Aortic Root Dimension Using Transthoracic Echocardiography: Results from the Copenhagen City Heart Study.

Findings regarding the relation between aortic size and risk factors are heterogeneous. This study aimed to generate new insights from a population-based adult cohort on aortic root dimensions and their association with age, anthropometric measures, and cardiac risk factors and evaluate the incidence of acute aortic events. Participants from the fifth examination round of the Copenhagen City Heart study (aged 20 to 98 years) with applicable echocardiograms and no history of aortic disease or valve surgery were included. Aorta diameter was assessed at the annulus, sinus of Valsalva, sinotubular junction, and the tubular part of the ascending aorta. The study population comprised 1,796 men and 2,316 women; mean age: 56.4 ± 17.0 and 56.9 ± 18.1 years, respectively. Men had larger aortic root diameters than women regardless of height indexing (p <0.01). Age, height, weight, systolic and diastolic blood pressure, mean arterial pressure, pulse pressure, hypertension, diabetes, ischemic heart disease, and smoking were positively correlated with aortic sinus diameter in the crude and gender-adjusted analyses. However, after full adjustment, only height, weight, and diastolic blood pressure remained significantly positively correlated with aortic sinus diameter (p <0.001). For systolic blood pressure and pulse pressure, the correlation was inverse (p <0.001). During follow-up (median 5.4 [quartile 1 to quartile 3 4.5 to 6.3] years), the incidence rate of first-time acute aortic events was 13.6 (confidence interval 4.4 to 42.2) per 100,000 person-years. In conclusion, beyond anthropometric measures, age, and gender, diastolic blood pressure was the only cardiac risk factor that was independently correlated with aortic root dimensions. The number of aortic events during follow-up was low.

Use of sugar in coffee and tea and long-term risk of mortality in older adult Danish men: 32 years of follow-up from a prospective cohort study.

BACKGROUND: Tea and coffee are the most consumed beverages worldwide and very often sweetened with sugar. However, the association between the use of sugar in tea or coffee and adverse events is currently unclear. OBJECTIVES: To investigate the association between the addition of sugar to coffee or tea, and the risk of all-cause mortality, cardiovascular mortality, cancer mortality and incident diabetes mellitus. METHODS: Participants from the prospective Copenhagen Male Study, included from 1985 to 1986, without cardiovascular disease, cancer or diabetes mellitus at inclusion, who reported regular coffee or tea consumption were included. Self-reported number of cups of coffee and tea and use of sugar were derived from the study questionnaires. Quantity of sugar use was not reported. Primary outcome was all-cause mortality and secondary endpoints were cardiovascular mortality, cancer mortality and incident diabetes mellitus, all assessed through the Danish national registries. The association between adding sugar and all-cause mortality was analyzed by Cox regression analysis. Age, smoking status, daily alcohol intake, systolic blood pressure, body mass index, number of cups of coffee and/or tea consumed per day and socioeconomic status were included as covariates. Vital status of patients up and until 22.03.2017 was assessed. Sugar could be added to either coffee, tea or both. RESULTS: In total, 2923 men (mean age at inclusion: 63±5 years) were included, of which 1007 (34.5%) added sugar. In 32 years of follow-up, 2581 participants (88.3%) died, 1677 in the non-sugar group (87.5%) versus 904 in the sugar group (89.9%). Hazard ratio of the sugar group compared to the non-sugar group was 1.06 (95% CI 0.98;1.16) for all-cause mortality. An interaction term between number of cups of coffee and/or tea per day and adding sugar was 0.99 (0.96;1.01). A subgroup analysis of coffee-only drinkers showed a hazard ratio of 1.11 (0.99;1.26). The interaction term was 0.98 (0.94;1.02). Hazard ratios for the sugar group compared to the non-sugar group were 1.11 (95% CI 0.97;1.26) for cardiovascular disease mortality, 1.01 (95% CI 0.87;1.17) for cancer mortality and 1.04 (95% CI 0.79;1.36) for incident diabetes mellitus. CONCLUSION: In the present population of Danish men, use of sugar in tea and/or coffee was not significantly associated with increased risk of mortality or incident diabetes.

Changes in cardiac time intervals over a decade and the risk of incident heart failure: The Copenhagen City Heart Study.

BACKGROUND: The cardiac time intervals include the isovolumic contraction time (IVCT), the left ventricular ejection time (LVET), the isovolumic relaxation time (IVRT) and the combination of all the cardiac time intervals in the myocardial performance index (MPI) (defined as [(IVCT+IVRT)/LVET)]. Whether the cardiac time intervals change over time and which clinical factors that accelerate these changes is not well-established. Additionally, whether these changes are associated with subsequent heart failure (HF), remains unknown. METHODS: We investigated participants from the general population (n = 1064) who had an echocardiographic examination including color tissue Doppler imaging performed in both the 4th and 5th Copenhagen City Heart Study. The examinations were performed 10.5 years apart. RESULTS: The IVCT, LVET, IVRT and MPI increased significantly over time. None of the investigated clinical factors were associated with increase in IVCT. Systolic blood pressure (standardized ß= - 0.09) and male sex (standardized ß= - 0.08) were associated with an accelerated decrease in LVET. Age (standardized ß=0.26), male sex (standardized ß=0.06), diastolic blood pressure (standardized ß=0.08), and smoking (standardized ß=0.08) were associated with an increase in IVRT, while HbA1c (standardized ß= - 0.06) was associated with a decrease in IVRT. Increasing IVRT over a decade was associated with an increased risk of subsequent HF in participants aged <65 years (per 10 ms increase: HR 1.33; 95%CI (1.02-1.72), p = 0.034). CONCLUSION: The cardiac time increased significantly over time. Several clinical factors accelerated these changes. An increase in IVRT was associated with an increased risk of subsequent HF in participants aged <65 years.

A Review of Major Danish Biobanks: Advantages and Possibilities of Health Research in Denmark.

Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health - Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications.

Socioeconomic disparity in cardiovascular disease: Possible biological pathways based on a proteomic approach.

BACKGROUND AND AIMS: Large social disparities in the occurrence of cardiovascular disease (CVD) have been documented but the underlying biological mechanisms are largely unknown. We investigated a panel of biomarkers linked to CVD to improve our understanding and quantify the biological pathways in socioeconomic disparity in CVD and their mediation through behavioural and biological risk factors. METHODS: We included 1142 participants from the Copenhagen City Heart Study aged 55-64 years. Socioeconomic position (SEP) was defined by the length of education and household income. Blood samples were analysed for 184 biomarkers (Olink). Pearson's correlation analysis and linear regression with multivariate adjustment for CVD risk factors were performed. RESULTS: The median length of education was 10 (IQR 7-11) years and associated with age, sex, BMI, smoking, blood pressure, physical activity and income. 48 biomarkers were significantly correlated (p < 0.05) to the length of education. The strongest negative associations were seen for interleukin-6 (IL-6), metalloproteinase 12, growth/differentiation factor 15 (GDF-15), retinoic acid receptor responder protein 2 (RARRES2), leptin (LEP), von Willebrand factor (vWF), and renin (REN) (all p < 0.0001) while the strongest positive associations were seen for chymotrypsin, paraoxonase, epidermal growth factor receptor (EGFR) and brother of CDO (cell adhesion and platelet activation) (all p < 0.001). Proportion mediated by CVD risk factors ranged from <1% to 100%. After multivariate adjustment, 14 biomarkers remained significantly associated with education. CONCLUSIONS: SEP was associated with multiple biomarkers, indicating pathways involving inflammation (IL-6, RARRES2), platelet-activation (vWF, IL-6), blood pressure (REN, LEP) and Mitogen-activated protein kinase cascade (GDF-15, EGFR) may contribute to the socioeconomic differences in CVD.

AHRR (cg05575921) Methylation Safely Improves Specificity of Lung Cancer Screening Eligibility Criteria: A Cohort Study.

BACKGROUND: Screening reduces lung cancer mortality, but specificities of eligibility criteria are low. We tested if leukocyte AHRR(cg05575921) methylation improves specificity of lung cancer screening eligibility criteria. METHODS: A total of 9,206 and 5,370 individuals of the 1991 to 1994 and 2001 to 2003 examinations of the Copenhagen City Heart Study, Denmark, were followed for lung cancer within 5 years after examination and mortality. Screening eligibility criteria (DANTE, DLCST, ITALUNG, LUSI, NELSON, NLST, and PLCOM2012) were evaluated, and AHRR (cg05575921) methylation extent at different methylation cut points was added. The model with the lowest number of eligible individuals per 5-year lung cancer was validated within the 2001 to 2003 examination. RESULTS: Eligibility criteria identified risk-groups ranging from 3,182 (DANTE) to 1,641 (ITALUNG) individuals. The positive predictive value was highest for PLCOM2012 (3.2%), while DANTE showed the highest negative predictive value (99.7%). Adding AHRR (cg05575921) methylation led to higher specificities for all criteria. Number of eligible individuals per 5-year lung cancer varied from 38 (NELSON) to 27 (NLST) with AHRR (cg05575921) methylation <55%. This last model led to a 21.9% lower screening burden and increased (P < 0.05) specificity of 84.0%. Findings were reproduced among the 5,334 individuals of the 2001 to 2003 examination. CONCLUSIONS: Adding AHRR (cg05575921) methylation on top of current eligibility criteria for lung cancer screening improves specificity by excluding those individuals with the lowest risk. IMPACT: The results point toward a potential clinical use of AHRR (cg05575921) methylation, which is a cost-effective measurement compared with lung CT scanning, to provide additional predictive risk information to identify eligible smokers for lung cancer screening. See related commentary by Hung, p. 698.

Association between Isometric and Allometric Height-Indexed Left Atrial Size and Atrial Fibrillation.

BACKGROUND: Height-based indexations for the evaluation of left atrial (LA) volumes have been proposed as an alternative method to account for body stature when body composition is abnormal. The aim of this study was to derive reference values for these indexation methods and to examine their association with atrial fibrillation (AF). METHODS: A healthy population was randomly split into derivation and validation cohorts (n = 493 each). The derivation cohort was used to derive reference values for iso- and allometric height-indexed LA volumes. Echocardiography included measurement of maximal LA volume (LAVmax) and minimal LA volume (LAVmin). Associations between these measures and AF were investigated in the validation cohort. Cox proportional-hazards regression was performed, adjusting for CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation) risk score. RESULTS: From 986 healthy subjects, allometric height-indexed exponents were determined to 1.72 and 1.56 for LAVmax and LAVmin, respectively. Upper reference values were determined to be LAVmax > 22.1 mL/m1.72 and LAVmin > 12.7 mL/m1.56. In the validation cohort, 41 patients (8%) developed AF during follow-up (median, 14.7 years). In unadjusted analyses, both isometric and allometric indexed LAVmax were associated with AF (hazard ratio, 1.07 [95% CI, 1.03-1.11; P < .001] and 1.11 [95% CI, 1.05-1.18; P < .001] per 1 mL/m and 1 mL/m1.72 increase, respectively) with equal C statistics of 0.63. Height-indexed LAVmin was also associated with AF, with higher C statistics than for LAVmax. All findings were consistent after multivariable adjustment. LAVmax > 22.1 mL/m1.72 posed an increased risk for AF (hazard ratio, 4.65; 95% CI, 1.83-11.86), but LAVmin > 12.7 mL/m1.56 carried a higher risk (hazard ratio, 6.33; 95% CI, 2.66-15.07). CONCLUSIONS: Both isometric and allometric height-indexed LA volumes are associated with AF in the general population. LAVmin is more strongly associated with AF than LAVmax regardless of indexation.

U-Shaped Association Between Duration of Sports Activities and Mortality: Copenhagen City Heart Study.

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.

Diastolic function assessed with speckle tracking over a decade and its prognostic value: The Copenhagen City Heart Study.

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. ß-coef. = .24, P < .001) and mean arterial blood pressure (MAP) (stand. ß-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.

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

OBJECTIVE: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations. METHODS: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes. RESULTS: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%. CONCLUSIONS: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.

Prognostic value of 12 novel cardiological biomarkers in stable coronary artery disease. A 10-year follow-up of the placebo group of the Copenhagen CLARICOR trial.

OBJECTIVE: To assess if 12 novel circulating biomarkers, when added to 'standard predictors' available in general practice, could improve the 10-year prediction of cardiovascular events and mortality in patients with stable coronary heart disease. DESIGN: The patients participated as placebo receiving patients in the randomised clarithromycin for patients with stable coronary artery disease (CLARICOR) trial at a random time in their disease trajectory. SETTING: Five Copenhagen University cardiology departments and a coordinating centre. PARTICIPANTS: 1998 participants with stable coronary artery disease. OUTCOMES: Death and composite of myocardial infarction, unstable angina pectoris, cerebrovascular disease and death. RESULTS: When only 'standard predictors' were included, 83.4% of all-cause death predictions and 68.4% of composite outcome predictions were correct. Log(calprotectin) and log(cathepsin-S) were not associated (p≥0.01) with the outcomes, not even as single predictors. Adding the remaining 10 biomarkers (high-sensitive assay cardiac troponin T; neutrophil gelatinase-associated lipocalin; osteoprotegerin; N-terminal pro-B-type natriuretic peptide; tumour necrosis factor receptor 1 and 2; pregnancy-associated plasma protein A; endostatin; YKL40; cathepsin-B), which were all individually significantly associated with the prediction of the two outcomes, increased the figures to 84.7% and 69.7%. CONCLUSION: When 'standard predictors' routinely available in general practices are used for risk assessment in consecutively sampled patients with stable coronary artery disease, the addition of 10 novel biomarkers to the prediction model improved the correct prediction of all-cause death and the composite outcome by <1.5%. TRIAL REGISTRATION NUMBER: NCT00121550.

Progression in risk factors during 36 years of follow-up and prediction of carotid intima-media thickness in a large cohort of adults with and without diabetes.

Carotid intima-media thickness (IMT) can assess the cumulative effect of atherosclerotic risk factors and provides an independent predictor of future cardiovascular (CV) risk. The aim of this study was to investigate the progression of conventional risk factors in 933 long-term survivors from a Danish cohort with and without diabetes mellitus (DM) as predictors for attained carotid IMT during 35.6 (0.7) years of follow-up. Persons who participated in the first, the last and one of the intermediate rounds of the Copenhagen City Heart Study, and who had had an ultrasound-derived measure of the carotid IMT performed at the last examination were included in the analyses. The risk factors varied between persons with and without DM during the 36 years, but the difference in blood pressure disappeared in the fifth examination, where, in addition, total cholesterol was found to be lower in persons with DM. In this cohort there were no difference in attained carotid IMT between persons with and without DM at the last examination. The following risk factors were found to best predict carotid IMT: age, maximum systolic BP, average systolic BP, average BMI, minimum BMI, sex and years of smoking. The prediction of carotid IMT was clinically poor with a root mean-squared error of prediction (RMSEP) of 0.134 mm and a 95% prediction error probability interval of (-0.22; 0.30). Furthermore, the distribution of prediction errors was skewed to the right indicating that the prediction errors were larger among persons with high carotid IMT.

The impact of cardiovascular risk factors on global longitudinal strain over a decade in the general population: the copenhagen city heart study.

Global longitudinal strain (GLS) declines throughout adult-life as the LV remodels and adapts. Information on the impact of cardiac risk factors such as male sex, obesity, smoking status, hypertension, hypercholesterolemia, and diabetes on GLS. over time has not yet been investigated. The present prospective longitudinal study included 689 participants of the 4th and 5th Copenhagen City Heart Study who had GLS measured at both timepoints. Mean age was 51 years and 45% were male. All participants underwent two echocardiographic examinations median 10.4 (IQR: 10.2, 10.9) years apart. Average decline in GLS during follow-up was -0.7%. High age, male sex, high body mass index, and mean arterial blood pressure (MAP) proved to be significantly associated with an accelerated decline in GLS. In a multivariable regression model including all the investigated cardiovascular risk factors, age (stand. ß-coef. = -0.10, P = 0.005), male sex (stand. ß-coef. = -0.16, P < 0.001), and MAP (stand. ß-coef. = -0.07, P = 0.009) were independent predictors of an accelerated decline in GLS during a 10-year period. Finally, the investigated risk factors had different regional impact after the same multivariable adjustments. Male sex had a significant impact on changes in longitudinal strain at the apical, mid-wall and basal segments, meanwhile MAP and age only accelerated changes in the mid-wall and basal longitudinal strain. In the general population age, male sex, and MAP are independent predictors of an accelerated decline in GLS over a 10-year period. Furthermore, MAP, male sex and age had different regional impact.

Serum osteoprotegerin as a long-term predictor for patients with stable coronary artery disease and its association with diabetes and statin treatment: A CLARICOR trial 10-year follow-up substudy.

BACKGROUND AND AIMS: Elevated circulating levels of osteoprotegerin (OPG) are known to add to the prediction of cardiovascular mortality. Our objective was to clarify the long-term risk associated with serum OPG and the possible influence of diabetes and statins on OPG levels in patients with stable coronary artery disease (CAD). METHODS: We assessed the placebo-treated group (n = 1998) from the CLARICOR trial (NCT00121550), a cohort with stable CAD. At entry, 15% of the participants had diabetes and 41% received statins. Serum OPG levels were measured in blood drawn at randomization. Participants were followed through public registers for 10 years. RESULTS: OPG levels correlated positively with diabetes status, age, CRP and female sex, but negatively with the use of statins. CAD participants with diabetes had significantly elevated serum OPG levels compared to participants without diabetes, p < 0.0001. The participants without diabetes treated with statins presented with significantly lower serum OPG levels than the corresponding non-statin-users (p < 0.0001). However, statin use showed no association with OPG levels in the participants with diabetes. High OPG levels at entry showed long-term associations with all-cause mortality and cardiovascular events (hazard ratio associated with factor 10 OPG increase 15.9 (95% CI 11.0-22.9) and 6.38 (4.60-8.90), p = 0.0001, even after adjustment for standard predictors (3.16 (1.90-5.25) and 2.29 (1.53-3.44), p < 0.0001). CONCLUSIONS: Circulating OPG holds long-term independent predictive ability for all-cause mortality and cardiovascular events in CAD participants. OPG levels were associated with diabetes, age, and female sex and statin treatment was associated with lower OPG levels in the absence of diabetes.

Possible Modifiers of the Association Between Change in Weight Status From Child Through Adult Ages and Later Risk of Type 2 Diabetes.

OBJECTIVE: We investigated the association between changes in weight status from childhood through adulthood and subsequent type 2 diabetes risks and whether educational attainment, smoking, and leisure time physical activity (LTPA) modify this association. RESEARCH DESIGN AND METHODS: Using data from 10 Danish and Finnish cohorts including 25,283 individuals, childhood BMI at 7 and 12 years was categorized as normal or high using age- and sex-specific cutoffs (<85th or ≥85th percentile). Adult BMI (20-71 years) was categorized as nonobese or obese (<30.0 or ≥30.0 kg/m2, respectively). Associations between BMI patterns and type 2 diabetes (989 women and 1,370 men) were analyzed using Cox proportional hazards regressions and meta-analysis techniques. RESULTS: Compared with individuals with a normal BMI at 7 years and without adult obesity, those with a high BMI at 7 years and adult obesity had higher type 2 diabetes risks (hazard ratio [HR]girls 5.04 [95% CI 3.92-6.48]; HRboys 3.78 [95% CI 2.68-5.33]). Individuals with a high BMI at 7 years but without adult obesity did not have a higher risk (HRgirls 0.74 [95% CI 0.52-1.06]; HRboys 0.93 [95% CI 0.65-1.33]). Education, smoking, and LTPA were associated with diabetes risks but did not modify or confound the associations with BMI changes. Results for 12 years of age were similar. CONCLUSIONS: A high BMI in childhood was associated with higher type 2 diabetes risks only if individuals also had obesity in adulthood. These associations were not influenced by educational and lifestyle factors, indicating that BMI is similarly related to the risk across all levels of these factors.

Cathepsin B and S as markers for cardiovascular risk and all-cause mortality in patients with stable coronary heart disease during 10 years: a CLARICOR trial sub-study.

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.

10-Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy.

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.

Heritability of resting heart rate and association with mortality in middle-aged and elderly twins.

OBJECTIVE: Resting heart rate (RHR) possibly has a hereditary component and is associated with longevity. We used the classical biometric twin study design to investigate the heritability of RHR in a population of middle-aged and elderly twins and, furthermore, studied the association between RHR and mortality. METHODS: In total, 4282 twins without cardiovascular disease were included from the Danish Twin Registry, hereof 1233 twin pairs and 1816 'single twins' (twins with a non-participating co-twin); mean age 61.7 (SD 11.1) years; 1334 (31.2%) twins died during median 16.3 (IQR 13.8-16.5) years of follow-up assessed through Danish national registers. RHR was assessed by palpating radial pulse. RESULTS: Within pair correlations for RHR adjusted for sex and age were 0.23 (95% CI 0.14 to 0.32) and 0.10 (0.03 to 0.17) for RHR in monozygotic (MZ) and dizygotic (DZ) twin pairs, respectively. Overall, heritability estimates were 0.23 (95% CI 0.15 to 0.30); 0.27 (0.15 to 0.38) for males and 0.17 (0.06 to 0.28) for females. In multivariable models adjusting for age, gender, body mass index, diabetes, hypertension, pulmonary function, smoking, physical activity and zygosity, RHR was significantly associated with mortality (eg, RHR >90 vs 61-70 beats per min: all-cause HR 1.56 (95% CI 1.21 to 2.03); cardiovascular 2.19 (1.30 to 3.67). Intrapair twin comparison revealed that the twin with the higher RHR was significantly more likely to die first and the probability increased with increase in intrapair difference in RHR. CONCLUSIONS: RHR is a trait with a genetic influence in middle-aged and elderly twins free of cardiovascular disease. RHR is independently associated with longevity even when familial factors are controlled for in a twin design.

Change in Body Mass Index Associated With Lowest Mortality in Denmark, 1976-2013.

IMPORTANCE: Research has shown a U-shaped pattern in the association of body mass index (BMI) with mortality. Although average BMI has increased over time in most countries, the prevalence of cardiovascular risk factors may also be decreasing among obese individuals over time. Thus, the BMI associated with lowest all-cause mortality may have changed. OBJECTIVE: To determine whether the BMI value that is associated with the lowest all-cause mortality has increased in the general population over a period of 3 decades. DESIGN, SETTING, AND PARTICIPANTS: Three cohorts from the same general population enrolled at different times: the Copenhagen City Heart Study in 1976-1978 (n = 13,704) and 1991-1994 (n = 9482) and the Copenhagen General Population Study in 2003-2013 (n = 97,362). All participants were followed up from inclusion in the studies to November 2014, emigration, or death, whichever came first. EXPOSURES: For observational studies, BMI was modeled using splines and in categories defined by the World Health Organization. Body mass index was calculated as weight in kilograms divided by height in meters squared. MAIN OUTCOMES AND MEASURES: Main outcome was all-cause mortality and secondary outcomes were cause-specific mortality. RESULTS: The number of deaths during follow-up was 10,624 in the 1976-1978 cohort (78% cumulative mortality; mortality rate [MR], 30/1000 person-years [95%CI, 20-46]), 5025 in the 1991-1994 cohort (53%; MR, 16/1000 person-years [95%CI, 9-30]), and 5580 in the 2003-2013 cohort (6%;MR, 4/1000 person-years [95%CI, 1-10]). Except for cancer mortality, the association of BMI with all-cause, cardiovascular, and other mortality was curvilinear (U-shaped). The BMI associated with the lowest all-cause mortality increased by 3.3 from the 1976-1978 cohort compared with the 2003-2013 cohort. [table: see text] The multivariable-adjusted hazard ratios for all-cause mortality for BMI of 30 or more vs BMI of 18.5 to 24.9 were 1.31 (95%CI, 1.23-1.39;MR, 46/1000 person-years [95%CI, 32-66] vs 28/1000 person-years [95%CI, 18-45]) in the 1976-1978 cohort, 1.13 (95%CI, 1.04-1.22; MR, 28/1000 person-years [95%CI, 17-47] vs 15/1000 person-years [95%CI, 7-31]) in the 1991-1994 cohort, and 0.99 (95%CI, 0.92-1.07;MR, 5/1000 person-years [95%CI, 2-12] vs 4/1000 person-years [95%CI, 1-11]) in the 2003-2013 cohort. CONCLUSIONS AND RELEVANCE Among 3 Danish cohorts, the BMI associated with the lowest all-cause mortality increased by 3.3 from cohorts enrolled from 1976-1978 through 2003-2013. Further investigation is needed to understand the reason for this change and its implications.