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Background Studies on the pulmonary consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are impeded by limited access to pre–SARS-CoV-2 examinations. Methods We invited Copenhagen General Population Study participants with a confirmed SARS-CoV-2 polymerase chain reaction (PCR) test during the first and second coronavirus disease 2019 waves in Denmark for a repeat chest computed tomography (CT) scan. Paired CT scans were independently assessed for interstitial and noninterstitial abnormalities by 2 trained radiologists. A semiquantitative CT score (ranging from 0 to 20) was used to quantify the extent of interstitial abnormalities. Results Of 111 SARS-CoV-2–infected individuals, 102 (91.2%) experienced symptoms and 12 (11.2%) were hospitalized. Follow-up examination was performed at median of 5.4 (interquartile range, 4.1–7.8) months after a positive SARS-CoV-2 PCR test. Of 67 individuals with paired CT scans, ground glass opacities and reticulation were present in 31 (46.3%) individuals post–SARS-CoV-2 compared to 23 (34.1%) pre–SARS-CoV-2 (mean CT score, 3.0 vs 1.3; P =.011). Results were similar for nonhospitalized individuals. We did not detect development of bronchiectasis, emphysema, or nodules. Conclusions SARS-CoV-2 infection in predominantly nonhospitalized individuals with mild disease was associated with a small increase in only interstitial lung abnormalities. [ABSTRACT FROM AUTHOR]

Aims The role of atherosclerosis in the pathogenesis of aortic enlargement is uncertain. We aimed to evaluate the relationship between the diameters of the ascending, descending and abdominal aorta, and coronary artery calcification. Methods and results Individuals in the Copenhagen General Population Study underwent thoracic and abdominal computed tomography. Maximal aortic diameters were measured in each aortic segment and coronary artery calcium scores (CACS) were calculated. Participants were stratified into five predefined groups according to CACSs and compared to aortic dimensions. The relation between aortic diameter and CACS was adjusted for risk factors for aortic dilatation in a multivariable model. A total of 2678 eligible individuals were included. In all segments of the aorta, aortic diameter was associated to CACSs, with mean increases in aortic diameters ranging from 0.7 to 3.5 mm in individuals with calcified coronary arteries compared to non-calcified subjects (P -value < 0.001). After correction for risk factors, individuals with CACS above 400 had larger ascending, descending and abdominal aortic diameter than the non-calcified reference group (P -value < 0.01). Conclusion Enlarged thoracic and abdominal aortic vascular segments are associated with co-existing coronary artery calcification in the general population. [ABSTRACT FROM AUTHOR]

Aims  Left ventricular (LV) myocardial crypts are considered a subtle marker of hypertrophic cardiomyopathy. However, crypts have also been observed in seemingly healthy individuals and it is unknown whether myocardial crypts are associated with adverse outcome. Methods and results  Myocardial crypts were defined as invaginations traversing >50% of the myocardial wall and assessed using contrast-enhanced cardiac computed tomography in 10 097 individuals from the Copenhagen General Population Study. Number of crypts, location, shape, penetrance, and volume were assessed. The endpoint was a composite of major adverse cardiovascular events and defined as death, myocardial infarction, heart failure, or stroke. Cox regression models were adjusted for clinical variables, medical history, electrocardiographic parameters, and cardiac chamber sizes. A total of 1199 LV myocardial crypts were identified in 915 (9.1%) individuals. Seven hundred (6.9%) had one crypt and 215 (2.1%) had multiple crypts. During a median follow-up of 4.0 years (interquartile range 1.5–6.7), major adverse cardiovascular events occurred in 619 individuals. Individuals with one or multiple crypts had a hazard ratio for major adverse cardiovascular events of 1.00 [95% confidence interval (CI): 0.72–1.40; P  = 0.98] and 0.90 (95% CI: 0.47–1.75; P  = 0.76), respectively, compared with those with no crypts. No specific pattern of crypt location, shape, penetrance, or volume was associated to an increased hazard ratio for major adverse cardiovascular events. Conclusion  LV myocardial crypts are frequent in the general population and are not associated with intermediate-term major adverse cardiovascular events. [ABSTRACT FROM AUTHOR]

Background: People with human immunodeficiency virus (PWH) may be at risk of nonalcoholic fatty liver disease. We compared the prevalence of moderate-to-severe hepatic steatosis (M-HS) in PWH with human immunodeficiency virus (HIV)-uninfected controls and determined risk factors for M-HS in PWH.Methods: The Copenhagen Co-Morbidity in HIV Infection study included 453 participants, and the Copenhagen General Population Study included 765 participants. None had prior or current viral hepatitis or excessive alcohol intake. Moderate-to-severe hepatic steatosis was assessed by unenhanced computed tomography liver scan defined by liver attenuation ≤48 Hounsfield units. Adjusted odds ratios (aORs) were computed by adjusted logistic regression.Results: The prevalence of M-HS was lower in PWH compared with uninfected controls (8.6% vs 14.2%, P < .01). In multivariable analyses, HIV (aOR, 0.44; P < .01), female sex (aOR, 0.08; P = .03), physical activity level (aOR, 0.09; very active vs inactive; P < .01), and alcohol (aOR, 0.89 per unit/week; P = .02) were protective factors, whereas body mass index (BMI) (aOR, 1.58 per 1 kg/m2; P < .01), alanine transaminase (ALT) (aOR, 1.76 per 10 U/L; P < .01), and exposure to integrase inhibitors (aOR, 1.28 per year; P = .02) were associated with higher odds of M-HS.Conclusions: Moderate-to-severe hepatic steatosis is less common in PWH compared with demographically comparable uninfected controls. Besides BMI and ALT, integrase inhibitor exposure was associated with higher prevalence of steatosis in PWH. [ABSTRACT FROM AUTHOR]

Background: Increased pericardial adipose tissue is associated with higher risk of cardiovascular disease. We aimed to determine whether human immunodeficiency virus (HIV) status was independently associated with larger pericardial adipose tissue volume and to explore possible HIV-specific risk factors.Methods: Persons with HIV (PWH) were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study and matched 1:1 on age and sex to uninfected controls. Pericardial adipose tissue volume was measured using cardiac computed tomography.Results: A total of 587 PWH and 587 controls were included. Median age was 52 years, and 88% were male. Human immunodeficiency virus status was independently associated with 17 mL (95% confidence interval [CI], 10-23; P < .001) larger pericardial adipose tissue volume. Larger pericardial adipose tissue volume was associated with low CD4+ nadir and prior use of stavudine, didanosine, and indinavir. Among PWH without thymidine analogue or didanosine exposure, time since initiating combination antiretroviral treatment (per 5-year use) was associated with l6 mL (95% CI, -6 to -25; P = .002) lower pericardial adipose tissue volume.Conclusions: Human immunodeficiency virus status was independently associated with larger pericardial adipose tissue volume. Severe immunodeficiency, stavudine, didanosine, and indinavir were associated with larger pericardial adipose tissue volume. Persons with HIV with prior exposure to these drugs may constitute a distinct cardiovascular risk population. [ABSTRACT FROM AUTHOR]

Introduction: Observational studies have found lower concentrations of plasma bilirubin in current smokers compared with former and never smokers. However, whether there is a causal relationship between smoking and bilirubin is unknown. In a Mendelian randomization analysis, we tested the hypothesis that higher tobacco consumption is causally associated with lower concentrations of plasma bilirubin.Methods: We genotyped 103 557 individuals aged 20-100 years from the Copenhagen General Population Study for the CHRNA3 rs1051730 genotype, known to be associated with higher tobacco consumption. Tobacco consumption was defined as daily and cumulative tobacco consumption.Results: In observational multivariable-adjusted analyses, a 10 g/day higher daily tobacco consumption was associated with a 0.28 µmol/L (95% confidence interval = 0.20 to 0.35) lower concentration of plasma bilirubin in current smokers, and a 10 pack-year higher cumulative tobacco consumption was associated with a 0.19 µmol/L (0.17 to 0.21) lower concentration of plasma bilirubin in former and current smokers. Using the CHRNA3 rs1051730 genotype as a proxy for daily and cumulative tobacco consumption, the difference in plasma bilirubin per T-allele was -0.12 µmol/L (-0.23 to -0.002) in current smokers and -0.09 µmol/L (-0.15 to -0.01) in current and former smokers combined. Furthermore, observationally bilirubin concentrations increased with time from smoking cessation in former smokers.Conclusion: Higher daily and cumulative tobacco consumption were associated with lower concentrations of plasma bilirubin in observational and genetic analyses, suggesting that the association is causal.Implications: Our results are compatible with two possible interpretations of previous observational studies, either that bilirubin is a mediator of smoking-induced respiratory disease or that the association between plasma bilirubin and respiratory disease stems from residual confounding because of smoking. Future studies should examine whether bilirubin is a causal risk factor for respiratory disease, or merely a marker of smoking status. [ABSTRACT FROM AUTHOR]

Aims Accurate assessment of aortic dimensions can be achieved using contrast-enhanced computed tomography. The aim of this study was to define normal values and determinants of aortic dimensions throughout multiple key anatomical landmarks of the aorta in healthy individuals from the Copenhagen General Population Study. Methods and results The study group consisted of 902 healthy subjects selected from 3000 adults undergoing cardiovascular thoracic and abdominal computed tomography-angiography (CTA), where systematic measurements of aortic dimensions were performed retrospectively. Individuals included were without any of the following predefined cardiovascular risk factors: (i) self-reported angina pectoris; (ii) hypertension; (iii) hypercholesterolaemia; (iv) taking cardiovascular prescribed medication including diuretics, statins, or aspirin; (v) overweight (defined as body mass index ≥30 kg/m2); (vi) diabetes mellitus (self-reported or blood glucose >8 mmol/L); and (vii) chronic obstructive pulmonary disease. Maximal aortic diameters were measured at seven aortic regions: sinuses of Valsalva, sinotubular junction, ascending aorta, mid-descending aorta, abdominal aorta at the diaphragm, abdominal aorta at the coeliac trunk, and infrarenal abdominal aorta. Median age was 52 years, and 396 (40%) were men. Men had significantly larger aortic diameters at all levels compared with women (P  <   0.001). Multivariable analysis revealed that sex, age, and body surface area were associated with increasing aortic dimensions. Conclusion Normal values of maximal aortic dimensions at key aortic anatomical locations by contrast-enhanced CTA have been defined. Age, sex, and body surface area were significantly associated with these measures at all levels of aorta. Aortic dimensions follow an almost identical pattern throughout the vessel regardless of sex. [ABSTRACT FROM AUTHOR]

Background: Results from randomized controlled trials (RCTs) have raised concern that the cholesterol-lowering drug ezetimibe might increase the risk of cancer. We tested the hypothesis that genetic variation in NPC1L1, mimicking treatment with ezetimibe, was associated with an increased risk of cancer.Methods: We included 67 257 individuals from the general population. Of these, 8333 developed cancer and 2057 died of cancer from 1968 to 2011. To mimic the effect of ezetimibe, we calculated weighted allele scores based on the low-density lipoprotein (LDL) cholesterol-lowering(= NPC1L1-inhibitory) effect of each variant. We tested the associations of the NPC1L1 allele scores with LDL cholesterol and with risk of any cancer, death from any cancer and 27 site-specific cancers. As a positive control, we tested the association of the NPC1L1 allele scores with risk of ischaemic vascular disease (IVD).Results: The NPC1L1 allele scores did not associate with risk of any cancer, death from any cancer or with any of 27 site-specific cancers. Hazard ratios (HRs) for a 1-unit increase in internally weighted allele scores were 1.00 (95% confidence interval: 0.98-1.02) for any cancer, and 1.02 (0.98-1.06) for cancer death. The corresponding HR for IVD was 0.97 (0.94-0.99). Results were similar for an externally weighted allele score and for a simple allele count. Finally, the null association with cancer was robust in sensitivity analyses.Conclusions: Lifelong, genetic inhibition of NPC1L1, mimicking treatment with ezetimibe, does not associate with risk of cancer. These results suggest that long-term treatment with ezetimibe is unlikely to increase the risk of cancer, in agreement with the overall evidence from ezetimibe RCTs. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that smoking influences mental health negatively. This study investigated whether high tobacco consumption is causally related to psychological distress in a Mendelian randomization design, using a variant in the nicotine acetylcholine receptor gene CHRNA3-known to influence individual tobacco consumption-as instrumental variable for tobacco consumption.Methods: Data from 90 108 participants in the Copenhagen General Population Study was used. Exposures included self-reported cigarettes/day and pack years and the CHRNA3 rs1051730 genotype as instrumental variable for tobacco consumption. Three dimensions of psychological distress were studied: Stress, fatigue, and hopelessness. Analyses with the CHRNA3 genotype were stratified by smoking status.Results: Self-reported amount of smoking was associated with all three dimensions of psychological distress. For instance among participants smoking 30 cigarettes/day or more, the odds ratio (OR) for stress was 1.67 (95% confidence interval [CI] 1.47-1.89) compared to never-smokers. Corresponding ORs for fatigue and hopelessness were 2.18 (95% CI 1.92-2.47) and 3.08 (95% CI 2.62-3.62). Among current smokers, homozygotes and heterozygotes for the CHRNA3 genotype had higher tobacco consumption than noncarriers. Nevertheless, the CHRNA3 genotype was not associated with psychological distress neither in current nor in former or never-smokers. For instance among current smokers, the OR for stress was 1.02 (95% CI 0.91-1.15) among homozygotes compared to noncarriers of the CHRNA3 genotype.Conclusions: Though a strong association between tobacco consumption and psychological distress was found, there was no clear evidence that high tobacco consumption was causally related to psychological distress.Implications: Smoking is associated with several mental health outcomes and smoking cessation is associated with improved mental health. Causality in the association between smoking and mental health is difficult to establish using observational data. Using a genotype known to influence tobacco consumption as instrumental variable for amount of smoking, we found no clear evidence of a direct causal path between high tobacco consumption and psychological distress. Whatever causes the strong association between tobacco consumption and psychological distress, the co-occurrence is important to consider both in interventions for smoking prevention and cessation. [ABSTRACT FROM AUTHOR]

Background: Results regarding telomere length and cancer risk are conflicting. We tested the hypothesis that long telomeres are associated with increased risk of any cancer and specific cancer types in genetic and observational analyses.Methods: Individuals (N = 95 568) from the Copenhagen City Heart Study and the Copenhagen General Population Study had the telomere length-associated genotypes rs7726159 (TERT), rs1317082 (TERC), and rs2487999 (OBFC1) determined, and 65 176 had telomere length measured. A total of 10 895 individuals had had a cancer diagnosis. Endpoints were any cancer and 25 specific cancer types. We conducted Cox regression analyses and logistic regression analyses. The three genotypes were combined as an allele sum.Results: Telomere length increased 67 base-pairs [95% confidence interval (CI) 61-74] per allele. In logistic regression models, the per-allele odds ratio (OR) for cancer was 1.05 (95% CI 1.03-1.07) for the allele sum, 1.05 (1.02-1.09) for rs7726159, 1.05 (1.02-1.08) for rs1317082 and 1.07 (1.02-1.12) for rs2487999. In contrast, the hazard ratio for any cancer was 1.01 (1.00-1.01) per 200-base-pair increase in telomere length in multivariable adjusted observational analysis. In genetic analyses according to specific cancer types, the per-allele odds ratio was 1.19 (1.12-1.27) for melanoma and 1.14 (1.06-1.22) for lung cancer.Conclusions: Genetic determinants of long telomeres are associated with increased cancer risk, particularly melanoma and lung cancer. This genetic predisposition to enhanced telomere maintenance may represent a survival advantage for pre-cancerous cells, allowing for multiple cell divisions leading to cancer development. [ABSTRACT FROM AUTHOR]

Background: In the clinic, the combination of obesity and chronic obstructive pulmonary disease (COPD) has been increasing. However, whether high body mass index (BMI) affects the risk of exacerbations and pneumonias in individuals with COPD is presently unknown. Genetics can be used to assess the causal role of high BMI in exacerbations and pneumonias in individuals with COPD. We tested the hypothesis that high BMI is associated with an increased risk of exacerbations and pneumonias in individuals with COPD, both observationally and genetically.Methods: We genotyped 93 894 individuals of Danish descent, aged 20-100 years, from the Copenhagen General Population Study, for FTO (rs9939609), MC4R (rs17782313) and TMEM18 (rs6548238), and created an allele score. A total of 10 883 individuals had spirometric COPD with forced expiratory volume in 1 s (FEV1) / forced vital capacity (FVC) < lower limit of normal (LLN). In these individuals, we observed 1453 exacerbations and 3390 pneumonias during 4.7 years of follow-up.Results: For each increase in allele score, BMI was 0.28 kg/m2 [95% confidence interval (CI): 0.25-0.30) higher. Age- and sex-adjusted genetic hazard ratios (HRs) per one allele score increase in individuals with COPD were 1.13 (1.01-1.27) for exacerbations, 1.10 (1.03-1.19) for pneumonias and 1.12 (1.04-1.21) for exacerbations and/or pneumonias. Corresponding multivariable adjusted observational HRs per unit (kg/m2) BMI increase were 0.98 (0.95-1.01), 0.99 (0.96-1.03) and 0.99 (0.96-1.01), respectively.Conclusions: Genetically determined high BMI was associated with an increased risk of recurrent exacerbations and pneumonias in individuals with COPD, whereas this was not the case for observationally determined high BMI. The genetic data are compatible with the notion that high BMI leads to increased risk of exacerbations and pneumonias in individuals with COPD. [ABSTRACT FROM AUTHOR]

Aims Normal values of left ventricular mass (LVM) and cardiac chamber sizes are prerequisites for the diagnosis of individuals with heart disease. LVM and cardiac chamber sizes may be recorded during cardiac computed tomography angiography (CCTA), and thus modality specific normal values are needed. Methods and results We studied 569 healthy subjects undergoing 320-detector CCTA as a part of the Copenhagen General Population Study. LVM as well as ventricular and atrial volumes was assessed with semi-automated software stratified by gender and age decades and indexed by body surface area (BSA). Mean age was 55 (range: 40-84) years, and 188 (33%) were men. BSA-indexed 97.5th percentile cut-off values: LVM = 80 and 65 gr/m², left ventricular volume = 97 and 83 mL/m², right ventricular volume = 120 and 102 mL/m², left atrial volume = 60 and 57 mL/m², and right atrial volume = 85 and 73 mL/m² for men and women, respectively. Men had greater absolute and indexed LVM and chamber volumes than women. For both genders, indexed ventricular volumes declined, whereas indexed atrial volumes increased in advancing age groups. For men, indexed LVM declined in advancing age groups. In multivariate analyses, gender, BSA, systolic blood pressure, and hard physical activity accounted for 63% of variance in LVM. Conclusion In this cross-sectional general population study, men have greater indexed LVM and chamber volumes than women, and cardiac indexed volumes vary between age groups in both genders. These findings demonstrate the need for age- and gender-specific normal values for clinical diagnostic purposes. [ABSTRACT FROM AUTHOR]

Background. Human immunodeficiency virus-infected individuals have increased risk of myocardial infarction (MI); however, the contribution from smoking and potentiating effects of HIV are controversial. Methods. From the Danish HIV Cohort Study and the Copenhagen General Population Study, we identified 3251 HIV-infected individuals and 13 004 population controls matched on age and gender. Data on MI were obtained from the National Hospital Registry and the National Registry of Causes of Death.We calculated adjusted incidence rate ratios (aIRR) for risk of MI and population-attributable fractions (PAF) of MI associated with smoking. Results. In never smokers, HIV was not associated with an increased risk ofMI (aIRR, 1.01; 95% confidence interval [CI], .41-2.54). In previous and current smokers, HIV was associated with a substantially increased risk of MI (aIRR, 1.78; 95% CI, .75-4.24 and aIRR, 2.83; 95% CI, 1.71-4.70). The PAF associated with ever smoking (previous or current) was 72% (95% CI, 55%-82%) for HIV-infected individuals and 24% (95% CI, 3%-40%) for population controls. If all current smokers stopped smoking, 42% (95% CI, 21%-57%) and 21% (95% CI, 12%-28%) of all MIs could potentially be avoided in these 2 populations. Conclusions. Smoking is associated with a higher risk of MI in the HIV-infected population than in the general population. Approximately 3 of 4 MIs among HIV-infected individuals are associated with ever smoking compared with only 1 of 4 MIs among population controls. Smoking cessation could potentially prevent more than 40% of MIs among HIV-infected individuals, and smoking cessation should be a primary focus in modern HIV care. [ABSTRACT FROM AUTHOR]