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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]

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]

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]

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]

: 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]