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Background Exposure to many contacts is the main risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while risk of serious disease and death is chiefly determined by old age and comorbidities. Relative and population-attributable fractions (PAFs) of multiple medical and social exposures for COVID-19 outcomes have not been evaluated among older adults. Objectives We describe the effect of multiple exposures on the odds of testing positive for the virus and of severe disease (hospital care or death) and PAFs in Swedish citizens aged 55 years and above. Methods We used national registers to follow all citizens aged 55 years and above with respect to (1) testing positive, (2) hospitalization, and (3) death between 31 January 2020 and 1 February 2021. Results Of 3,410,241 persons, 156,017 (4.6%, mean age 68.3 years) tested positive for SARS-CoV-2, while 35,999 (1.1%, mean age 76.7 years) were hospitalized or died (12,384 deaths, 0.4%, mean age 84.0 years). Among the total cohort, the proportion living without home care or long-term care was 98.8% among persons aged 55-64 and 22.1% of those aged 95 and above. After multiple adjustment, home care and long-term care were associated with odds ratios of 7.9 (95% confidence interval [CI] 6.8-9.1) and 22.5 (95% CI 19.6-25.7) for mortality, with PAFs of 21.9% (95% CI 20.9-22.9) and 33.3% (95% CI 32.4-34.3), respectively. Conclusion Among Swedish residents aged 55 years and above, those with home care or long-term care had markedly increased risk for COVID-19 death during the first year of the pandemic, with over 50% of deaths attributable to these factors. Funding Agencies|Swedish Heart and Lung Foundation [2018-0366]; Swedish Research Council [2018-0366, 2020-05792, 2021-06545]; Swedish state [ALFGBG717211, AFGBG-965885]; VRREG [2019-00193, 2019-00198, 201900245, 2019-00209]; Science for Life Laboratory from the Knut and Alice Wallenberg Foundation [2020.0241]; Swedish Research Council for Health, Working Life and Welfare [2021-00304]

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with increased secretion of apoB-containing lipoproteinsand 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. Methods: 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). Results: 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. Conclusions: 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.

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 general- and age specific risk of being hospitalized, in need of intensive care, or dying, adjusted for age, socioeconomic factors and coexisting conditions, compared to individuals without diabetes. Machine learning models were used to find predictors of outcomes among COVID-19-positive individuals with diabetes. Results Until June 30, 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%) cases requiring ICU care, while there were 68 (0.13%) and 4,020 (0.80%) deaths, which we compared with 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 (ORs of 1.21(95% CI 0.94-1.52) and 1.13(95% CI 0.88-1.48)). Age and socioeconomic factors were the dominating features for predicting hospitalization and death in both types of diabetes. Conclusions Type 2 diabetes were associated with increased odds for all of the outcomes, whereas patients with type 1 diabetes had moderately increased odds of hospitalization but not ICU care and death.

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 to22.5 kg/m

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.

OBJECTIVEType 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 METHODSUsing 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.RESULTSUntil 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.CONCLUSIONSType 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.

Aims Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function. Methods and results Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg–/– mice). In 9- to 10-week-old hUgcg–/– mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg–/– mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg–/– mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors. Conclusions Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function., Graphical Abstract Cardiac glycosphingolipids are required to maintain β-adrenergic signaling and contractile capacity in cardiomyocytes and to preserve normal heart function.

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.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.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.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%.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.

Objective Incretins are known to influence lipid metabolism in the intestine when administered as pharmacologic agents. The aggregate influence of endogenous incretins on chylomicron production and clearance is less clear, particularly in light of opposing effects of co-secreted hormones. Here, we tested the hypothesis that physiological levels of incretins may impact on production or clearances rates of chylomicrons and VLDL. Design and methods A group of 22 overweight/obese men was studied to determine associations between plasma levels of glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) after a fat-rich meal and the production and clearance rates of apoB48- and apoB100-containing triglyceride-rich lipoproteins. Subjects were stratified by above- and below-median incretin response (area under the curve). Results Stratification yielded subgroups that differed about two-fold in incretin response. There were neither differences in apoB48 production rates in chylomicrons or VLDL fractions nor in apoB100 or triglyceride kinetics in VLDL between men with above- vs below-median incretin responses. The men with above-median GLP-1 and GLP-2 responses exhibited higher postprandial plasma and chylomicron triglyceride levels, but this could not be related to altered kinetic parameters. No differences were found between incretin response subgroups and particle clearance rates. Conclusion We found no evidence for a regulatory effect of endogenous incretins on contemporaneous chylomicron or VLDL metabolism following a standardised fat-rich meal. The actions of incretins at pharmacological doses may not be reflected at physiological levels of these hormones.

Background As opposed to the decreasing overall rates of coronary heart disease (CHD) incidence and overall cardiovascular disease (CVD) mortality, heart failure (HF) and stroke incidence are increasing in young people, potentially due to rising rates of obesity and reduced cardiorespiratory fitness (CRF). Objectives We investigated trends in early major CVD outcomes in a large cohort of young men. Methods Successive cohorts of Swedish military conscripts from 1971 to 1995 (N = 1,258,432; mean age, 18.3 years) were followed, using data from the National Inpatient and Cause of Death registries. Cox proportional hazard models were used to analyse changes in 21-year CVD event rates. Results 21-year CVD and all-cause mortality and incidence of acute myocardial infarction (AMI) decreased progressively. Compared with the cohort conscripted in 1971-1975 (reference), the hazard ratios (HRs) for the last 1991-1995 cohort were 0.50 [95% confidence interval (CI) 0.42-0.59] for CVD mortality; 0.57 (95% CI 0.54-0.60) for all-cause mortality; and 0.63 (95% CI 0.53-0.75) for AMI. In contrast, the incidence of ischaemic stroke, intracerebral haemorrhage and HF increased with HRs of 1.43 (95% CI 1.17-1.75), 1.30 (95% CI 1.01-1.68) and 1.84 (95% CI 1.47-2.30), respectively. During the period, rates of obesity increased from 1.04% to 2.61%, whilst CRF scores decreased slightly. Adjustment for these factors influenced these secular trends only moderately. Conclusion Secular trends of young-onset CVD events demonstrated a marked shift from AMI and CVD mortality to HF and stroke incidence. Trends were significantly, though moderately, influenced by changing baseline BMI and CRF.

Aims This study aims to investigate the association of resting heart rate (RHR) measured in late adolescence with long‐term risk of cause‐specific heart failure (HF) and subtypes of cardiomyopathy (CM), with special attention to cardiorespiratory fitness. Methods and results We performed a nation‐wide, register‐based cohort study of all Swedish men enrolled for conscription in 1968–2005 (n = 1 008 363; mean age = 18.3 years). RHR and arterial blood pressure were measured together with anthropometrics as part of the enlistment protocol. HF and its concomitant diagnoses, as well as all CM diagnoses, were collected from the national inpatient, outpatient, and cause of death registries. Risk estimates were calculated by Cox‐proportional hazards models while adjusting for potential confounders. During follow‐up, there were 8400 cases of first hospitalization for HF and 3377 for CM. Comparing the first and fifth quintiles of the RHR distribution, the hazard ratio (HR) for HF associated with coronary heart disease, diabetes, or hypertension was 1.25 [95% confidence interval (CI) = 1.13–1.38] after adjustment for body mass index, blood pressure, and cardiorespiratory fitness. The corresponding HR was 1.43 (CI = 1.08–1.90) for HF associated with CM and 1.34 (CI = 1.16–1.54) for HF without concomitant diagnosis. There was an association between RHR and dilated CM [HR = 1.47 (CI = 1.27–1.71)] but not hypertrophic, alcohol/drug‐induced, or other cardiomyopathies. Conclusions Adolescent RHR is associated with future risk of HF, regardless of associated aetiological condition. The association was strongest for HF associated with CM, driven by the association with dilated CM. These findings indicate a causal pathway between elevated RHR and myocardial dysfunction that warrants further investigation.

Aims The aim of this study was to investigate the relation between body mass index (BMI) in young women, using weight early in pregnancy as a proxy for pre-pregnancy weight, and risk for early cardiovascular disease (CVD) and mortality. Methods and results In this prospective, registry-based study, we used weight data in early pregnancy from women, registered in the Swedish Medical Birth Registry, and who gave birth between 1982 and 2014 (n = 1,495,499; median age 28.3 years). Of the women, 118,212 (7.9%) were obese (BMI ≥ 30 kg/m2) and 29,630 (2.0%) severely obese (BMI ≥ 35 kg/m2). After a follow-up of median 16.3 years, we identified 3295 and 4375 cases of acute myocardial infarction (AMI) and ischemic stroke (IS) corresponding to 13.4 and 17.8 per 100,000 observation years, respectively, occurring at mean ages of 49.8 and 47.3 years. Compared to women with a BMI 20– Conclusion A significant increase in the risk for early AMI, IS and CVD death was noticeable in overweight young women, with a marked increase in obese women.

BACKGROUND As the population of obese and severely obese young adults grows, it is becoming increasingly important to recognize the long-term risks associated with adolescent obesity. OBJECTIVES This study aimed to determine the association between body mass index (BMI) in young men at enlistment for military service and later risk of venous thromboembolism (VTE). METHODS Nationwide register-based prospective cohort study of men enlisting 1969 to 2005, followed through the Swedish National Patient and Cause of Death registries. We identified 1 639 838 men (mean age, 18.3 years) free of prior venous thromboembolism, of whom 29 342 were obese (BMI 30 to

Aim: We aim to assess the risk of heart failure in patients with obesity with and without gastric bypass surgery compared with population controls. Methods and results: This cohort study included all patients aged 20–65 years with a first ever registered principal diagnosis of obesity in the Swedish Patient Register in 2001–2013. These patients were matched by age, sex, and region with two population controls from the general Swedish population without obesity diagnosis. The obesity cohort was divided into two groups: 27 882 patients who had undergone gastric bypass surgery within 2 years of obesity diagnosis and 39 564 patients who had not undergone such surgery. These groups were compared with 55 149 and 78 004 matched population controls, respectively. Cox regression provided hazard ratios (HR) with 95% confidence intervals (CI), adjusted for age, education, and sex. During follow-up (maximum 10 years, median 4.4 years, and interquartile range 2.5–7.2 years), 1884 participants were hospitalized for heart failure. Compared with population controls, gastric bypass patients had no excess risk of heart failure during the initial 0–≤4 years of follow-up (HR = 1.35 [95% CI = 0.96–1.91]) but a marked increased risk during the final >4–10 years of follow-up (HR = 3.28 [95% CI = 2.25–4.77]). Non-operated patients with obesity had a marked excess risk of heart failure throughout the study period compared with population controls. Conclusions: Gastric bypass for obesity seems to reduce the risk of heart failure to levels similar to the general population during the initial 4 years after surgery, but not thereafter.

Overweight and obesity have been identified as risk factors for severe COVID-19; however, prospective cohort studies investigating the association between overweight early in life and severity of COVID-19 are lacking.This study included 1,551,670 Swedish men, born between 1950 and 1987, with BMI registered at age 18 years. They were followed until January 9, 2021. COVID-19 cases and comorbidities were identified through the National Patient, Intensive Care, and Cause of Death registries. Outcomes included the following: 1) hospitalization; 2) intensive care unit admission; and 3) death.The study found 4,315 cases (mean age = 56.4 years [SD 8.8]) of patients hospitalized because of COVID-19, of which 729 were admitted to an intensive care unit, and altogether there were 224 deaths. The risk for hospital admission increased with higher values of BMI at age 18 years, despite adjustment for comorbidities, from an odds ratio (OR) of 1.19 (95% CI: 1.08-1.31) at BMI = 22.5 to 25 to an OR of 1.68 (95% CI: 1.39-2.02) at BMI ≥ 30, compared with BMI = 18.5 to 20. ORs for intensive care unit admission were 1.44 (95% CI: 1.13-1.84) at BMI = 22.5 to 25 and 2.61 (95% CI: 1.73-3.93) at BMI ≥ 30.Higher BMI in early adulthood was associated with severe COVID-19 many years later, with a risk increase starting already at BMI ≥ 22.5. This underlines the necessity of preventive actions against overweight in youth to offer protection against coming viral pandemics.

High body mass index (BMI) is associated with severe COVID-19 but findings regarding the need of intensive care (IC) and mortality are mixed. Using electronic health records, we identified all patients in western Sweden hospitalised with COVID-19 to evaluate 30-day mortality or assignment to IC. Adjusted logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for outcomes. Of totally 9761 patients, BMI was available in 7325 (75%), included in the study. There was a marked inverse association between BMI and age (underweight and normal weight patients were on average 78 and 75 years, whereas overweight and obese were 68 and 62 years). While older age, male sex and several comorbidities associated with higher mortality after multivariable adjustment, BMI did not. However, BMI ≥ 30 kg/m2 (OR 1.46, 95% CI 1.21–1.75) was associated with need of IC; this association was restricted to women (BMI ≥ 30; OR 1.96 (95% CI 1.41–2.73), and not significant in men; OR 1.22 (95% CI 0.97–1.54). In this comprehensive hospital population with COVID-19, BMI was not associated with 30-day mortality risk. Among the obese, women, but not men, had a higher risk of assignment to IC.

Background The phospholipase domain-containing 3 gene (PNPLA3)-148M variant is associated with liver steatosis but its influence on the metabolism of triglyceride-rich lipoproteins remains unclear. Here, we investigated the kinetics of large, triglyceride-rich very-low-density lipoprotein (VLDL), (VLDL1), and smaller VLDL2 in homozygotes for the PNPLA3-148M variant. Methods and results The kinetics of apolipoprotein (apo) B100 (apoB100) and triglyceride in VLDL subfractions were analysed in nine subjects homozygous for PNPLA3-148M and nine subjects homozygous for PNPLA3-148I (controls). Liver fat was >3-fold higher in the 148M subjects. Production rates for apoB100 and triglyceride in VLDL1 did not differ significantly between the two groups. Likewise, production rates for VLDL2-apoB100 and -triglyceride, and fractional clearance rates for both apoB100 and triglyceride in VLDL1 and VLDL2, were not significantly different. Conclusions Despite the higher liver fat content in PNPLA3 148M homozygotes, there was no increase in VLDL production. Equally, VLDL production was maintained at normal levels despite the putative impairment in cytosolic lipid hydrolysis in these subjects.

Background There is a need for high-quality research regarding exercise interventions for persons with anxiety disorders. We investigate whether a 12-week exercise intervention, with different intensities, could reduce anxiety symptoms in patients with anxiety disorders. Methods 286 patients were recruited from primary care in Sweden. Severity of symptoms was self-assessed using the Beck Anxiety Inventory (BAI) and the Montgomery Asberg Depression Rating Scale (MADRS-S). Participants were randomly assigned to one of two group exercise programs with cardiorespiratory and resistance training and one control/standard treatment non-exercise group, with 1:1:1 allocation. Results Patients in both exercise groups showed larger improvements in both anxiety and depressive symptoms compared to the control group. No differences in effect sizes were found between the two groups. To study a clinically relevant improvement, BAI and MADRS-S were dichotomized with the mean change in the control group as reference. In adjusted models the odds ratio for improved symptoms of anxiety after low-intensity training was 3.62 (CI 1.34–9.76) and after moderate/high intensity 4.88 (CI 1.66–14.39), for depressive symptoms 4.96 (CI 1.81–13.6) and 4.36 (CI 1.57–12.08) respectively. There was a significant intensity trend for improvement in anxiety symptoms. Limitations The use of self-rating measures which bears the risk of an under- or overestimation of symptoms. Conclusions A 12-week group exercise program proved effective for patients with anxiety syndromes in primary care. These findings strengthen the view of physical exercise as an effective treatment and could be more frequently made available in clinical practice for persons with anxiety issues.

Objective 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 non-operated obese patients and matched non-obese 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 20-65 years with obesity diagnosis in the nationwide Swedish Patient Registry in 2001-2013 were included. These participants were divided into those who underwent RYGB within 2 years of obesity diagnosis (n=28,204) and non-operated (n=40,827), and were matched for age, sex, and region with two non-obese 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 non-operated 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 non-obese 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]). Conclusions RYGB for obesity might not decrease the risk of ischemic stroke, but seems to decrease the risk of myocardial infarction back to population levels.

Obesity rates in adolescence and young adulthood have increased in Sweden, reflecting global trends. To which extent this occurs across different socioeconomic strata has not been clarified. The aim of the present study was to investigate trends in social inequalities in body mass index (BMI) in young/mid-adulthood Swedish women. We obtained weight and height for all women aged 20–45 years, at their first registered pregnancy (2 (SD 3.2) to 24.3 kg/m2 (SD 4.4) between 1982 and 2013. Simultaneously, the prevalence of overweight and obesity (BMI ≥ 25 kg/m2) increased from 18.1 to 33.4% while that of moderate obesity (BMI ≥ 30 to 2) and severe obesity (BMI ≥ 35 kg/m2) increased markedly from 3.4 and 0.4% to 7.4 and 3.1%, respectively. The prevalence of moderate and severe obesity more than doubled during the study period across all educational levels. In conclusion, BMI and moderate and severe obesity increased markedly among young/mid-adulthood Swedish women regardless of education with a widening gap between those with lower and higher education. These growing social inequalities in BMI are likely to cause a rising divide in serious health problems following early and long-lasting obesity.

openaire: EC/H2020/305707/EU//RESOLVE Aims: To investigate how apolipoprotein C-III (apoC-III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC-III, and whether improvement of glycaemic control using the glucagon-like peptide-1 analogue liraglutide for 16 weeks modifies apoC-III dynamics. Materials and Methods: Postprandial apoC-III kinetics were assessed after a bolus injection of [5,5,5- 2 H 3 ]leucine using ultrasensitive mass spectrometry techniques. We compared apoC-III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non-diabetic subjects. Liver fat content, subcutaneous abdominal and intra-abdominal fat were determined using proton magnetic resonance spectroscopy. Results: Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC-III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC-III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC-III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC-III secretion rate was higher in subjects with type 2 diabetes compared with BMI-matched non-diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042). Conclusions: The results reveal that the secretion rate of apoC-III is associated with elevation of triglyceride-rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC-III.

Publisher Copyright: © 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved. Aim: To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal. Materials and Methods: Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal. Results: Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p

IntroductionIn type 1 diabetes, potential loss of life-years is greatest in those who are youngest at the time of onset. Using data from a nationwide cohort of patients with type 1 diabetes, we aimed to study risk factor trajectories by age at diagnosis.Research design and methodsWe stratified 30 005 patients with type 1 diabetes aged 18–75 years into categories based on age at onset: 0–10, 11–15, 16–20, 21–25, and 26–30 years. HbA1c, albuminuria, estimated glomerular filtration rate (eGFR), body mass index (BMI), low-denisty lipoprotein (LDL)-cholesterol, systolic blood pressure (SBP), and diastolic blood pressure trends were analyzed using mixed models. Variable importance for baseline HbA1c was analyzed using conditional random forest and gradient boosting machine approaches.ResultsIndividuals aged ≥16 years at onset displayed a relatively low mean HbA1c level (~55–57 mmol/mol) that gradually increased. In contrast, individuals diagnosed at ≤15 years old entered adulthood with a mean HbA1c of approximately 70 mmol/mol. For all groups, HbA1c levels stabilized at a mean of approximately 65 mmol/mol by about 40 years old. In patients who were young at the time of onset, albuminuria appeared at an earlier age, suggesting a more rapid decrease in eGFR, while there were no distinct differences in BMI, SBP, and LDL-cholesterol trajectories between groups. Low education, higher age, and poor risk factor control were associated with higher HbA1c levels.ConclusionsYoung age at the diabetes onset plays a substantial role in subsequent glycemic control and the presence of albuminuria, where patients with early onset may accrue a substantial glycemic load during this period.

Introduction: Whether infection with SARS-CoV-2 leads to excess risk of requiring hospitalization or intensive care in persons with diabetes has not been reported, nor have risk factors in diabetes associated with increased risk for these outcomes. Methods: We included 44,639 and 411,976 adult patients with type 1 and type 2 diabetes alive on Jan 1, 2020, and compared them to controls matched for age, sex, and county of residence (n=204,919 and 1,948,900). Standardized rates of hospitalizations, admissions to intensive care and death were estimated and hazard ratios were calculated using Cox regression analyses. Findings: There were 10,486 hospitalizations and 1,416 admissions into intensive care. A total of 1,175 patients with diabetes and 1,820 matched controls died from COVID-19, of these 53·2% had been hospitalized and 10·7% had been in intensive care. Patients with type 2 diabetes, compared to controls, displayed a hazard ratio (HR) of 2·22, 95%CI 2·13-2·32) of being hospitalized, which decreased to HR 1·40, 95%CI 1·34-1·47) after adjustment for sociodemographic factors, pharmacological treatment and comorbidities, had higher risk for admission to intensive care (HR 2·49, 95%CI 2·22-2·79, decreasing to 1·42, 95%CI 1·25-1·62 after adjustment, and increased risk for death (HR 2·19, 95%CI 2·03-2·36, adjusted 1·50, 95%CI 1·39-1·63). HR for hospitalization for type 1 diabetes was 2·10, 95%CI 1·72-2·57), decreasing to 1·25, 95%CI 0·3097-1·62) after adjustment· Patients with diabetes type 1 were twice as likely to require intensive care for COVID-19, however, not after adjustment (HR 1·49, 95%CI 0·75-2·92), and more likely to die (HR 2·90, 95% CI 1·6554-5·47), but not independently of other factors (HR 1·38, 95% CI 0·64-2·99). Among people with diabetes, elevated glycated hemoglobin levels were associated with higher risk for most outcomes. Interpretation: In this nationwide study, type 2 diabetes was independently associated with increased risk of hospitalization, admission to intensive care and death for COVID-19, whereas type 1 diabetes was not independently associated with excess risk for any outcome. Funding Statement: This work was supported by grants from: the Swedish state under an agreement concerning research and education of doctors [ALFGBG-717211]; the Swedish Heart and Lung Foundation [2018- 0366]; the Swedish Research Council [2013-05187, VRREG 2019-00193, 2020-05792] Declaration of Interests: Professor Eliasson reports personal fees (expert panels, lectures) from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Mundipharma, Navamedic, NovoNordisk, RLS Global, grants and personal fees from Sanofi, all outside the submitted work. NN declare that they have no conflict of interest. MG reports personal fees (scientific advisory boards, lectures) from Gilead Sciences, GSK/ViiV, MSD, Biogen, Amgen, Novocure, Novo Nordic and research grants from Gilead Sciences, all outside the submitted work. All other authors have nothing to disclose. Ethics Approval Statement: The Swedish Ethical Review Authority approved the study.

Supplemental Digital Content is available in the text., Background: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population. Methods: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data. Results: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population. Conclusions: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.

Objective: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL 1 (very low-density lipoprotein) and VLDL 2 ; and apoB100 in VLDL 1 , VLDL 2 , IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL 1 . In contrast, the fractional catabolic rates of VLDL 2 -apoB100 and VLDL 2 -triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL 2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL 2 - and IDL-apoB100 concentrations. Conclusions: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL 1 ) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL 2 , IDL, LDL). Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02948777.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 (TM6SF2) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM65F2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein 13100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VIOL subtractions: large triglyceride-rich VLDL, and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise. VLDL,-triglyceride production was 35% lower in the TMSSF2 E167K carriers. In contrast, the direct production rates for VLDL2 apo13100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL1. The impaired secretion of VLDL1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.

AimsAtrial fibrillation (AF) is associated with arterial thromboembolism, mainly ischaemic stroke, while venous thromboembolism (VTE) in AF is less well studied. The aim of this study, therefore, was to examine the relationship between AF and VTE, including pulmonary embolism (PE) and deep venous thrombosis (DVT).Methods and resultsAF cases without previous VTE, ischaemic stroke or pulmonary arterial hypertension were identified from the Swedish Inpatient Registry between 1987 and 2013 and compared to two population controls per case without AF matched for age, sex, and county with respect to the incidence of VTE, PE, and DVT. In total, 463 244 AF cases were compared to 887 336 population controls. In both men and women, VTE rates were higher among AF patients the first 30 days after an AF diagnosis [40.2 vs. 5.7 in men and 55.7 vs. 6.6 in women per 1000 person-years at risk, respectively; hazard ratios 6.64 (95% confidence interval, 5.74–7.69) and 7.56 (6.47–8.83)]; and then decreasing, simultaneously with an increasing number of AF patients being treated with oral anticoagulation. VTE risk was similar to controls after 9 months in men but remained slightly elevated in women.ConclusionAF is strongly associated with an increased risk of VTE during the first months after diagnosis. Introduction of anticoagulant therapy soon after AF diagnosis might reduce the risk of VTE as well as of ischaemic stroke.

Background: \ud Renewed interest in triglyceride-rich lipoproteins as causative agents in cardiovascular disease mandates further exploration of the integrated metabolism of chylomicrons and very low-density lipoproteins (VLDL).\ud \ud Methods: \ud Novel tracer techniques and an integrated multi-compartmental model were used to determine the kinetics of apoB48- and apoB100-containing particles in the chylomicron and VLDL density intervals in 15 subjects with a wide range of plasma triglyceride levels.\ud \ud Results: \ud Following a fat-rich meal, apoB48 appeared in the chylomicron, VLDL1 and VLDL2 fractions in all subjects. Chylomicrons cleared rapidly from the circulation but apoB48-containing VLDL accumulated, and over the day were 3-fold higher in those with high versus low plasma triglyceride. ApoB48-containing particles were secreted directly into both the chylomicron and VLDL fractions at rates that were similar across the plasma triglyceride range studied. During fat absorption, whilst most triglyceride entered the circulation in chylomicrons, the majority of apoB48 particles were secreted into the VLDL density range.\ud \ud Conclusion: \ud The intestine secretes apoB48-containing particles not only as chylomicrons but also directly into the VLDL1 and VLDL2 density ranges both in the basal state and during dietary lipid absorption. Over the day, apoB48-containing particles appear to comprise about 20–25% of circulating VLDL and, especially in those with elevated triglycerides, form part of a slowly cleared ‘remnant’ particle population, thereby potentially increasing CHD risk. These findings provide a metabolic understanding of the potential consequences for increased CHD risk when slowed lipolysis leads to the accumulation of remnants, especially in individuals with hypertriglyceridemia.

Objectives Recent reports suggest an association between the inflammatory response after aneurysmal subarachnoid haemorrhage (aSAH) and patients' outcome. The primary aim of this study was to identify a potential association between the inflammatory response after aSAH and 1-year outcome. The secondary aim was to investigate whether the inflammatory response after aSAH could predict the development of delayed cerebral ischaemia (DCI). Materials and methods This prospective observational pilot study included patients with an aSAH admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, between May 2015 and October 2016. The patients were stratified according to the extended Glasgow Outcome Scale (GOSE) as having an unfavourable (score: 1-4) or favourable outcome (score: 5-8). Furthermore, patients were stratified depending on development of DCI or not. Patient data and blood samples were collected and analysed at admission and after 10 days. Results Elevated serum concentrations of inflammatory markers such as tumour necrosis factor-α and interleukin (IL)-6, IL-1Ra, C-reactive protein and intercellular adhesion molecule-1 were detected in patients with unfavourable outcome. When adjustments for Glasgow coma scale were made, only IL-1Ra remained significantly associated with poor outcome (p = 0.012). The inflammatory response after aSAH was not predictive of the development of DCI. Conclusion Elevated serum concentrations of inflammatory markers were associated with poor neurological outcome 1-year after aSAH. However, inflammatory markers are affected by many clinical events, and when adjustments were made, only IL-1Ra remained significantly associated with poor outcome. The robustness of these results needs to be tested in a larger trial.

The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine by performing a 7-day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.

Supplemental Digital Content is available in the text., Background: Incidence rates of cardiomyopathies, which are a common cause of heart failure in young people, have increased during the last decades. An association between body weight in adolescence and future cardiomyopathy among men was recently identified. Whether or not this holds true also for women is unknown. The aim was therefore to determine whether for young women being overweight or obese is associated with a higher risk of developing cardiomyopathy. Methods: This was a registry-based national prospective cohort study with data collected from the Swedish Medical Birth Register, 1982 to 2014, with up to 33 years of follow-up. Included women were of childbearing age (18–45 years) during the initial antenatal visit in their first or second pregnancy (n=1 393 346). We obtained baseline data on body mass index (BMI), smoking, education, and previous disorders. After exclusions, mainly because of previous disorders, the final sample was composed of 1 388 571 women. Cardiomyopathy cases were identified by linking the Medical Birth Register to the National Patient and Cause of Death registers. Results: In total, we identified 1699 cases of cardiomyopathy (mean age at diagnosis, 46.2 [SD 9.1] years) during the follow-up with an incidence rate of 5.9 per 100 000 observation years. Of these, 481 were diagnosed with dilated cardiomyopathy, 246 had hypertrophic cardiomyopathy, 61 had alcohol/drug-induced cardiomyopathy, and 509 had other forms. The lowest risk for being diagnosed with a cardiomyopathy was detected at a BMI of 21 kg/m2, with a gradual increase in risk with higher BMI, particularly for dilated cardiomyopathy, where a hazard ratio of 4.71 (95% CI, 2.81–7.89) was found for severely obese subjects (BMI ≥35 kg/m2), as compared with BMI 20 to

Background Type 2 diabetes is a major health problem in the world, and is strongly associated with impaired cardiac function and increased mortality. The causal relationship between type 2 diabetes and impaired cardiac function is still incompletely understood but changes in the cardiac lipid metabolism are believed to be a contributing factor. The objective of this study was to determine the lipid profile in human myocardial biopsies collected in vivo from patients with type 2 diabetes and compare to non-diabetic controls. Method We conducted full lipidomics analyses, using mass spectrometry, of 85 right atrial biopsies obtained from diabetic and non-diabetic patients undergoing elective cardiac surgery. The patients were characterized clinically and serum was analyzed for lipids and biochemical markers. Results The groups did not differ in BMI and in circulating triglycerides. We demonstrate that type 2 diabetes is associated with alterations in the cardiac lipidome. Interestingly, the absolute amount of lipids is not altered in the diabetic myocardium. However, triglycerides with longer fatty acyl chains are more abundant and there is a higher degree of unsaturated fatty acid chains in triglycerides in diabetic myocardium. Conclusions Our study reveals that type 2 diabetes is a relatively strong determinant of the human cardiac lipidome (compared to other clinical variables). Although the total lipid content in the diabetic myocardium is not increased, the lipid composition is markedly affected.

Aims/hypothesis Type 2 diabetes is an established risk factor for heart failure, but age-specific data are sparse. We aimed to determine excess risk of heart failure, based on age, glycaemic control and kidney function in comparison with age- and sex-matched control individuals from the general population. Methods Individuals with type 2 diabetes registered in the Swedish National Diabetes Registry 1998–2012 (n = 266,305) were compared with age-, sex- and county-matched control individuals without diabetes (n = 1,323,504), and followed over a median of 5.6 years until 31 December 2013. Results We identified 266,305 individuals with type 2 diabetes (mean age 62.0 years, 45.3% women) and 1,323,504 control individuals. Of the individuals with type 2 diabetes and control individuals, 18,715 (7.0%) and 50,157 (3.8%) were hospitalised with a diagnosis of heart failure, respectively. Comparing individuals with diabetes with those in the control group, men and women with type 2 diabetes who were younger than 55 years of age had HRs for hospitalisation for heart failure of 2.07 (95% CI 1.73, 2.48) and 4.59 (95% CI 3.50, 6.02), respectively, using analyses adjusted for socioeconomic variables and associated conditions. Younger age, poorer glycaemic control and deteriorating renal function were all associated with increased excess risk of heart failure in those with type 2 diabetes compared with the control group. However, people with diabetes who were ≥75 years and without albuminuria or with good glycaemic control (HbA1c ≤52 mmol/mol [≤6.9%]) had a similar risk of hospitalisation for heart failure as control individuals in the same age group. Conclusions/interpretation Men and women aged

ObjectiveTo investigate the possible connection between cardiorespiratory fitness (CRF) and muscle strength in early adulthood and severity of COVID-19 later in life.DesignProspective registry-based cohort study.Participants1 559 187 Swedish men, undergoing military conscription between 1968 and 2005 at a mean age of 18.3 (SD 0.73) years.Main outcome measuresHospitalisation, intensive care or death due to COVID-19 from March to September 2020, in relation to CRF and muscle strength.ResultsHigh CRF in late adolescence and early adulthood had a protective association with severe COVID-19 later in life with OR (95% CI) 0.76 (0.67 to 0.85) for hospitalisation (n=2 006), 0.61 (0.48 to 0.78) for intensive care (n=445) and 0.56 (0.37 to 0.85) for mortality (n=149), compared with the lowest category of CRF. The association remains unchanged when controlled for body mass index (BMI), blood pressure, chronic diseases and parental education level at baseline, and incident cardiovascular disease before 2020. Moreover, lower muscle strength in late adolescence showed a linear association with a higher risk of all three outcomes when controlled for BMI and height.ConclusionsPhysical fitness at a young age is associated with severity of COVID-19 many years later. This underscores the necessity to increase the general physical fitness of the population to offer protection against future viral pandemics.

Purpose of review Abdominal obesity is associated with a number of important metabolic abnormalities including liver steatosis, insulin resistance and an atherogenic lipoprotein profile (termed dyslipidemia). The purpose of this review is to highlight recent progress in understanding the pathogenesis of this dyslipidemia. Recent findings Recent results from kinetic studies using stable isotopes indicate that the hypertriglyceridemia associated with abdominal obesity stems from dual mechanisms: (1) enhanced secretion of triglyceride-rich lipoproteins and (2) impaired clearance of these lipoproteins. The over-secretion of large triglyceride-rich VLDLs from the liver is linked to hepatic steatosis and increased visceral adiposity. The impaired clearance of triglyceride-rich lipoproteins is linked to increased levels of apolipoprotein C-III, a key regulator of triglyceride metabolism. Summary Elucidation of the pathogenesis of the atherogenic dyslipidemia in abdominal obesity combined with the development of novel treatments based on apolipoprotein C-III may in the future lead to better prevention, diagnosis and treatment of the atherogenic dyslipidemia in abdominal obesity.

Background The incidence of heart failure (HF) is decreasing in older ages, but increasing rates have been observed among younger persons in Sweden. Therefore, we investigated the relationship between risk of hospitalization for HF and body mass index (BMI). Methods This was a prospective registry-based cohort study. We included 1,374,031 women aged 18–45 years (mean age 27.9 years) who gave birth during 1982–2014, and were registered in the Medical Birth Register. Information on hospitalization because of HF was collected through linkage to the National Inpatient Register. Results Compared to women with a BMI of 20–2, women with a BMI of 22.5–2, respectively. The multiple-adjusted HRs (95% CI) associated with risk of HF per one-unit increase in BMI in women with a BMI ≥ 22.5 kg/m2 ranged from 1.01 (0.97–1.06) for HF related to valvular disease to 1.14 (1.12–1.15) for coronary heart disease, diabetes, or hypertension. Conclusion Increasing body weight was strongly associated with the risk of early HF in women. Compared with lean women, the risk for HF started to increase at high-normal BMI levels, and was nearly five-fold in women with a BMI ≥ 35 kg/m2.

Background/Introduction Elevated resting heart rate (RHR) is a known risk factor for HF. Whether elevated RHR is also associated with cardiomyopathy (CM), a common cause of heart failure in the young, is unknown. Purpose To investigate the association of resting heart rate (RHR) measured in late adolescence with long term risk of various subtypes of CM with special attention to cardiorespiratory fitness (CRF), an important predictor of RHR and myocardial dysfunction. Methods We followed a cohort of Swedish men enrolled for conscription in 1968–2005 (n=1,008,485; mean age=18.3 years) until December 2014. Outcomes of CM were collected from the national inpatient- (IPR), outpatient- (OPR) and cause of death registries and were divided into categories: 1) dilated, 2) hypertrophic, 3) alcohol/drug-induced, and 4) other. Cox proportional hazard models were used to analyze the longitudinal association between RHR and outcomes while adjusting for potential confounders, including body mass index (BMI), arterial blood pressure and cardiorespiratory fitness (CRF). CRF was measured by maximum capacity ergometer testing as part of the enlistment protocol. Results During a mean follow up of 34 years, there were 3500 cases of a first hospitalization for CM (mean age at diagnosis, 50.1 years). Comparing the highest with the lowest quintile of the RHR distribution, we found a positive association between RHR and dilated CM (hazard ratio (HR) = 1.58 [confidence interval (CI) = 1.37–1.82]) after adjustment for BMI, age at conscription, conscription year, test center, and baseline comorbidities (diabetes, hypertension, congenital heart disease). There no significant association with alcohol/drug-induced (HR=1.32 [CI=0.94–1.85]) or other categories of CM. Conclusion Adolescent RHR is associated with future risk CM, independently of blood pressure, BMI and CRF. The association was driven by dilated CM. These findings are suggestive of a causal pathway between elevated heart rate and adverse cardiac remodeling that warrants further investigation. Acknowledgement/Funding The Swedish Heart and Lung Foundation, the Swedish Research Council, the Swedish Council for Health, Working Life and Welfare

Background Cardiovascular disease (CVD) mortality is decreasing in Western countries, including Sweden. However, there are reports of increases in incidence in young people with respect to heart failure (HF) and atrial fibrillation (AF). The magnitude and causes of these changes are only partly known. Aims We investigated secular trends in incidence in CVD outcomes and their attenuation by changes in body mass index (BMI). The outcomes were risk of acute myocardial infarction (AMI), heart failure (HF) and atrial fibrillation (AF) as well as cardiovascular and all-cause death in a population of Swedish adolescents. Methods We followed a cohort of Swedish men enrolled for military service conscription in 1969–1996 (n=1,326,082; mean age=18.3) until December 2016, collected from the national inpatient (IPR) and outpatient registries (OPR). Cox-proportional hazard models were used to analyse the longitudinal change in incidence by with respect to early (0–21 years) of follow-up for subgroups with conscription 1968–1971, 1971–1976, 1976–1981, 1981–1986, 1986–1991, 1991–1996 (with the group born 1971–1976 as reference). Adjustments for potential confounders including BMI were performed. Results We found that CVD and all-cause mortality and MI decreased progressively during the follow-up with hazard ratios (HR) of 0.51, 95% confidence interval (CI) 0.43–0.62, HR 0.51 CI 0.57–0.62, and 0.60 CI 0.50–0.72, respectively. In contrast, we found increases in the incidence of HF (HR 1.86, CI 1.48–2.33], and AF (HR 8.26, CI 6.87–9.92). Adjustments for changes in BMI partly attenuated the changes in secular trends. Cubic spline models showed where the changes in secular trends were most prominent. Conclusion The incidences of cardiovascular outcomes show diverging secular changes. While MI and cardiovascular mortality are continually decreasing, there is an increase in HF and AF. The associations appear to be partly explained by changes in index BMI over time. Acknowledgement/Funding grants from the Swedish Government and the county councils, the ALF–GBG-719761, ALFGBG-751111, Swedish Stroke Association, Göteborg Medical Society

Background Cardiorespiratory fitness and physical activity have well–known cardio–protective effects. Along with reports on declining levels of physical activity globally, heart failure caused by cardiomyopathy is increasing among young people. Still, it is unknown whether poor fitness in adolescence can be associated with cardiomyopathy in adulthood. Purpose To study a possible link between cardiorespiratory fitness in adolescence and being diagnosed with cardiomyopathy in adulthood. Methods A nationwide register-based prospective cohort study of 1,668,893 young men (mean age 18.3 years, SD 0.7), enlisting for compulsory military service 1969–2005. Body mass index (BMI) and blood pressure were registered at baseline, along with test results for fitness. Values were trichotomized and about 13.5% were classified as having poor cardiorespiratory fitness. Cardiomyopathy diagnoses were identified from the National Hospital Register and Cause of Death Register, during an up to 46-year follow-up, and divided into categories: 1) dilated, 2) hypertrophic, 3) alcohol/drug-induced, and 4) other. Hazard ratios (HR) were calculated with Cox proportional hazards models. Results During follow-up (median 27 years; interquartile interval 19–35 years), 4,477 cases of cardiomyopathy were registered, of which 2,631 (59%) were dilated, 673 (15%) were hypertrophic, and 480 (11%) were alcohol/drug-induced. Poor cardiorespiratory fitness was strongly associated with elevated risk of both dilated (HR 1.59, 95% confidence interval (CI) 1.38–1.83) and alcohol/drug–induced cardiomyopathy (HR 2.32, 95% CI 1.68–3.20), adjusted for BMI, age at conscription, conscription year, test center, and baseline comorbidities (diabetes, hypertension, congenital heart disease). Conclusion The present study shows that poor cardiorespiratory fitness in adolescence may be associated with both dilated and alcohol/drug–induced cardiomyopathy in adulthood. This strengthens the evidence of fitness as a cardio–protective factor, and brings further support to the importance of interventions promoting physical activity already in childhood. Acknowledgement/Funding The Swedish Research Council, The Swedish Heart and Lung Foundation

OBJECTIVE Low weight has been associated with increased mortality risks in type 1 diabetes. We aimed to investigate the importance of weight and weight gain/loss in the Swedish population diagnosed with type 1 diabetes. RESEARCH DESIGN AND METHODS Patients with type 1 diabetes (n = 26,125; mean age 33.3 years; 45% women) registered in the Swedish National Diabetes Registry from 1998 to 2012 were followed from the first day of study entry. Cox regression was used to calculate risk of death from cardiovascular disease (CVD), major CVD events, hospitalizations for heart failure (HF), and total deaths. RESULTS Population mean BMI in patients with type 1 diabetes increased from 24.7 to 25.7 kg/m2 from 1998 to 2012. Over a median follow-up of 10.9 years, there were 1,031 deaths (33.2% from CVD), 1,460 major CVD events, and 580 hospitalizations for HF. After exclusion of smokers, patients with poor metabolic control, and patients with a short follow-up time, there was no increased risk for mortality in those with BMI 25 kg/m2 was associated with a minor increase in risk of mortality, major CVD, and HF. In women, associations with BMI were largely absent. Weight gain implied an increased risk of mortality and HF, while weight loss was not associated with higher risk. CONCLUSIONS Risk of major CVD, HF, CVD death, and mortality increased with increasing BMI, with associations more apparent in men than in women. After exclusion of factors associated with reverse causality, there was no evidence of an obesity paradox.

Supplemental Digital Content is available in the text., Background: Modifiable lifestyle factors in relation to risk for cardiomyopathy, a common and increasing cause of heart failure in the young, have not been widely studied. We sought to investigate a potential link between obesity, a recognized predictor of early heart failure, in adolescence and being diagnosed with cardiomyopathy in adulthood. Methods: This was a nationwide register-based prospective cohort study of 1 668 893 adolescent men (mean age, 18.3 years; SD, 0.7 years) who enlisted for compulsory military service from 1969 to 2005. At baseline, body mass index (BMI), blood pressure, and medical disorders were registered, along with test results for fitness and muscle strength. Cardiomyopathy diagnoses were identified from the National Hospital Register and Cause of Death Register during an up to 46-year follow-up and divided into categories: dilated, hypertrophic, alcohol/drug-induced, and other. Hazard ratios were calculated with Cox proportional hazards models. Results: During follow-up (median, 27 years; Q1–Q3, 19–35 years), 4477 cases of cardiomyopathy were identified, of which 2631 (59%) were dilated, 673 (15%) were hypertrophic, and 480 (11%) were alcohol/drug-induced. Increasing BMI was strongly associated with elevated risk of cardiomyopathy, especially dilated, starting at levels considered normal (BMI, 22.5–8-fold increased risk at BMI ≥35 kg/m2 compared with BMI of 18.5 to

Background: Whether infection with SARS-CoV-2 leads to excess risk of requiring hospitalization or intensive care in persons with diabetes has not been reported, nor have risk factors in diabetes associated with increased risk for these outcomes. Methods: We included 44,639 and 411,976 adult patients with type 1 and type 2 diabetes alive on Jan 1, 2020, and compared them to controls matched for age, sex, and county of residence (n=204,919 and 1,948,900). Age- and sex-standardized rates for COVID-19 related hospitalizations, admissions to intensive care and death, were estimated and hazard ratios were calculated using Cox regression analyses. Findings: There were 10,486 hospitalizations and 1,416 admissions into intensive care. A total of 1,175 patients with diabetes and 1,820 matched controls died from COVID-19, of these 53.2% had been hospitalized and 10.7% had been in intensive care. Patients with type 2 diabetes, compared to controls, displayed an ageand sex-adjusted hazard ratio (HR) of 2.22, 95%CI 2.13-2.32) of being hospitalized for COVID-19, which decreased to HR 1.40, 95%CI 1.34-1.47) after further adjustment for sociodemographic factors, pharmacological treatment and comorbidities, had higher risk for admission to ICU due to COVID-19 (age- and sexadjusted HR 2.49, 95%CI 2.22-2.79, decreasing to 1.42, 95%CI 1.25-1.62 after adjustment, and increased risk for death due to COVID-19 (age- and sex-adjusted HR 2.19, 95%CI 2.03-2.36, complete adjustment 1.50, 95%CI 1.39-1.63). Age- and sex-adjusted HR for COVID-19 hospitalization for type 1 diabetes was 2.10, 95%CI 1.72-2.57), decreasing to 1.25, 95%CI 0.3097-1.62) after adjustment. Patients with diabetes type 1 were twice as likely to require intensive care for COVID-19, however, not after adjustment (HR 1.49, 95%CI 0.75-2.92), and more likely to die (HR 2.90, 95% CI 1.6554-5.47) from COVID-19, but not independently of other factors (HR 1.38, 95% CI 0.64-2.99). Among patients with diabetes, elevated glycated hemoglobin levels were associated with higher risk for most outcomes. Interpretation: In this nationwide study, type 2 diabetes was independently associated with increased risk of hospitalization, admission to intensive care and death for COVID-19. There were few admissions into intensive care and deaths in type 1 diabetes, and although hazards were significantly raised for all three outcomes, there was no independent risk persisting after adjustment for confounding factors. (C) 2021 The Authors. Published by Elsevier Ltd. Funding Agencies|Swedish Heart and Lung FoundationSwedish Heart-Lung Foundation [20180366]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2013-05187, VRREG 201900193, 2020-05792]; [ALFGBG-717211]

Background Risk prediction models for cardiovascular death are important for providing advice on lifestyle and in decision-making regarding primary preventive drug treatment. The latest Swedish version of the Systematic COronary Risk Evaluation (SCORE 2015) has yet not been tested in the population. Objective The objective of this study was to estimate the prevalence of high and very high risk of fatal cardiovascular disease (CVD) of the current population according to 2015 SCORE Sweden and to evaluate the predictive accuracy of the 2003 Swedish version of SCORE (2003 SCORE Sweden) and 2015 SCORE Sweden in a population with declining CVD mortality. Methods We estimated the high and very high risk group for cardiovascular death for individuals 40–65 years of age in the 2014 Northern Sweden MONICA population survey excluding subjects with known diabetes or previous CVD ( n = 813). Using the 1999 MONICA survey ( n = 3347) followed up for 10 years for CVD mortality, we assessed the calibration of both 2003 and 2015 SCORE Sweden. Results In 2014 2.6% of the population was considered at high or very high risk for fatal CVD, 95% were men and 76% were in the age group 60–65 years. Including subjects with a single markedly elevated risk factor, known diabetes or CVD, 12% of the population was at high or very high risk. During 10 years of follow-up of the 1999 cohort, 34 CVD deaths (24 men and 10 women) occurred. The 2003 SCORE overestimated the risk of death from CVD (ratio predicted/observed 2.3, P Conclusion The 2015 SCORE Sweden more adequately than 2003 SCORE Sweden predicts the number of deaths. In 2014, the proportion of high-risk individuals is small in northern Sweden. The main use of 2015 SCORE Sweden would therefore be as an educational tool between the physician and people without diabetes or CVD in a consultation regarding cardiovascular risk.

BackgroundMyocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia.Methods and resultsWe generated Plin5−/− mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5−/− mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction.ConclusionOur findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia.

Background: Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women. Material and methods: The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modeling in 60 women with wide-ranging body mass index (19.5-32.9kg/m2). Results: Plasma apoC-II and apoC-III concentrations were positively associated with the concentration of plasma triglycerides, VLDL1- and VLDL¬2- apoB-100 and triglyceride (all P Conclusions: In women, plasma apoC-II and apoC-III concentrations are regulated by their respective production rates and are significant, independent determinants of the kinetics and plasma concentrations of TRLs.

Background The burden of cardiovascular disease and death has plummeted over recent decades in Sweden and comparable countries. But might it soon increase as a result of population aging? Few studies have formally investigated future stroke trends. The aim of this study was therefore to quantify the future burden of ischemic stroke in Sweden until 2030. Methods We developed and validated a discrete open cohort Markov model for ischemic stroke (IS) in the Swedish population. We used population data from Statistics Sweden, the Swedish inpatient registry and cause-specific death registries to calculate IS prevalence and absolute numbers from 2000 to 2010. We then estimated future trends in IS incidence and mortality rates until 2030 using a BAPC (Bayesian aged-period cohort) approach. We also conducted sensitivity analyses to better quantify uncertainty around model inputs and outputs. Results Overall IS prevalence was predicted to decrease by approximately 20% between 2010 and 2030, from 170 to 137 per 10 000 population and from 183 to 157 per 10 000 in men and from 157 to 116 per 10 000 in women. During the same period, the overall number of IS patients might fall by just 3%, from 1 27 000 in 2010 to 1 23 000 in 2030 (decreasing from 59 000 to 52 000 in women, and increasing modestly in men, from 68 000 to 71,000). Worryingly, the prevalence of IS in young people aged IS prevalence in elderly people aged >85 years was predicted to fall by a third, from 1180 to 800 per 10 000 population. However, the actual number of IS patients might increase from 29 470 to 31,800, reflecting a growing elderly population. Conclusion Ischaemic stroke prevalence in Sweden might well fall by 20% between 2010 and 2030. However, the overall number of IS patients could remain above 1 20 000 per year. More worrying still, IS cases among the older citizens will increase due to population ageing, as will morbidity among the youngest groups. To reduce the future burden of stroke, Sweden needs a more ambitious and comprehensive prevention strategy.