Body mass index and risk of cancer in young women.

It is unclear how increasing body mass index (BMI) influences risk of cancer in young women. We used data from the Medical Birth, Patient and Cause of Death registers collected between 1982 and 2014 to determine the risk of obesity-related cancer types, breast cancer, all cancer and cancer-related death in relation to BMI in 1,386,725 women, aged between 18 and 45 years, in Sweden. During a median follow-up of 16.3 years (IQR 7.7-23.5), 9808 women developed cancer. The hazard ratio (HR) of endometrial and ovarian cancer increased with higher BMI from 1.08 (95% CI 0.93-1.24) and 1.08 (95% CI 0.96-1.21) among women with BMI 22.5-< 25 to 2.33 (95% CI 1.92-2.83) and 1.48 (95% CI 1.24-1.77), respectively, among women with BMI ≥ 30. There were linear and positive associations between BMI and incident cancer in the ovary, colon, endometrium, pancreas, rectum, gallbladder, esophageal cancer and renal cell carcinoma, as well as death from obesity-related cancer forms. In conclusion, we found that elevated BMI in young women linearly associated with several obesity-related cancer forms, including death from these cancers.

Large-scale plasma proteomics in the UK Biobank modestly improves prediction of major cardiovascular events in a population without previous cardiovascular disease.

AIMS: Improved identification of individuals at high risk of developing cardiovascular disease would enable targeted interventions and potentially lead to reductions in mortality and morbidity. Our aim was to determine whether use of large-scale proteomics improves prediction of cardiovascular events beyond traditional risk factors (TRFs). METHODS: Using proximity extension assays, 2919 plasma proteins were measured in 38 380 participants of the UK Biobank. Both data- and literature-based feature selection and trained models using extreme gradient boosting machine learning were used to predict risk of major cardiovascular events (MACE: fatal and non-fatal myocardial infarction, stroke and coronary artery revascularisation) during a 10-year follow-up. Area under the curve (AUC) and net reclassification index (NRI) were used to evaluate the additive value of selected protein panels to MACE prediction by Systematic COronary Risk Evaluation 2 (SCORE2) or the 10 TRFs used in SCORE2. RESULTS: SCORE2 and SCORE2 refitted to UK Biobank data predicted MACE with AUCs of 0.740 and 0.749, respectively. data-driven selection identified 114 proteins of greatest relevance for prediction. Prediction of MACE was not improved by using these proteins alone (AUC of 0.758) but was significantly improved by combining these proteins with SCORE2 or the 10 TRFs (AUC=0.771, p<001, NRI=0.140, and AUC=0.767, p=0.03, NRI 0.053, respectively). Literature-based protein selection (113 proteins from five previous studies) also improved risk prediction beyond TRFs while a random selection of 114 proteins did not. CONCLUSIONS: Large-scale plasma proteomics with data-driven and literature-based protein selection modestly improves prediction of future MACE beyond TRFs.

The risk of having a myocardial infarction or stroke is usually assessed by clinical scores including traditional risk factors for cardiovascular disease. The development of new technologies enables the rapid measurement of an increasing number of blood proteins. In this study, we applied machine learning techniques in a UK-based cohort of 38 380 participants with 2919 blood proteins measured. We obtained a set of 114 proteins which improved the prediction of the 10-year risk of major cardiovascular event when added to traditional risk factors. Improvements were also achieved using a set of 113 proteins found in previous studies. However, the magnitude of these improvements was relatively low and the clinical utility of combining these proteins with traditional risk factors in primary prevention will have to be further investigated.

Plasma proteomics for prediction of subclinical coronary artery calcifications in primary prevention.

BACKGROUND AND AIMS: Recent developments in high-throughput proteomic technologies enable the discovery of novel biomarkers of coronary atherosclerosis. The aims of this study were to test if plasma protein subsets could detect coronary artery calcifications (CAC) in asymptomatic individuals and if they add predictive value beyond traditional risk factors. METHODS: Using proximity extension assays, 1,342 plasma proteins were measured in 1,827 individuals from the Impaired Glucose Tolerance and Microbiota (IGTM) study and 883 individuals from the Swedish Cardiopulmonary BioImage Study (SCAPIS) aged 50-64 years without history of ischaemic heart disease and with CAC assessed by computed tomography. After data-driven feature selection, extreme gradient boosting machine learning models were trained on the IGTM cohort to predict the presence of CAC using combinations of proteins and traditional risk factors. The trained models were validated in SCAPIS. RESULTS: The best plasma protein subset (44 proteins) predicted CAC with an area under the curve (AUC) of 0.691 in the validation cohort. However, this was not better than prediction by traditional risk factors alone (AUC = 0.710, P = .17). Adding proteins to traditional risk factors did not improve the predictions (AUC = 0.705, P = .6). Most of these 44 proteins were highly correlated with traditional risk factors. CONCLUSIONS: A plasma protein subset that could predict the presence of subclinical CAC was identified but it did not outperform nor improve a model based on traditional risk factors. Thus, support for this targeted proteomics platform to predict subclinical CAC beyond traditional risk factors was not found.

Incidence of type 2 diabetes after gastric by-pass surgery in a Swedish controlled cohort study.

AIMS: To assess the long-term risk of developing type 2 diabetes in patients with obesity who have undergone gastric bypass surgery compared to non-operated patients with obesity and the general population. METHODS: This study included 71,495 patients aged 20-65 years with a principal diagnosis of obesity in the Swedish Patient Register in 2001-2013. Of these, 23,099 had undergone gastric bypass and 32,435 had not. Each patient was matched by age, sex and geographic region with two controls from the general population without obesity diagnosis, i.e., 44,735 controls for the gastric bypass cohort and 62,522 controls for the non-operated cohort with obesity. Operated and non-operated patients with obesity were also directly compared using Cox regression analysis, providing hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, education, and sex. RESULTS: During a median follow-up of 4.3 years (interquartile range [IQR] 2.4, 7.0 years), 3792 (11.7%) non-operated patients with obesity developed type 2 diabetes (incidence rate 22.8/1000 person-years, 95% CI 22.1-23.6) compared to 394 (1.7%) among gastric bypass patients (incidence rate 4.0/1000 person-years, 95% CI 3.6-4.5). The latter incidence was comparable to population controls (3.5/1000 person-years, 95% CI 3.2-3.8). Gastric bypass patients had 85% lower risk of diabetes compared to non-operated patients with obesity during the first six years of follow-up (HR 0.15; 95% CI 0.13-0.17). CONCLUSION: Gastric bypass surgery for obesity seems to reduce the risk of developing type 2 diabetes to levels similar to that of the general population during the first six years of follow-up but not thereafter.

Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis.

BACKGROUND: Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate. OBJECTIVES: The authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle. METHODS: Genome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed. RESULTS: The Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis. CONCLUSIONS: We conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population.

Body mass index and fitness in late adolescence and risk of cardiovascular disease, respiratory disease, and overall death after COVID-19.

Objective: Since obesity and poor fitness appear to be unfavorable for both cardiovascular health and coping with viral infections such as COVID-19, they are of specific interest in light of the increased risk of cardiovascular and respiratory events now seen after infection with SARS-CoV-2. Therefore, the aim of the present study was to investigate how body mass index (BMI) and cardiorespiratory fitness (CRF) in late adolescence are associated with the risk of cardiovascular disease (CVD), respiratory disease, and mortality after COVID-19. Methods: In this study, 1.5 million 18-year-old Swedish men with BMI and CRF measured during enlistment for military service 1968-2005 were included. Hospitalized and non-hospitalized COVID-19 cases were identified through the Patient Register or positive polymerase chain reaction tests, and age-matched with non-infected controls. CVD, respiratory disease, and mortality after COVID-19 were divided into <60days, 60-180days, >180days post-infection. Cox regression models were used. Results: Hospitalized COVID-19 cases (n = 9839), compared to controls, had >10-fold, 50 to 70-fold, and >70-fold hazards of CVD, respiratory disease, and mortality over the initial 60 days post-infection with little variation across BMI or CRF categories. The elevated risks persisted at declining levels >180 days. For non-hospitalized COVID-19 cases (n = 181,822), there was a 4- to 7-fold increased acute mortality risk, and high CRF was associated with lower risk of post-infectious respiratory disease. Conclusions: The high hazards of adverse outcomes during the first two months after COVID-19 hospitalization, and across BMI and CRF categories, declined rapidly but were still elevated after six months. Adolescent CRF was associated with respiratory disease after COVID-19 without hospitalization, which gives further support to the health benefits of physical activity.

Randomized open-label trial of semaglutide and dapagliflozin in patients with type 2 diabetes of different pathophysiology.

The limited understanding of the heterogeneity in the treatment response to antidiabetic drugs contributes to metabolic deterioration and cardiovascular complications1,2, stressing the need for more personalized treatment1. Although recent attempts have been made to classify diabetes into subgroups, the utility of such stratification in predicting treatment response is unknown3. We enrolled participants with type 2 diabetes (n = 239, 74 women and 165 men) and features of severe insulin-deficient diabetes (SIDD) or severe insulin-resistant diabetes (SIRD). Participants were randomly assigned to treatment with the glucagon-like peptide 1 receptor agonist semaglutide or the sodium-glucose cotransporter 2 inhibitor dapagliflozin for 6 months (open label). The primary endpoint was the change in glycated haemoglobin (HbA1c). Semaglutide induced a larger reduction in HbA1c levels than dapagliflozin (mean difference, 8.2 mmol mol-1; 95% confidence interval, -10.0 to -6.3 mmol mol-1), with a pronounced effect in those with SIDD. No difference in adverse events was observed between participants with SIDD and those with SIRD. Analysis of secondary endpoints showed greater reductions in fasting and postprandial glucose concentrations in response to semaglutide in participants with SIDD than in those with SIRD and a more pronounced effect on postprandial glucose by dapagliflozin in participants with SIDD than in those with SIRD. However, no significant interaction was found between drug assignment and the SIDD or SIRD subgroup. In contrast, continuous measures of body mass index, blood pressure, insulin secretion and insulin resistance were useful in identifying those likely to have the largest improvements in glycaemic control and cardiovascular risk factors by adding semaglutide or dapagliflozin. Thus, systematic evaluation of continuous pathophysiological variables can guide the prediction of the treatment response to these drugs and provide more information than stratified subgroups ( NCT04451837 ).

The relationship between genetic liver fat and coronary heart disease is explained by apoB-containing lipoproteins.

BACKGROUND: The relationship between genetically-driven liver fat and coronary heart disease (CHD) remains unclear. ApoB-containing lipoproteins are known causal factors for CHD and may explain this relationship. METHODS AND RESULTS: We conducted a genome-wide association study (GWAS) in the UK Biobank to identify genetic variants associated with liver fat. We then investigated the effects that these genetic variants had on both apoB-containing lipoproteins and CHD. Using Mendelian Randomization (MR) analyses, we examined if the relationship between genetically-driven liver fat and CHD could be attributed to its effect on apoB-containing lipoproteins. We found 25 independent liver-fat associated single-nucleotide polymorphisms (SNPs) with differing effects on lipoprotein metabolism. The SNPs were classified into three groups/clusters. The first cluster (N = 3 SNPs) displayed lipoprotein-raising effects. The second cluster (N = 12 SNPs) displayed neutral effects on lipoproteins and the third cluster (N = 10 SNPs) displayed lipoprotein-lowering effects. For every 1% higher liver fat, the first cluster showed an increased risk of CHD (OR = 1.157 [95% CI: 1.108-1.208]). The second cluster showed a non-significant effect on CHD (OR = 0.988 [95% CI: 0.965-1.012], whereas the third cluster showed a protective effect of increased liver fat on CHD (OR = 0.942 [95% CI: 0.897-0.989]). When adjusting for apoB, the risk for CHD became null. CONCLUSIONS: Here, we identify 25 liver-fat associated SNPs. We find that SNPs that increase, decrease or have neutral effects on apoB-containing lipoproteins show increased, decreased or neutral effects on CHD, respectively. Therefore, the relationship between genetically-driven liver fat and CHD is mediated by the causal effect of apoB.

Prepregnancy overweight and obesity and long-term risk of venous thromboembolism in women.

Overweight and obesity rates have increased in recent decades, particularly among the younger population. The long-term consequences of obesity with respect to early venous thromboembolism (VTE) in women have not been established. The aim was to investigate the association between body mass index (BMI) in early pregnancy as a proxy for non-pregnant weight and long-term post-pregnancy risk of VTE in women. This registry-based prospective cohort study analysed data from the Swedish Medical Birth Registry, linked to the National Patient and the National Cause of Death Registries for information on post-pregnancy long-term risk of VTE. Cox proportional hazards model were used to determine the association between BMI at baseline and VTE events during follow-up starting 1 year after baseline. The mean age at registration was 27.5 (standard deviation, 4.9) years. During a median follow-up duration of 12 years (interquartile range, 6-21 years) starting 1 year after the first antenatal visit, 1765 and 2549 women had a deep vein thrombosis and/or pulmonary embolism. The risk of VTE linearly increased with increasing BMI. Compared to women with 20 ≤ BMI < 22.5 kg/m2, women with high normal weight, i.e. with a BMI of 22.5-25.0 kg/m2, had an adjusted hazard ratio (HR) of 1.30 (95% confidence interval [CI] 1.19-1.41), whereas those with a BMI of 30-35 kg/m2 and ≥ 35 kg/m2 (severe obesity) had an adjusted HR of 2.35 (95% CI 2.04-2.70) and 3.47 (95% CI 2.82-4.25, respectively. Using BMI in early pregnancy as a proxy for pre-pregnancy or non-pregnant BMI in young women, we found a significantly increased risk of post-pregnancy long-term risk of VTE even in those with high normal BMI, compared with lean women, whereas those with severe obesity had a markedly high risk.

Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy.

AIMS/HYPOTHESIS: This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk. METHODS: To investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL. RESULTS: The fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL1 and VLDL2 density ranges (all p < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 ± 57 vs 446 ± 57 mg/day; p < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 ± 25 vs 82 ± 58 pools/day; p=0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 ± 2.2 vs 1.0 ± 1.8 pools/day; p < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation (p < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL2. CONCLUSIONS/INTERPRETATION: Abnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in individuals with type 2 diabetes on statins may help to explain the residual risk of CVD and may be suitable targets for interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02948777.

Mediating role of atherogenic lipoproteins in the relationship between liver fat and coronary artery calcification.

Non-alcoholic fatty liver disease (NAFLD) is associated with increased secretion of apoB-containing lipoproteins and increased risk of coronary heart disease (CHD). ApoB-containing lipoproteins include low-density lipoproteins (LDLs) and triglyceride-rich lipoproteins (TRLs); and since both LDLs and TRLs are causally related to CHD, they may mediate a portion of the increased risk of atherosclerosis seen in people with NAFLD. In a cohort of 4161 middle aged men and women, we performed mediation analysis in order to quantify the mediating effect of apoB-containing lipoproteins in the relationship between liver fat and atherosclerosis-as measured by coronary artery calcium score (CACS). We found plasma apoB to mediate 17.6% (95% CI 11-24) of the association between liver fat and CACS. Plasma triglycerides and TRL-cholesterol (both proximate measures of TRL particles) mediated 22.3% (95% CI 11-34) and 21.6% (95% CI 10-33) of the association respectively; whereas LDL-cholesterol mediated 5.4% (95% CI 2.0-9.4). In multivariable models, the mediating effect of TRL-cholesterol and plasma triglycerides showed, again, a higher degree of mediation than LDL-cholesterol, corroborating the results seen in the univariable models. In summary, we find around 20% of the association between liver fat and CACS to be mediated by apoB-containing lipoproteins. In addition, we find that TRLs mediate the majority of this effect whereas LDLs mediate a smaller effect. These results explain part of the observed CAD-risk burden for people with NAFLD and further suggest that TRL-lowering may be particularly beneficial to mitigate NAFLD-associated coronary artery disease risk.

Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK Biobank study.

AIMS: The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to be resolved. METHODS AND RESULTS: Single-nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (TRL/remnant-C) and LDL cholesterol (LDL-C) were identified in the UK Biobank population. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apolipoprotein B (apoB). Likewise, in a multivariable model, TRL/remnant-C and LDL-C also exhibited independent associations with CHD with odds ratios per 1 mmol/L higher cholesterol of 2.59 [95% confidence interval (CI): 1.99-3.36] and 1.37 [95% CI: 1.27-1.48], respectively. To examine the per-particle atherogenicity of TRL/remnants and LDL, SNPs were categorized into two clusters with differing effects on TRL/remnant-C and LDL-C. Cluster 1 contained SNPs in genes related to receptor-mediated lipoprotein removal that affected LDL-C more than TRL/remnant-C, whereas cluster 2 contained SNPs in genes related to lipolysis that had a much greater effect on TRL/remnant-C. The CHD odds ratio per standard deviation (Sd) higher apoB for cluster 2 (with the higher TRL/remnant to LDL ratio) was 1.76 (95% CI: 1.58-1.96), which was significantly greater than the CHD odds ratio per Sd higher apoB in cluster 1 [1.33 (95% CI: 1.26-1.40)]. A concordant result was obtained by using polygenic scores for each cluster to relate apoB to CHD risk. CONCLUSION: Distinct SNP clusters appear to impact differentially on remnant particles and LDL. Our findings are consistent with TRL/remnants having a substantially greater atherogenicity per particle than LDL.

Pulmonary embolism and deep venous thrombosis after COVID-19: long-term risk in a population-based cohort study.

Background: Venous thromboembolism (VTE) (pulmonary embolism (PE) or deep venous thrombosis (DVT)) is common during acute COVID-19. Long-term excess risk has not yet been established. Objective: To study long-term VTE risk after COVID-19. Methods: Swedish citizens aged 18-84 years, hospitalized and/or testing positive for COVID-19 between January 1, 2020, and September 11, 2021 (exposed), stratified by initial hospitalization, were compared to matched (1:5) non-exposed population-derived subjects without COVID-19. Outcomes were incident VTE, PE or DVT recorded within 60, 60-<180, and ≥180 days. Cox regression was used for evaluation and a model adjusted for age, sex, comorbidities and socioeconomic markers developed to control for confounders. Results: Among exposed patients, 48,861 were hospitalized for COVID-19 (mean age 60.6 years) and 894,121 were without hospitalization (mean age 41.4 years). Among patients hospitalized for COVID-19, fully adjusted hazard ratios (HRs) during 60-<180 days were 6.05 (95% confidence interval (CI) 4.80─7.62) for PE and 3.97 (CI 2.96─5.33) for DVT, compared to non-exposed with corresponding estimates among COVID-19 without hospitalization 1.17 (CI 1.01─1.35) and 0.99 (CI 0.86─1.15), based on 475 and 2,311 VTE events, respectively. Long-term (≥180 days) HRs in patients hospitalized for COVID-19 were 2.01 (CI 1.51─2.68) for PE and 1.46 (CI 1.05─2.01) for DVT while non-hospitalized had similar risk to non-exposed, based on 467 and 2,030 VTE events, respectively. Conclusions: Patients hospitalized for COVID-19 retained an elevated excess risk of VTE, mainly PE, after 180 days, while long-term risk of VTE in individuals with COVID-19 without hospitalization was similar to the non-exposed.

Age and sex differences in cause-specific excess mortality and years of life lost associated with COVID-19 infection in the Swedish population.

BACKGROUND: Estimating excess mortality and years of life lost (YLL) attributed to coronavirus disease 19 (COVID-19) infection provides a comprehensive picture of the mortality burden on society. We aimed to estimate the impact of the COVID-19 pandemic on age- and sex-specific excess mortality and YLL in Sweden during the first 17 months of the pandemic. METHODS: In this population-based observational study, we calculated age- and sex-specific excess all-cause mortality and excess YLL during 2020 and the first 5 months of 2021 and cause-specific death [deaths from cardiovascular disease (CVD), cancer, other causes and deaths excluding COVID-19] in 2020 compared with an average baseline for 2017-19 in the whole Swedish population. RESULTS: COVID-19 deaths contributed 9.9% of total deaths (98 441 deaths, 960 305 YLL) in 2020, accounting for 75 151 YLL (7.7 YLL/death). There were 2672 (5.7%) and 1408 (3.0%) excess deaths, and 19 141 (3.8%) and 3596 (0.8%) excess YLL in men and women, respectively. Men aged 65-110 years and women aged 75-110 years were the greatest contributors. Fewer deaths and YLL from CVD, cancer and other causes were observed in 2020 compared with the baseline adjusted to the population size in 2020. CONCLUSIONS: Compared with the baseline, excess mortality and YLL from all causes were experienced in Sweden during 2020, with a higher excess observed in men than in women, indicating that more men died at a younger age while more women died at older ages than expected. A notable reduction in deaths and YLL due to CVD suggests a displacement effect from CVD to COVID-19.

Severe COVID-19 Infection in Type 1 and Type 2 Diabetes During the First Three Waves in Sweden.

OBJECTIVE: Type 2 diabetes is an established risk factor for hospitalization and death in COVID-19 infection, while findings with respect to type 1 diabetes have been diverging. RESEARCH DESIGN AND METHODS: Using nationwide health registries, we identified all patients aged ≥18 years with type 1 and type 2 diabetes in Sweden. Odds ratios (ORs) describe the general and age-specific risk of being hospitalized, need for intensive care, or dying, adjusted for age, socioeconomic factors, and coexisting conditions, compared with individuals without diabetes. Machine learning models were used to find predictors of outcomes among individuals with diabetes positive for COVID-19. RESULTS: Until 30 June 2021, we identified 365 (0.71%) and 11,684 (2.31%) hospitalizations in 51,402 and 504,337 patients with type 1 and 2 diabetes, respectively, with 67 (0.13%) and 2,848 (0.56%) requiring intensive care unit (ICU) care and 68 (0.13%) and 4,020 (0.80%) dying (vs 7,824,181 individuals without diabetes [41,810 hospitalizations (0.53%), 8,753 (0.11%) needing ICU care, and 10,160 (0.13%) deaths). Although those with type 1 diabetes had moderately raised odds of being hospitalized (multiple-adjusted OR 1.38 [95% CI 1.24-1.53]), there was no independent effect on ICU care or death (OR of 1.21 [95% CI 0.94-1.52] and 1.13 [95% CI 0.88-1.48], respectively). Age and socioeconomic factors were the dominating features for predicting hospitalization and death in both types of diabetes. CONCLUSIONS: Type 2 diabetes was associated with increased odds for all outcomes, whereas patients with type 1 diabetes had moderately increased odds of hospitalization but not ICU care and death.

Pre-diabetes is associated with attenuation rather than volume of epicardial adipose tissue on computed tomography.

The volume of epicardial adipose tissue (EATV) is increased in type-2 diabetes (T2D), while its attenuation (EATA) appears to be decreased. Similar patterns have been suggested in pre-diabetes, but data is scarce. In both pre-diabetes and T2D, any independent role of EATV and EATA in disease development remains to be proven, a task complicated by their substantial co-variation with other anthropometrics, e.g. BMI, waist circumference, and abdominal visceral adipose tissue (VAT). EATV and EATA was quantified in computed tomography (CT) images in a population study (n = 1948) using an automatic technique. Data was available on BMI, waist circumference, abdominal visceral adipose tissue (VAT) area, insulin resistance (IR) and glucose tolerance, the latter ranging from normal (NGT), over pre-diabetes (impaired fasting glucose [IFG, n = 414] impaired glucose tolerance [IGT, n = 321] and their combination [CGI, n = 128]), to T2D. EATV was increased in pre-diabetes, T2D and IR in univariable analyses and when adjusting for BMI, however not when adjusting for waist or VAT. EATA was reduced in pre-diabetes, T2D and IR in univariable analyses and when adjusting for BMI and waist, however not when adjusting for VAT. Adjustment for other co-variates had little influence on the results. In conclusion, EATV is increased and EATA reduced in pre-diabetes, T2D and IR, however, significant co-variation with other anthropometrics, especially VAT, obscures their function in disease development. The current results do not exclude a pathophysiological role of epicardial fat, but future studies need to adjust for anthropometrics, or focus on the microenvironment within the pericardial sac.

Risk of Myocardial Infarction, Ischemic Stroke, and Mortality in Patients Who Undergo Gastric Bypass for Obesity Compared With Nonoperated Obese Patients and Population Controls.

OBJECTIVE: The aim of this study was to estimate risks of myocardial infarction, ischemic stroke, and cardiovascular-related and all-cause mortality after Roux-en-Y gastric bypass (RYGB) for obesity compared with nonop-erated obese patients and matched nonobese population controls. BACKGROUND: Few studies have assessed the influence of RYGB on fatal and non-fatal myocardial infarction and ischemic stroke, and the results vary between studies. METHOD: All patients aged 20 to 65 years with obesity diagnosis in the nationwide Swedish Patient Registry in 2001 to 2013 were included. These participants were divided into those who underwent RYGB within 2 years of obesity diagnosis (n = 28,204) and nonoperated (n = 40,827), and were matched for age, sex, and region with 2 nonobese population controls. Participants were followed until onset of outcome disease, death, or end of follow-up. Multivariable Cox regression provided hazard ratios (HR) with 95% confidence intervals (95% CI). RESULTS: Compared with nonoperated patients with obesity, RYGB patients had a reduced risk of myocardial infarction [HR = 0.44 (95% CI 0.28-0.63)], similar risk of ischemic stroke [HR = 0.79 (95% CI 0.54-1.14)], and decreased risks of cardiovascular-related [HR = 0.47 (95% CI 0.35-0.65)] and all-cause mortality [HR = 0.66 (95% CI 0.54-0.81)] within the first 3 years of follow-up, but not later. Compared with nonobese population controls, RYGB patients had excess risks of ischemic stroke [HR = 1.57 (95% CI 1.08-2.29)], cardiovascular-related mortality [HR = 1.82 (95% CI 1.29-2.60)], and all-cause mortality [HR = 1.42 (95% CI 1.16-1.74)], but not of myocardial infarction [HR = 1.02 (95% CI 0.72-1.46)]. CONCLUSION: RYGB for obesity might not decrease the risk of ischemic stroke, but seems to decrease the risk of myocardial infarction back to population levels.

COVID-19 in people aged 18-64 in Sweden in the first year of the pandemic: Key factors for severe disease and death.

Background: Studies on risk factors for severe COVID-19 in people of working age have generally not included non-working persons or established population attributable fractions (PAFs) for occupational and other factors. Objectives: We describe the effect of job-related, sociodemographic, and other exposures on the incidence, relative risks and PAFs of severe COVID-19 in individuals aged 18-64. Methods: We conducted a registry-based study in Swedish citizens aged 18-64 from 1 January 2020 to 1 February 2021 with respect to COVID-19-related hospitalizations and death. Results: Of 6,205,459 persons, 272,043 (7.5%) were registered as infected, 3399 (0.05%) needed intensive care, and 620 (0.01%) died, with an estimated case fatality rate of 0.06% over the last 4-month period when testing was adequate. Non-Nordic origin was associated with a RR for need of intensive care of 3·13, 95%CI 2·91-3·36, and a PAF of 32·2% after adjustment for age, sex, work, region and comorbidities. In a second model with occupation as main exposure, and adjusted for age, sex, region, comorbidities and origin, essential workers had an RR of 1·51, 95%CI, 1·35-1·6, blue-collar workers 1·18, 95%CI 1·06-1·31, school staff 1·21, 95%CI 1·01-1·46, and health and social care workers 1·89, 95%CI 1·67-2·135) compared with people able to work from home, with altogether about 13% of the PAF associated with these occupations. Essential workers and blue-collar workers, but no other job categories had higher risk of death, adjusted RRs of 1·79, 95%CI 1·34-2·38 and 1·37, 95%CI 1·04-1·81, with adjusted PAFs of altogether 9%. Conclusion: Among people of working age in Sweden, overall mortality and case fatality were low. Occupations that require physical presence at work were associated with elevated risk of needing intensive care for COVID-19, with 14% cases attributable to this factor, and 9% of deaths.

Body Mass Index in Adolescence and Long-Term Risk of Early Incident Atrial Fibrillation and Subsequent Mortality, Heart Failure, and Ischemic Stroke.

Background We sought to determine the role of obesity in adolescent men on development of atrial fibrillation (AF) and subsequent associated clinical outcomes in subjects diagnosed with AF. Methods and Results We conducted a nationwide, register-based, cohort study of 1 704 467 men (mean age, 18.3±0.75 years) enrolled in compulsory military service in Sweden from 1969 through 2005. Height and weight, blood pressure, fitness, muscle strength, intelligence quotient, and medical disorders were recorded at baseline. Records obtained from the National Inpatient Registry and the Cause of Death Register were used to determine incidence and clinical outcomes of AF. During a median follow-up of 32 years (interquartile range, 24-41 years), 36 693 cases (mean age at diagnosis, 52.4±10.6 years) of AF were recorded. The multivariable-adjusted hazard ratio (HR) for AF increased from 1.06 (95% CI, 1.03-1.10) in individuals with body mass index (BMI) of 20.0 to <22.5 kg/m2 to 3.72 (95% CI, 2.44-5.66) among men with BMI of 40.0 to 50.0 kg/m2, compared with those with BMI of 18.5 to <20.0 kg/m2. During a median follow-up of ≈6 years in patients diagnosed with AF, we identified 3767 deaths, 3251 cases of incident heart failure, and 921 cases of ischemic stroke. The multivariable-adjusted HRs for all-cause mortality, incident heart failure, and ischemic stroke in AF-diagnosed men with baseline BMI >30 kg/m2 compared with those with BMI <20 kg/m2 were 2.86 (95% CI, 2.30-3.56), 3.42 (95% CI, 2.50-4.68), and 2.34 (95% CI, 1.52-3.61), respectively. Conclusions Increasing BMI in adolescent men is strongly associated with early AF, and with subsequent worse clinical outcomes in those diagnosed with AF with respect to all-cause mortality, incident heart failure, and ischemic stroke.

Postprandial metabolism of apolipoproteins B48, B100, C-III, and E in humans with APOC3 loss-of-function mutations.

BackgroundApolipoprotein C-III (apoC-III) is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear.MethodsWe investigated the kinetics of apolipoproteins B48 and B100 (apoB48 and apoB100) in chylomicrons, VLDL1, VLDL2, IDL, and LDL in patients heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the postprandial state to provide a more comprehensive view of the influence of this protein on TG transport.ResultsCompared with non-LOF variant participants, a genetically determined decrease in apoC-III resulted in marked acceleration of lipolysis of TG-rich lipoproteins (TRLs), increased removal of VLDL remnants from the bloodstream, and substantial decrease in circulating levels of VLDL1, VLDL2, and IDL particles. Production rates for apoB48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and noncarriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor were the concentration and clearance rate of LDL-apoB100.ConclusionThese findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention.Trial registrationClinicalTrials.gov NCT04209816 and NCT01445730.FundingSwedish Heart-Lung Foundation, Swedish Research Council, ALF grant from the Sahlgrenska University Hospital, Novo Nordisk Foundation, Sigrid Juselius Foundation, Helsinki University Hospital Government Research funds, Finnish Heart Foundation, and Finnish Diabetes Research Foundation.