderline significant (P =0.06) in an independent case–control study including 933 patients and 8068 controls. Conclusion: This is the first study to suggest that ZNF202 could be a new candidate gene for IHD and MI in the general population. [Copyright &y& Elsevier]

When alcohol consumption is related to outcome, associations between alcohol type and health outcomes may occur simply because of the ethanol in the beverage type. When one analyzes the consequences of consumption of beer, wine, and spirits, the total alcohol intake must therefore be taken into account. However, owing to the linear dependency between total alcohol intake and the alcohol content of each beverage type, the effects cannot be separated from each other or from the effect of ethanol. In nutritional epidemiology, similar problems regarding intake of macronutrients and total energy intake have been addressed, and four methods have been proposed to solve the problem: energy partition, standard, density, and residual. The aim of this study was to evaluate the usefulness of the energy adjustment methods in alcohol analyses by using coronary heart disease as an example. Data obtained from the Copenhagen City Heart Study were used. The standard and energy partition methods yielded similar results for continuous, and almost similar results for categorical, alcohol variables. The results from the density method differed, but nevertheless were concordant with these. Beer and wine drinkers, in comparison with findings for nondrinkers, had lower risk of coronary heart disease. Except for the case of men drinking beer, the effect seemed to be associated with drinking one drink per week. The standard method derives influence of substituting alcohol types at constant total alcohol intake and complements the estimates of adding consumption of a particular alcohol type to the total intake. For most diseases, the effect of ethanol predominates over that of substances in the beverage type, which makes the density method less relevant in alcohol analyses. [Copyright &y& Elsevier]

: ObjectivesWe investigated associations between single nucleotide polymorphisms (SNPs) in the hepatic lipase promoter, levels of high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD). Our primary hypothesis was that these SNPs associate with IHD after adjustment for HDL levels.: BackgroundHepatic lipase influences HDL metabolism, and may thus affect reverse cholesterol transport and consequently risk of IHD.: MethodsWe genotyped 9,121 white subjects aged 20 to 93 years from the Copenhagen City Heart Study, 456 of whom had incident IHD, as well as 921 Danish patients with IHD for the −216, −480, and −729 SNPs in the hepatic lipase promoter.: ResultsFrequencies of wild-type, triple heterozygotes, and triple mutation homozygotes in the general population were 61%, 33%, and 5%, respectively. Compared with wild-type, HDL cholesterol levels were 4% (0.06 mmol/l) and 10% (0.15 mmol/l) higher in heterozygotes and mutation homozygotes; the equivalent values for apolipoprotein A1 were 3% and 7% higher. In prospective and case-control studies, mutation homozygotes versus wild-type had relative risk (RR) and odds ratio (OR) for IHD of 1.5 (95% confidence interval [CI]: 1.0 to 2.2) and 1.4 (CI: 1.1 to 1.9) when adjusted for age, gender, and HDL cholesterol. In individuals with the ∊43 apolipoprotein E genotype, RR and OR for IHD in mutation homozygotes versus wild-type was 2.9 (CI: 1.5 to 5.6) and 2.0 (CI: 1.2 to 3.2).: ConclusionsHepatic lipase promoter SNPs are associated with increased HDL cholesterol and, paradoxically, an increased risk of IHD after adjustment for HDL cholesterol, and particularly in individuals with apolipoprotein E ∊43 genotype. Implications are that increased HDL levels may in certain situations be not protective, but rather associated with increased IHD risk. [Copyright &y& Elsevier]