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Aims 3D echocardiographic (3DE) assessment of the left atrium (LA) is a new modality of potential clinical value. Age- and sex-based normative values are needed to benchmark these parameters for clinical use. Methods and results Of 4466 participants in the 5th Copenhagen City Heart Study, a prospective longitudinal cohort study on the general population, 2082 participants underwent 3DE of the LA. Healthy participants were included to establish normative values for LA strain, volume, and function by 3DE. The effects of age and sex were also evaluated. After excluding participants with comorbidities, 979 healthy participants (median age 44 years, 39.6% males) remained. The median and limits of normality (2.5th and 97.5th percentiles) for functional and volumetric measures were as follows: LA reservoir strain (LASr) 30.8% (18.4–44.2%), LA conduit strain (LAScd) 19.1% (6.8–32.0%), LA contractile strain 11.7% (4.3–22.2%), total LA emptying fraction (LAEF) 61.4% (47.8–71.0%), passive LAEF 37.7% (17.4–53.9%), active LAEF 37.4% (22.2–52.5%), LA minimum volume index (LAVimin) 10.2 (5.9–18.5) mL/m2, and LA maximum volume index (LAVimax) 26.8 (16.5–40.1) mL/m2. All parameters changed significantly with increasing age (P value for all <0.001). Significant sex-specific differences were observed for all parameters except active LAEF and LAVimax. Sex significantly modified the association between age and LASr (P for interaction < 0.001), LAScd (P for interaction < 0.001), LAVimin (P for interaction = 0.037), and total LAEF (P for interaction = 0.034) such that these parameters deteriorated faster with age in females than males. Conclusion We present age- and sex-specific reference material including limits of normality for LA strain, volume, and function by 3DE. [ABSTRACT FROM AUTHOR]

Aims Pressure-strain loop (PSL) analysis is a novel echocardiographic tool capable of assessing myocardial work non-invasively. In this study, we aim to evaluate the prognostic value of myocardial work indices in the general population. Methods and results This was a prospective community-based cohort study (n = 4466). PSL analyses were performed to acquire global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency (GWE). The endpoint was a composite of heart failure or cardiovascular death (HF/CVD). Survival analysis was applied. A total of 3932 participants were included in this analysis (median age: 58 years, 43% men). Of these, 124 (3%) experienced the outcome during a median follow-up period of 3.5 years [interquartile range (IQR): 2.6–4.4 years]. Hypertension significantly modified the association between all work indices and outcome (P for interaction < 0.05), such that work indices posed a higher risk of outcome in non-hypertensive than in hypertensive participants. After adjusting for Atherosclerosis Risk in Communities (ARIC)-HF risk variables, all work indices predicted outcome in non-hypertensive participants, but only GWI, GCW, and GWE predicted outcome in hypertensive participants [GWI: hazard ratio (HR) = 1.12 (1.07–1.16), per 100 mmHg% decrease; GCW: HR = 1.12 (1.08–1.17), per 100 mmHg% decrease; GWE: HR = 1.08 (1.04–1.12), per 1% decrease]. Only GWE significantly increased C -statistics when added to ARIC-HF risk variables in hypertensive participants (C -stat 0.865 vs. 0.877, P for increment = 0.003). Conclusion Hypertension modifies the association between myocardial work indices and HF/CVD in the general population. All work indices are associated with outcome in normotensive participants. GWI, GCW, and GWE are independently associated with outcome in hypertension, but only GWE improves risk prediction. [ABSTRACT FROM AUTHOR]

Aims This study investigated left atrial (LA) parameters as measured on transthoracic echocardiography as predictors of incident heart failure (HF) in a community cohort. Methods and results In a large general population study (n = 2221), participants underwent a health examination with echocardiography. The maximum and minimum LA volumes indexed to body surface area (LAVImax and LAVImin) were measured and the LA emptying fraction (LAEF) and LA expansion index (LAEI) were calculated. Among 1951 participants without atrial fibrillation or significant valve disease, the mean age was 59±16 years and 58% were women. At baseline, 1% (n = 16) had a left ventricular ejection fraction of <50%, 44% had hypertension, and 10% had diabetes. During follow-up (median 15.8 years, interquartile range: 11.3-16.2 years), 187 (10%) participants were diagnosed with incident HF. Participants who were diagnosed with HF during follow-up had a larger LAVImax and LAVImin and a lower LAEF and LAEI compared to participants without HF. In unadjusted analysis, LAVImax, LAVImin, LAEF and LAEI were predictors of incident HF. After multivariable adjustment for clinical and echocardiographic parameters, only LAVImin remained an independent predictor of incident HF (hazard ratio per 1 standard deviation increase: 1.22 [95% confidence interval 1.01-1.47], p = 0.038). Conclusion In the general population, LAVImin is an independent predictor of incident HF. LAVImax, currently the only LA measure in a routine echocardiographic examination, was not an independent predictor of incident HF. [ABSTRACT FROM AUTHOR]

Aims Left atrial enlargement predicts incident atrial fibrillation (AF). However, the prognostic value of peak atrial longitudinal strain (PALS) for predicting incident AF in participants from the general population is currently unknown. Our aim was to investigate if PALS can be used to predict AF and ischaemic stroke in the general population. Methods and results A total of 400 participants from the general population underwent a health examination, including two-dimensional speckle tracking echocardiography of the left atrium. The primary endpoint was incident AF at follow-up. All participants with known AF and prior stroke at baseline were excluded (n  = 54). The secondary endpoint consisted of the composite of AF and ischaemic stroke. During a median follow-up of 16 years, 36 participants (9%) were diagnosed with incident AF and 30 (7%) experienced an ischaemic stroke, resulting in 66 (16%) experiencing the composite outcome. PALS was a univariable predictor of AF [per 5% decrease: hazard ratio (HR) 1.42; 95% confidence interval (CI) (1.19–1.69), P  < 0.001]. However, the prognostic value of PALS was modified by age (P  = 0.002 for interaction). After multivariable adjustment PALS predicted AF in participants aged <65 years [per 5% decrease: HR 1.46; 95% CI (1.06–2.02), P  = 0.021]. In contrast, PALS did not predict AF in participants aged ≥65 years after multivariable adjustment [per 5% decrease: HR 1.05; 95% CI (0.81–1.35), P  = 0.72]. PALS also predicted the secondary endpoint in participants aged <65 years and the association remained significant after multivariable adjustment. Conclusion In a low-risk general population, PALS provides novel prognostic information on the long-term risk of AF and ischaemic stroke in participants aged <65 years. [ABSTRACT FROM AUTHOR]

Background: The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) may be a more accurate measure of LV filling pressure then ratio of early filling pressure to early tissue velocity. The aim of the study was to investigate the impact of age, sex, obesity, smoking, hypertension, hypercholesterolemia, diabetes, physical activity level, socioeconomic, and psychosocial status on E/e'sr over a decade. Additionally, the predictive value of ΔE/e'sr on future major adverse cardiovascular events (MACE) has never been explored. Method: The study included 623 participants from the general population, who participated in the 4th and 5th Copenhagen City Heart Study (CCHS4 and CCHS5). Examinations were median 10 years apart. MACE was the composite endpoint of heart failure, myocardial infarction, and all‐cause death. Results: Follow‐up time was median 5.7 years, and 43 (7%) experienced MACE. Mean age was 51 ± 14 years, and 43% were male. Mean ΔE/e'sr was 2.1 ± 23.0 cm. After multivariable adjustment for demographic, clinical, and biochemistry variables, high age (stand. β‐coef. =.24, P <.001) and mean arterial blood pressure (MAP) (stand. β‐coef. =.17, P <.001) were significantly associated with an accelerated increase in E/e'sr In multivariable Cox regression, E/e'sr at CCHS5 and ΔE/e'sr were independent predictors of MACE (HR = 1.20, 95% CI [1.01; 1.42] per 10 cm increase for both). ΔE/e'sr did only provide incremental prognostic value to change in left atrial volume index of the conventional diastolic measurements. Conclusion: In the general population, age and MAP were predictors of an accelerated increase in E/e'sr over a decade. E/e'sr at CCHS5 and ΔE/e'sr were independent predictors of future MACE. [ABSTRACT FROM AUTHOR]

Life-course epidemiology seeks to better understand the mechanisms that lead to the development of chronic diseases. An example is the mechanism leading from body size to coronary heart disease (CHD); one way to acquire a better understanding of this mechanism is to investigate to what extent it works through other risk factors. In this paper, the dynamic path analysis model is presented as a tool to analyze these dynamic mechanisms in life-course epidemiology. A key feature of dynamic path analysis is its ability to decompose the total effect of a risk factor into a direct effect (not mediated by other variables) and indirect effects (mediated through other variables). This is illustrated by examining the associations between repeated measurements of body mass index (BMI) and systolic blood pressure (SBP) and the risk of CHD in a sample of Danish men between 1976 and 2006. The effect of baseline BMI on the risk of CHD is decomposed into a direct effect and indirect effects going through later BMI, concurrent SBP, or later SBP. In conclusion, dynamic path analysis is a flexible tool that by the decomposition of effects can be used to increase the understanding of mechanisms that underlie the etiology of chronic disease. [ABSTRACT FROM AUTHOR]

Background: Potassium supplementation reduces the risk of cardiovascular mortality and stroke in population studies; however, the prognostic impact of mild hypokalemia in the general population has not been thoroughly investigated. We aimed to investigate associations between mild hypokalemia and endpoints in the general population.Methods: Participants (aged 48-76 years) from the general population study "Copenhagen City Heart Study" (n = 5916) were studied. Participants were divided into groups according to baseline values of plasma potassium (potassium): hypokalemia (<3.7 mmol/L, n = 758), normokalemia (3.7-4.5 mmol/L, n = 4973), and high potassium (>4.5 mmol/L, n = 185). Hypokalemia was further divided as potassium <3.4 mmol/L and 3.4-3.6 mmol/L. The primary endpoints were all-cause mortality and nonfatal validated ischemic stroke. The secondary endpoint was acute myocardial infarction (AMI). We adjusted for conventional risk factors, diuretics, and atrial fibrillation at baseline.Results: Mean potassium in the hypokalemic group was 3.5 mmol/L (range, 2.6-3.6 mmol/L) and was associated (P < 0.05) with increased systolic blood pressure, higher CHA2DS2-VASc score, and increased use of diuretics as compared with normokalemia. Baseline atrial fibrillation was equally frequent across groups. Median follow-up-time was 11.9 years (Q1-Q3: 11.4-12.5 years). Hypokalemia was borderline associated with increased stroke risk in a multivariable Cox model (including adjustment for competing risk) as compared with normokalemia (hazard ratio [HR] 1.40; 95% confidence interval [CI], 1.00-1.98). The subgroup with potassium <3.4 mmol/L had higher stroke risk (HR 2.10; 95% CI, 1.19-3.73) and mortality risk (HR 1.32; 95% CI, 1.01-1.74) as compared with normokalemia. Hypokalemia was not associated with AMI, and no increased risk of mortality was seen with concomitant AMI and hypokalemia. No associations were seen with high potassium.Conclusion: In a general population mild hypokalemia is associated with increased stroke risk and, to a lesser degree, increased mortality risk. [ABSTRACT FROM AUTHOR]

Background: Most adults ingest alcoholic beverages. Alcohol shows strong and positive associations with blood pressure (BP). We hypothesized that intake of red wine, white wine, beer, and spirits and dessert wine show similar associations with BP in the general population., Methods: We included 104,467 males and females aged 20-100 years in the analysis of the Danish general population. Alcohol use and type of alcohol were assessed by questionnaire. Blood pressure was measured by automated digital BP manometer. Multivariable linear regression models were used when analyzing the association between number of drinks per week and BP, stratified by sex and adjusted for relevant confounders. Each alcohol type (red wine, white wine, beer, and spirits and dessert wine) was analyzed in similar models including adjustment for other alcohol types., Results: Most of the subjects (76,943 [73.7%]) drank more than 1 type of alcohol. However, 12,093 (12.6%) consumed red wine only, 4288 (4.5%) beer only, 1815 (1.9%) white wine only, and 926 (1.0%) spirits and dessert wine only. There was a dose-response association between total drinks per week and systolic and diastolic BP (SBP, DBP) (P < .001). The crude difference was 11 mmHg SBP and 7 mmHg DBP between high (>35 drinks per week) and low (1-2 drinks per week) alcohol intake. Overall, SBP was increased by 0.15-0.17 mmHG, and DBP was increased by 0.08-0.15 mmHg per weekly drink. After stratification for age and sex, effects were slightly higher among females and among individuals aged less than 60 years., Conclusion: Alcohol intake is associated with highly significant increased SPB and DBP. The effect is similar for red wine, white wine, beer, and spirits., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: 3D echocardiographic (3DE) assessment of the left atrium (LA) is a new modality of potential clinical value. Age- and sex-based normative values are needed to benchmark these parameters for clinical use., Methods and Results: Of 4466 participants in the 5th Copenhagen City Heart Study, a prospective longitudinal cohort study on the general population, 2082 participants underwent 3DE of the LA. Healthy participants were included to establish normative values for LA strain, volume, and function by 3DE. The effects of age and sex were also evaluated. After excluding participants with comorbidities, 979 healthy participants (median age 44 years, 39.6% males) remained. The median and limits of normality (2.5th and 97.5th percentiles) for functional and volumetric measures were as follows: LA reservoir strain (LASr) 30.8% (18.4-44.2%), LA conduit strain (LAScd) 19.1% (6.8-32.0%), LA contractile strain 11.7% (4.3-22.2%), total LA emptying fraction (LAEF) 61.4% (47.8-71.0%), passive LAEF 37.7% (17.4-53.9%), active LAEF 37.4% (22.2-52.5%), LA minimum volume index (LAVimin) 10.2 (5.9-18.5) mL/m2, and LA maximum volume index (LAVimax) 26.8 (16.5-40.1) mL/m2. All parameters changed significantly with increasing age (P value for all <0.001). Significant sex-specific differences were observed for all parameters except active LAEF and LAVimax. Sex significantly modified the association between age and LASr (P for interaction < 0.001), LAScd (P for interaction < 0.001), LAVimin (P for interaction = 0.037), and total LAEF (P for interaction = 0.034) such that these parameters deteriorated faster with age in females than males., Conclusion: We present age- and sex-specific reference material including limits of normality for LA strain, volume, and function by 3DE., Competing Interests: Conflict of interest: M.Y.: none; F.J.O.: none; K.G.S.: advisory board: Sanofi Pasteur; M.C.H.L.: none; N.D.J.: none; F.L.L.: none; G.B.J.: none; P.Sc.: none; R.M.: none; P.Sø.: advisory board: Biotronik; and T.B.-S.: Steering Committee member of the Amgen-financed GALACTIC-HF trial; Steering Committee member of the Boehringer Ingelheim–financed SHARP3 trial; chief investigator of the Sanofi Pasteur–financed ‘NUDGE-FLU’ trial; chief investigator of the Sanofi Pasteur–financed ‘DANFLU-1’ trial; chief investigator of the Sanofi Pasteur–financed ‘DANFLU-2’ trial; Steering Committee member of ‘LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System’ trial; advisory board: Sanofi Pasteur, Amgen, and GSK; speaker honorarium: Bayer, Novartis, Sanofi Pasteur, and GSK; and research grants: GE Healthcare, AstraZeneca, Novo Nordisk, and Sanofi Pasteur., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Mitral regurgitation (MR) can be difficult to quantify. We sought to investigate whether the MR jet area to left atrial (LA) area ratio (MR/LA ratio) method for quantifying MRs can be used to predict incident atrial fibrillation (AF) in the general population., Methods and Results: The study included 4466 participants from the 5th Copenhagen City Heart Study, a prospective general population study, who underwent transthoracic echocardiography. MR jet area was measured and indexed to LA area. The endpoint was incident AF. MR was quantified in 4042 participants (mean age: 57 years, 43% men). Of these, 198 (4.9%) developed AF during a median follow-up period of 5.3 years (interquartile range: 4.4-6.1 years). MR was present in 1938 participants (48%) including 1593 (39%) trace/mild MRs (MR/LA ratio ≤ 20% and ≤4 cm2). In unadjusted analysis, MR/LA ratio was associated with incident AF [HR: 1.06 (1.00-1.13), P = 0.042 per 5% increase] but not after adjusting for CHARGE-AF score. However, the association was modified by age (P for interaction = 0.034), such that MR/LA ratio was associated with AF only in participants ≤ 73 years. In these participants, MR/LA ratio 'was' independently associated with AF after adjusting for CHARGE-AF score [HR: 1.14 (1.06-1.24), P = 0.001, per 5% increase]. This finding persisted when restricting the analysis to participants without moderate or severe MR and normal LA size [HR: 1.35 (1.09-1.68), P = 0.005, per 5% increase]., Conclusion: MR, including even trace regurgitations quantified by MR/LA ratio, is independently associated with incident AF in individuals ≤ 73 years of age., Competing Interests: Conflict of interest: M.Y.: none. F.J.O.: none. A.S.: none. K.G.S.: advisory board: Sanofi Pasteur. M.C.H.L.: none. N.D.J.: none. M.T.J.: none. G.B.J.: none. P.S.: none. R.M.: none. T.B.-S.: Steering Committee member of the Amgen financed GALACTIC-HF trial. Chief investigator of the Sanofi Pasteur financed ‘NUDGE-FLU’ trial. Chief investigator of the Sanofi Pasteur financed ‘DANFLU-1’ trial. Chief investigator of the Sanofi Pasteur financed ‘DANFLU-2’ trial. Steering Committee member of ‘LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System’ trial. Advisory board: Sanofi Pasteur, Amgen, and GSK. Speaker honorarium: Bayer, Novartis, Sanofi Pasteur, and GSK. Research grants: GE Healthcare, Sanofi Pasteur, Novo Nordisk, and AstraZeneca., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To investigate the association between the duration of weekly leisure-time sports activity and all-cause mortality., Methods: As part of the prospective Copenhagen City Heart Study, 8697 healthy adults completed a comprehensive questionnaire about leisure-time sports activities. Duration (minutes per week) of leisure-time sports activities was recorded for tennis, badminton, soccer, handball, cycling, swimming, jogging, calisthenics, health club activities, weightlifting, and other sports. The primary end point was all-cause mortality, and the median follow-up was 25.6 years. The association between duration of leisure-time sports activities and all-cause mortality was studied using multivariable Cox proportional hazards regression analysis., Results: Compared with the reference group of 2.6 to 4.5 hours of weekly leisure-time sports activities, we found an increased risk for all-cause mortality for those with 0 hours (hazard ratio [HR], 1.51; 95% CI, 1.29 to 1.76), for those with 0.1 to 2.5 hours (HR, 1.24; 95% CI, 1.05 to 1.46), and for those with more than 10 hours (HR, 1.18; 95% CI, 1.00 to 1.39) of weekly leisure-time sports activities. These relationships were generally consistent with additional adjustments for potential confounders among subgroups of age, sex, education, smoking, alcohol intake, and body mass index, when the first 5 years of follow-up were excluded, and for cardiovascular disease mortality., Conclusion: We observed a U-shaped association between weekly duration of leisure sports activities and cardiovascular and all-cause mortality, with lowest risk for those participating in 2.6 to 4.5 weekly hours, being consistent across subgroups. Participation in sport activities should be promoted, but the potential risk of very high weekly hours of sport participation should be considered for inclusion in guidelines and recommendations., (Copyright © 2021. Published by Elsevier Inc.)

Background: Global longitudinal strain (GLS) is a sensitive marker of myocardial dysfunction and atrial reservoir function. We sought to evaluate its value for predicting atrial fibrillation (AF) in the general population., Methods: Participants from the Copenhagen City Heart Study examined with echocardiography, including speckle tracking analyses, were included. The endpoint was AF obtained through national registries. Proportional hazards Cox regression was applied, including multivariable adjustments made for CHADS 2 and CHARGE-AF risk factors. Abnormal GLS was defined as >-18%., Results: The data from 1,309 participants were analyzed. Of those, 153 (12%) developed AF during a median follow-up time of 15.9 years. The follow-up was 100%. The mean age was 57 years, 38% had hypertension, and GLS was  - 18%. In unadjusted analysis, GLS was a univariable predictor of outcome (1.08 (1.04-1.13), p < 0.001, per 1% absolute decrease), but did not remain an independent predictor after adjusting for neither CHADS 2 nor CHARGE-AF risk factors. However, hypertension modified the relationship between GLS and AF (p for interaction = 0.010), such that GLS only predicted AF in subjects without hypertension. In participants without hypertension, GLS remained an independent predictor of AF after adjusting for CHADS 2 and CHARGE-AF (HR = 1.11 (1.03-1.20) and HR = 1.09 (1.01-1.19), respectively). In these participants, an abnormal GLS was associated with a more than twofold increased risk of AF (HR = 2.16 (1.26-3.72). The incidence rate was 3.17 and 6.81 per 1000 person-years for normal vs. abnormal GLS, respectively., Conclusion: Global longitudinal strain predicts AF in individuals without hypertension from the general population, independently of common risk scores., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective Prolonged seated immobility during long-distance flights is related to an increased risk of venous thromboembolism (VTE), but little, if anything, is known about the risk related to sedentary work. The objective of this paper was to examine the risk of VTE according to sitting posture at work. Methods This prospective study includes a total of 78 936 participants from the Copenhagen City Heart Study and the Copenhagen General Population Study, all without previous thromboembolic events and aged <65 years. An assessment of the number of hours spent in sitting position at work was assigned each participant at baseline using a job exposure matrix. VTE was identified through national patient registries. Survival analyses were performed to determine the risk of VTE according to sedentary position at work with adjustment for a range of known determinants including lifestyle and coagulation factors. Results During the follow-up period of 582 411 person years (mean follow-up, 7.4 years) 911 participants experienced their first VTE event. Multivariable adjusted analyses showed no difference in risk of VTE between occupational sitting ≥6.5 hours/day and occupational sitting ≤3.5 hours/day (hazard ratio 1.11, 95% confidence interval 0.92-1.34). Conclusion This study does not support the hypothesis that sedentary work is a risk factor for VTE in the general population. Whether certain occupations with particularly high exposure to immobilized sitting positions are associated with thromboembolic events is not addressed.

Aims: The incidence of atrial fibrillation (AF) has increased significantly over the last decades. Population height is changing in many countries. Height is an important risk factor for AF. The aim of the present study was to assess the role of changes in population height in the increased risk of AF., Methods and Results: The Copenhagen City Heart Study comprises 18 852 randomly selected men and women aged 20-93 years, studied in four separate cross-sectional surveys in 1976-78, 1981-83, 1991-94, and 2001-03, including physical examination, electrocardiogram (ECG), and standard questionnaires. Hospitalization and mortality data were collected from public registers. Prevalent AF was determined from ECGs and incident AF from register diagnoses. During follow-up, age-standardized prevalence of AF increased significantly from 1.35% to 2.11% in men and from 0.67% to 1.07% in women (P < 0.001). Incident AF increased four-fold in both men and women [hazard ratio (HR) 4.16, 95% confidence interval (CI) 3.27-5.29; P < 0.001]. In multivariable Fine and Gray subdistribution hazards regression analyses, height was consistently an important risk factor for incident AF with HRs between 1.35 (95% CI 1.10-1.66; P = 0.004) and 1.65 (95% CI 1.40-1.93; P < 0.001). Population height increased with 3.3 cm for men and 2.1 cm for women, and population attributable risks for height was 20-30%., Conclusion: Height is a powerful risk factor for AF. Adult height is attained at age 20, while AF incidence occurs 50 years later. Given a causal relationship between height and AF incidence, increased population height in Denmark will contribute to an increase in AF occurrence for at least 25 more years.

Objective: To evaluate the differential improvements in life expectancy associated with participation in various sports., Patients and Methods: The Copenhagen City Heart Study (CCHS) is a prospective population study that included detailed questionnaires regarding participation in different types of sports and leisure-time physical activity. The 8577 participants were followed for up to 25 years for all-cause mortality from their examination between October 10, 1991, and September 16, 1994, until March 22, 2017. Relative risks were calculated using Cox proportional hazards models with full adjustment for confounding variables., Results: Multivariable-adjusted life expectancy gains compared with the sedentary group for different sports were as follows: tennis, 9.7 years; badminton, 6.2 years; soccer, 4.7 years; cycling, 3.7 years; swimming, 3.4 years; jogging, 3.2 years; calisthenics, 3.1 years; and health club activities, 1.5 years., Conclusion: Various sports are associated with markedly different improvements in life expectancy. Because this is an observational study, it remains uncertain whether this relationship is causal. Interestingly, the leisure-time sports that inherently involve more social interaction were associated with the best longevity-a finding that warrants further investigation., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease., Methods: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs., Results: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05-1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07-1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events., Conclusions: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease., Methods and Results: CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C-reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample (hazard ratio per SD increase, 1.13; 95% confidence interval, 1.05-1.22; P =0.001 for TNFR1; hazard ratio, 1.16; 95% confidence interval, 1.08-1.24; P <0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%)., Conclusions: Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The CLARICOR trial reported that clarithromycin compared with placebo increased all-cause mortality in patients with stable coronary heart disease. This study investigates the effects of clarithromycin versus placebo during 10years follow up., Methods: The CLARICOR trial is a randomised, placebo-controlled trial including 4373 patients with stable coronary heart disease. The interventions were 2weeks of clarithromycin 500mg a day versus placebo. 10year follow up was performed through Danish public registers and analysed with Cox regression., Results: Clarithromycin increased all-cause mortality (hazard ratio (HR): 1.10, 95% confidence interval (CI): 1.00-1.21) and cerebrovascular disease during 10years (HR: 1.19, 95% CI: 1.02-1.38). The increased mortality and morbidity were restricted to patients not on statin at entry (HR: 1.16, 95% CI: 1.04-1.31, and HR: 1.25, 95% CI: 1.03-1.50). The assumption of constant HR during the 10years was violated for cardiovascular death (P=0.01) and cardiovascular death outside hospital (P<0.0005). Analyses of the effects over time showed that clarithromycin increased cardiovascular mortality during the first three years (HR: 1.42, 95% CI: 1.09-1.84) due to increased cardiovascular mortality outside hospital in patients not on statin (HR: 2.36, 95% CI: 1.60-3.50). During the last 4years, cardiovascular death outside hospital was lower in the clarithromycin group (HR: 0.64, 95% CI: 0.46-0.88)., Conclusion: Clarithromycin increased mortality due to cardiovascular death outside hospital and cerebrovascular morbidity in patients with stable coronary heart disease who were not on statin. The increased cardiovascular mortality was years later compensated, likely through frailty attrition., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: The aim of this study is to evaluate whether a changing population alcohol intake is capable of setting off a shift in the blood pressure distribution in the untreated part of a population. The focus is on subjects with an alcohol intake well below the limits of alcoholism because these subjects make out the majority of the population. The Copenhagen City Heart Study is a prospective longitudinal epidemiological study. The untreated study population was followed over 20years. Specially trained technicians using a blinded sphygmomanometer measured BP once with the subject in the sitting position. The BP measurement was fully standardised and the measurement method was unchanged throughout the observation period. A questionnaire concerning drinking habits was completed by the participants and double-checked by the technicians. The results were a decreasing population systolic BP and an increasing self-reported alcohol intake. The population increase was based on an increasing proportion of light to moderate drinkers. There was no effect of a moderately increasing alcohol intake as a covariate in a multivariate analysis of population systolic BP., Conclusion: A moderately increasing population alcohol intake cannot explain the observed changes in population systolic blood pressure., (Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Patients with stable coronary artery disease (CAD) have a poor prognosis. The aim of the study was to evaluate the extent to which serum high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement alone or together could be prognostic biomarkers in patients with stable CAD., Materials and Methods: During the 2.6-year follow-up period 270 patients among the 4264 patients with stable CAD in the CLARICOR trial suffered myocardial infarction (MI) and 377 died (187 cardiovascular deaths (CVD))., Results: Serum NT-proBNP was significantly associated with MI (hazard ratio (HR), 1. 65 (refers to a 2.72 fold increase in serum level, p = 0.0005), CVD (HR, 2.42, p < 0.0005) and non-CVD (HR, 1.79, p < 0.0005). When correcting for hs-CRP, NT-proBNP was still significantly associated with MI (HR, 1.63, p = 0.0005), CVD (HR, 2.36, p < 0.0005) and non-CVD (HR, 1.66, p < 0.0005). Serum hs-CRP was compared to NT-proBNP less associated with MI (HR, 1.20, p = 0.001), CVD (HR, 1.39, p < 0.0005) and non-CVD (HR, 1.67, p < 0.0005). When corrected for NT-proBNP, hs-CRP was only associated with non-CVD (HR, 1.51, p < 0.0005). When adjusting for cardiovascular risk factors hs-CRP predicted non-CVD (HR, 1.46) and all-cause death (HR, 1.24) and NT-proBNP predicted MI (HR, 1.50), CVD (HR, 1.98), non-CVD (HR, 1.39), and all-cause death (HR, 1.62)(p < 0.0005 for all)., Conclusion: Increased serum NT-proBNP was a stronger predictor of MI, cardiovascular death and non-cardiovascular death than hs-CRP in patients with stable CAD. Once NT-proBNP was taken into account, hs-CRP did not improve predictions.

Objectives: To elucidate potential mechanisms for the clarithromycin-induced excess mortality observed in the CLARICOR trial during 2.6 year follow-up of patients with stable coronary artery disease., Methods: Cox analyses using out-of-hospital death as a proxy for sudden death compared to in-hospital (nonsudden) death., Result: In 100 of 189 (53%) cardiovascular (CV) deaths in which it was possible to examine the question, there was a strong association between place of death and the classification of CV death as sudden or not-sudden. The excess mortality in the clarithromycin group was confined to sudden CV death in patients not on statins at trial entry (HR: 2.61, 95% CI: 1.69-4.05, p < 0.0005). Other categories of deaths showed no marked drug-placebo difference., Conclusions: Short-term clarithromycin administration was significantly associated with increased risk of sudden CV death in stable coronary heart disease patients not using statins., (Copyright © 2011 S. Karger AG, Basel.)

Objectives: We have reported increased 2.6-year mortality in clarithromycin- versus placebo-exposed stable coronary heart disease patients, but meta-analysis of randomized trials in coronary heart disease patients showed no significant effect of antibiotics on mortality. Here we report the 6-year mortality of clarithromycin- versus placebo-exposed patients and updated meta-analyses., Methods: Centrally randomized, placebo controlled multicenter trial. All parties were blinded. Analyses were by intention to treat. Meta-analyses followed the Cochrane Collaboration methodology., Results: We randomized 4,372 patients with stable coronary heart disease to clarithromycin 500 mg (n = 2,172) or placebo (n = 2,200) once daily for 2 weeks. Mortality was followed through public register. Nine hundred and twenty-three patients (21.1%) died. Six-year mortality was significantly higher in the clarithromycin group (hazard ratio 1.21, 95% confidence interval 1.06-1.38). Adjustment for entry characteristics (sex, age, prior myocardial infarction, center, and smoking) did not change the results (1.18, 1.04-1.35). Addition of our data to that of other randomized trials on antibiotics for patients with coronary heart disease versus placebo/no intervention (17 trials, 25,271 patients, 1,877 deaths) showed a significantly increased relative risk of death from antibiotics of 1.10 (1.01-1.20) without heterogeneity., Conclusions: Our results stress the necessity to consider carefully the strength of the indication before administering antibiotics to patients with coronary heart disease., (Copyright 2008 S. Karger AG, Basel.)

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.