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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]

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.

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.

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

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.

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.

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

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.

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

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 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.

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: 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.

Objectives— Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL 1 ) triglycerides. Approach and Results— A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of triglycerides and apoB in VLDL 1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate ( r =0.44, P r =0.45, P r =0.49, P r =0.55, P 1 -triglycerides and VLDL 1 -apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL 1 -triglycerides ( r =0.56, P 1 -apoB ( r =0.53, P 1 -triglycerides ( r =0.48, P 1 -apoB ( r =0.51, P Conclusions— Plasma triglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL 1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity.

Background— In heart failure and reduced ejection fraction, the prognostic role of heart rate (HR) in atrial fibrillation (AF) is unknown and the effectiveness of β-blockers has recently been questioned in AF. Methods and Results— A total of 18 858 patients with heart failure and reduced ejection fraction registered with Swedish Heart Failure Registry were included in this study: patients with sinus rhythm (SR; n=11 466) and patients with AF (n=7392). The outcome measure was all-cause mortality. Compared with HR ≤60 beats per minute, the adjusted hazard ratios for mortality in SR were 1.26 for HR=61 to 70 beats per minute, 1.37 for HR=71 to 80 beats per minute, 1.52 for HR=81 to 90 beats per minute, 1.63 for HR=91 to 100 beats per minute, and 2.69 for HR >100 beats per minute. However, in AF, the hazard ratio increased only for HR >100 beats per minute (1.30; P =0.001). β-blocker use was associated with reduced mortality in SR (hazard ratio, 0.77; P =0.011) and in AF (hazard ratio, 0·71; P 100 beats per minute (1.29; P =0.003) compared with HR ≤60 beats per minute. Conclusions— In patients with heart failure and reduced ejection fraction, a higher HR was associated with increased mortality in SR, but in AF, this is true only for HR >100 beats per minute. β-blocker use was associated with reduced mortality both in SR and in AF.

OBJECTIVE Type 2 diabetes is strongly associated with obesity, but the mortality risk related to elevated body weight in people with type 2 diabetes compared with people without diabetes has not been established. RESEARCH DESIGN AND METHODS We prospectively assessed short- and long-term mortality in people with type 2 diabetes with a recorded diabetes duration ≤5 years identified from the Swedish National Diabetes Register (NDR) between 1998 and 2012 and five age- and sex-matched control subjects per study participant from the general population. RESULTS Over a median follow-up of 5.5 years, there were 17,546 deaths among 149,345 patients with type 2 diabetes (mean age 59.6 years [40% women]) and 68,429 deaths among 743,907 matched control subjects. Short-term all-cause mortality risk (≤5 years) displayed a U-shaped relationship with BMI, with hazard ratios (HRs) ranging from 0.81 (95% CI 0.75–0.88) among patients with diabetes and BMI 30 to CONCLUSIONS Our findings suggest that the apparent paradoxical findings in other studies in this area may have been affected by reverse causality. Long-term, overweight (BMI 25 to

ObjectivePostprandial hypertriglyceridemia is an important risk factor for cardiovascular disease. The mechanisms are still unclear. Here it was tested if hepatic de novo lipogenesis (DNL) and lipid oxidation influence the postprandial responses of triglyceride-rich lipoproteins (TRL) in humans. MethodsThe contribution of hepatic DNL to hepatic TRL production was analyzed in 67 men and women with a moderate range of BMI after a fat-rich meal. Also, lipase activities, liver fat, and 3-OH-butyrate were quantitated as an indicator of -oxidation. Lipoproteins and metabolic markers were measured in fasting and postprandial blood samples. ResultsPostprandial DNL correlates with postprandial TG and apolipoprotein (apo) C-III responses in plasma and with TG, apoB48 and apoB100 responses in TRLs and their larger remnant particles. Fasting and 8-h postprandial DNL was inversely related to 3-OH-butyrate but not to liver fat content. Fasting apoC-III and 3-OH-butyrate, but not liver fat, independently predicted fasting DNL. ConclusionsThe fasting and 8-h postprandial rate of DNL was inversely associated with the hepatic lipid oxidation in humans. DNL contributes significantly to the TG content in TRLs but not to the amount of liver fat, suggesting that an imbalance between DNL and fat oxidation contributes to postprandial atherogenic dyslipidemia.

Background: Obesity is highly associated with elevated serum triglycerides, hepatic steatosis and type 2 diabetes (T2D). The I148M (rs738409) genetic variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is known to modulate hepatic triglyceride accumulation, leading to steatosis. No association between PNPLA3 I148M genotype and T2D in Europeans has been reported. Aim of this study is to examine the relationship between PNPLA3 I148M genotypes and serum triglycerides, insulin resistance and T2D susceptibility by testing a gene-environment interaction model with severe obesity. Methods and Findings: PNPLA3 I148M was genotyped in a large obese cohort, the SOS study (n = 3,473) and in the Go-DARTS (n = 15,448), a T2D case-control study. Metabolic parameters were examined across the PNPLA3 I148M genotypes in participants of the SOS study at baseline and at 2- and 10-year follow up after bariatric surgery or conventional therapy. The associations with metabolic parameters were validated in the Go-DARTS study. Serum triglycerides were found to be lower in the PNPLA3 148M carriers from the SOS study at baseline and from the Go-DARTS T2D cohort. An increased risk for T2D conferred by the 148M allele was found in the SOS study (O.R. 1.09, 95% C.I. 1.01-1.39, P = 0.040) and in severely obese individuals in the Go-DARTS study (O.R. 1.37, 95% C.I. 1.13-1.66, P = 0.001). The 148M allele was no longer associated with insulin resistance or T2D after bariatric surgery in the SOS study and no association with the 148M allele was observed in the less obese (BMI

IF 5.531; International audience; Context: The metabolism of high-density lipoprotein (HDL) is severely impaired in individuals with abdominal obesity. However, the specific metabolism of apolipoprotein (apo)-A-II, the second major apolipoprotein of HDL, remains poorly known. The relationships between HDL apoA-II catabolism and other metabolic variables that may be modified in abdominal obesity, such as very low-density lipoprotein (VLDL) subspecies (VLDL1, VLDL2) kinetics, remain to be investigated.Objectives: Our aim was to study the associations between apoA-II fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and apoA-I.Design: We carried out a multicenter in vivo kinetic study using stable isotopes (deuterated leucine and glycerol) in 62 individuals with abdominal obesity.Results: In a univariate analysis, apoA-II FCR was positively correlated with body mass index, sc fat, liver fat, apoA-I FCR, apoA-I production rate (PR), apoA-II pool, apoA-II PR, VLDL1-triglyceride PR, VLDL2-triglyceride PR, VLDL2-triglyceride (TG) FCR, and VLDL2-apoB FCR and negatively with HDL cholesterol to apoA-I ratio. After adjustment for apoA-I FCR, a strong positive correlation between apoA-II FCR and VLDL1-TG indirect FCR was observed (r = 0.520, P < .0001). In a multivariate analysis, apoA-II FCR was independently and positively associated with apoA-I FCR (P < .0001) and VLDL1-TG indirect FCR (P < .0001). Both variables explained 59.7% of the variability in apoA-II FCR.Conclusions: We show that, in abdominally obese individuals, apoA-II FCR is positively and independently associated with both apoA-I FCR and VLDL1-TG indirect FCR. These data suggest that, in a condition of delayed VLDL1 catabolism, such as abdominal obesity, retention of apoA-II in the VLDL1 pool may occur, with an effect on apoA-II catabolism. The consequences of this link between VLDL1 catabolism and apoA-II catabolism remain to be determined.

OBJECTIVE: In Sweden, previous favourable trends in blood cholesterol levels have recently levelled off or even increased in some age groups since 2003, potentially reflecting changing fashions and attitudes towards dietary saturated fatty acids (SFA). We aimed to examine the potential effect of different SFA intake on future coronary heart disease (CHD) mortality in 2025. METHODS: We compared the effect on future CHD mortality of two different scenarios for fat intake a) daily SFA intake decreasing to 10 energy percent (E%), and b) daily SFA intake rising to 20 E%. We assumed that there would be moderate improvements in smoking (5%), salt intake (1g/day) and physical inactivity (5% decrease) to continue recent, positive trends. RESULTS: In the baseline scenario which assumed that recent mortality declines continue, approximately 5,975 CHD deaths might occur in year 2025. Anticipated improvements in smoking, dietary salt intake and physical activity, would result in some 380 (-6.4%) fewer deaths (235 in men and 145 in women). In combination with a mean SFA daily intake of 10 E%, a total of 810 (-14%) fewer deaths would occur in 2025 (535 in men and 275 in women). If the overall consumption of SFA rose to 20 E%, the expected mortality decline would be wiped out and approximately 20 (0.3%) additional deaths might occur. CONCLUSION: CHD mortality may increase as a result of unfavourable trends in diets rich in saturated fats resulting in increases in blood cholesterol levels. These could cancel out the favourable trends in salt intake, smoking and physical activity.

To develop novel strategies for prevention and treatment of dyslipidaemia, it is essential to understand the pathophysiology of dyslipoproteinaemia in humans. Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion and/or catabolism. Traditional methods that measure plasma lipoprotein concentrations only provide static estimates of lipoprotein metabolism and hence limited mechanistic information. By contrast, the use of tracers labelled with stable isotopes and mathematical modelling provides a powerful tool for probing lipid and lipoprotein kinetics in vivo and furthering understanding of the pathogenesis of dyslipoproteinaemia.

The aim of this study was to use lipidomics to determine if the lipid composition of apolipoprotein-B-containing lipoproteins is modified by dyslipidaemia in type 2 diabetes and if any of the identified changes potentially have biological relevance in the pathophysiology of type 2 diabetes.VLDL and LDL from normolipidaemic and dyslipidaemic type 2 diabetic women and controls were isolated and quantified with HPLC and mass spectrometry. A detailed molecular characterisation of VLDL triacylglycerols (TAG) was also performed using the novel ozone-induced dissociation method, which allowed us to distinguish vaccenic acid (C18:1 n-7) from oleic acid (C18:1 n-9) in specific TAG species.Lipid class composition was very similar in VLDL and LDL from normolipidaemic type 2 diabetic and control participants. By contrast, dyslipidaemia was associated with significant changes in both lipid classes (e.g. increased diacylglycerols) and lipid species (e.g. increased C16:1 and C20:3 in phosphatidylcholine and cholesteryl ester and increased C16:0 [palmitic acid] and vaccenic acid in TAG). Levels of palmitic acid in VLDL and LDL TAG correlated with insulin resistance, and VLDL TAG enriched in palmitic acid promoted increased secretion of proinflammatory mediators from human smooth muscle cells.We showed that dyslipidaemia is associated with major changes in both lipid class and lipid species composition in VLDL and LDL from women with type 2 diabetes. In addition, we identified specific molecular lipid species that both correlate with clinical variables and are proinflammatory. Our study thus shows the potential of advanced lipidomic methods to further understand the pathophysiology of type 2 diabetes.

Objective To better understand the postprandial clearance of triglyceride-rich lipoproteins (TRLs) and its relation to the fasting kinetics of TRLs. Methods Two studies were performed on 30 male subjects: a fasting kinetic study to determine the fasting secretion and clearance rates of apolipoprotein B (apoB) 100 and triglycerides in the very low-density lipoprotein 1 and 2 (VLDL1 and VLDL2) fractions; and a postprandial study to determine the postprandial accumulation of apoB48, apoB100 and triglycerides in the chylomicron, VLDL1 and VLDL2 fractions. Results from these two studies were combined to characterize the postprandial clearance of TRLs in a physiologically relevant setting. Results Our results show that postprandial accumulation of the apoB48-carrying chylomicrons can be predicted from the clearance capacity of the lipolytic pathway, determined in the fasting state. Furthermore, we show that chylomicrons and VLDL1 particles are not cleared equally by the lipoprotein lipase pathway, and that chylomicrons seem to be the preferred substrate. Subjects with a rapid fasting lipid metabolism accumulate lower levels of postprandial triglycerides with less accumulation of apoB100 in the VLDL1 fraction and a faster transfer of apoB100 into the VLDL2 fraction. In contrast, fasting VLDL1 secretion does not predict postprandial triglyceride accumulation. Conclusions Non-fasting triglyceride levels have recently been identified as a major predictor of future cardiovascular events. Here we show that the capacity of the lipolytic pathway is a common determinant of both the fasting and non-fasting triglyceride levels and may thus play an important role in the development of dyslipemia and atherosclerosis.

Objective— Obesity increases the risk of cardiovascular disease and premature death. However, not all obese subjects develop the metabolic abnormalities associated with obesity. The aim of this study was to clarify the mechanisms that induce dyslipidemia in obese subjects. Methods and Results— Stable isotope tracers were used to elucidate the pathophysiology of the dyslipidemia in hypertriglyceridemic ( n =14) and normotriglyceridemic ( n =14) obese men (with comparable body mass index and visceral fat volume) and in normotriglyceridemic nonobese men ( n =10). Liver fat was determined using proton magnetic resonance spectroscopy, and subcutaneous abdominal and visceral fat were measured by magnetic resonance imaging. Serum triglycerides in obese subjects were increased by the combination of increased secretion and severely impaired clearance of triglyceride-rich very-low-density lipoprotein 1 particles. Furthermore, increased liver and subcutaneous abdominal fat were linked to increased secretion of very-low-density lipoprotein 1 particles, whereas increased plasma levels of apolipoprotein C-III were associated with impaired clearance in obese hypertriglyceridemic subjects. Conclusion— Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects with similar levels of visceral adiposity. The results emphasize the clinical importance of assessing hypertriglyceridemic waist in obese subjects to identify subjects at high cardiometabolic risk.

OBJECTIVE Apolipoprotein CIII (apoCIII) is an independent risk factor for cardiovascular disease, but the molecular mechanisms involved are poorly understood. We investigated potential proatherogenic properties of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes. RESEARCH DESIGN AND METHODS LDL was isolated from control subjects, subjects with type 2 diabetes, and apoB transgenic mice. LDL-biglycan binding was analyzed with a solid-phase assay using immunoplates coated with biglycan. Lipid composition was analyzed with mass spectrometry. Hydrolysis of LDL by sphingomyelinase was analyzed after labeling plasma LDL with [3H]sphingomyelin. ApoCIII isoforms were quantified after isoelectric focusing. Human aortic endothelial cells were incubated with desialylated apoCIII or with LDL enriched with specific apoCIII isoforms. RESULTS We showed that enriching LDL with apoCIII only induced a small increase in LDL-proteoglycan binding, and this effect was dependent on a functional site A in apoB100. Our findings indicated that intrinsic characteristics of the diabetic LDL other than apoCIII are responsible for further increased proteoglycan binding of diabetic LDL with high-endogenous apoCIII, and we showed alterations in the lipid composition of diabetic LDL with high apoCIII. We also demonstrated that high apoCIII increased susceptibility of LDL to hydrolysis and aggregation by sphingomyelinases. In addition, we demonstrated that sialylation of apoCIII increased with increasing apoCIII content and that sialylation of apoCIII was essential for its proinflammatory properties. CONCLUSIONS We have demonstrated a number of features of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes that could explain the proatherogenic role of apoCIII.

After recently being recognized as a feature of the metabolic syndrome, fatty liver has evolved as a key player in the pathogenesis of dyslipidemia. Development of nonalcoholic fatty liver disease comes from an imbalance between the influx and production of fatty acids and the use of fatty acids for oxidation or secretion as very low density lipoprotein (VLDL) triglycerides. Previously, we have shown a strong relationship between increased liver fat and overproduction of large VLDL particles. We observed recently that in patients with high liver fat, insulin was unable to regulate VLDL production. The result is increased concentrations of VLDL particles in the circulation. Consequently, changes are seen in the metabolism of other lipoproteins that interact with VLDL particles, the net result being decreased high-density lipoprotein cholesterol and increased formation of small, dense low-density lipoprotein. In this article, we review recent findings on the development of fatty liver and its role in the diabetic dyslipidemia pathogenesis.

Overproduction of VLDL(1) seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL(1) production by insulin in participants with a broad range of liver fat content.A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol during a hyperinsulinaemic-euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group.The results showed a rapid drop in VLDL(1)-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL(1) secretion. The VLDL(1) suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL(1) and VLDL(2) secretion in participants with low liver fat: VLDL(1) secretion decreased acutely after insulin infusion whereas VLDL(2) secretion increased.Insulin downregulates VLDL(1) secretion and increases VLDL(2) secretion in participants with low liver fat but fails to suppress VLDL(1) secretion in participants with high liver fat, resulting in overproduction of VLDL(1). Thus, liver fat is associated with lack of VLDL(1) suppression in response to insulin.

Background Android fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis, and greater secretion of large very low‐density lipoprotein ( VLDL ) particles in men. Since abdominal obesity is becoming increasingly prevalent in women, we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre‐ and postmenopausal women. Methods and Results We used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 [0.02 to 0.08] and 0.095 [0.08 to 0.11], respectively). Thirty women were premenopausal aged 35 to 45 and they were matched for abdominal obesity with 28 postmenopausal women aged 55 to 65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404±30 versus 268±26 mg/kg lean mass, P VLDL (160±11 versus 142±13). However, postmenopausal status had a pronounced effect on the characteristics of small VLDL particles, which were considerably triglyceride‐enriched (production ratio of VLDL 2 ‐ triglyceride:apolipoprotein B 30±5.3 versus 19±1.6, P r s =−0.49, P =0.006), de novo lipogenesis ( r s =0.55, P =0.003), and desaturation ( r s =0.48, P =0.012) were closely correlated with abdominal obesity‐driven large VLDL ‐triglyceride secretion rate. Conclusions In women, abdominal obesity is a major driver of hepatic large VLDL particle secretion, whereas postmenopausal status was characterized by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in postmenopausal obesity.

In metabolic diseases such as Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease, the systemic regulation of postprandial metabolite concentrations is disturbed. To understand this dysregulation, a quantitative and temporal understanding of systemic postprandial metabolite handling is needed. Of particular interest is the intertwined regulation of glucose and non-esterified fatty acids (NEFA), due to the association between disturbed NEFA metabolism and insulin resistance. However, postprandial glucose metabolism is characterized by a dynamic interplay of simultaneously responding regulatory mechanisms, which have proven difficult to measure directly. Therefore, we propose a mathematical modelling approach to untangle the systemic interplay between glucose and NEFA in the postprandial period. The developed model integrates data of both the perturbation of glucose metabolism by NEFA as measured under clamp conditions, and postprandial time-series of glucose, insulin, and NEFA. The model can describe independent data not used for fitting, and perturbations of NEFA metabolism result in an increased insulin, but not glucose, response, demonstrating that glucose homeostasis is maintained. Finally, the model is used to show that NEFA may mediate up to 30-45% of the postprandial increase in insulin-dependent glucose uptake at two hours after a glucose meal. In conclusion, the presented model can quantify the systemic interactions of glucose and NEFA in the postprandial state, and may therefore provide a new method to evaluate the disturbance of this interplay in metabolic disease. Funding Agencies|European Union [305707]; Linkoping Initiative within Life Science Technologies; Ostergotland County Council; Swedish Research Council; AstraZeneca

Context Mathematical models may help the analysis of biological systems by providing estimates of otherwise un-measurable quantities such as concentrations and fluxes. The variability in such systems makes it difficult to translate individual characteristics to group behavior. Mixed effects models offer a tool to simultaneously assess individual and population behavior from experimental data. Lipoproteins and plasma lipids are key mediators for cardiovascular disease in metabolic disorders such as diabetes mellitus type 2. By the use of mathematical models and tracer experiments fluxes and production rates of lipoproteins may be estimated. Results We developed a mixed effects model to study lipoprotein kinetics in a data set of 15 healthy individuals and 15 patients with type 2 diabetes. We compare the traditional and the mixed effects approach in terms of group estimates at various sample and data set sizes. Conclusion We conclude that the mixed effects approach provided better estimates using the full data set as well as with both sparse and truncated data sets. Sample size estimates showed that to compare lipoprotein secretion the mixed effects approach needed almost half the sample size as the traditional method.

The use of stable isotopes in conjunction with compartmental modeling analysis has greatly facilitated studies of the metabolism of the apolipoprotein B (apoB)-containing lipoproteins in humans. The aim of this study was to develop a multicompartment model that allows us to simultaneously determine the kinetics of apoB and triglyceride (TG) in VLDL(1) and VLDL(2) after a bolus injection of [(2)H(3)]leucine and [(2)H(5)]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Here, we describe the model and present the results of its application in a fasting steady-state situation in 17 subjects with lipid values representative of a Western population. Analysis of the correlations showed that plasma TG was determined by the VLDL(1) and VLDL(2) apoB and TG fractional catabolic rate. Furthermore, the model showed a linear correlation between VLDL(1) TG and apoB production. A novel observation was that VLDL TG entered the circulation within 21 min after its synthesis, whereas VLDL apoB entered the circulation after 33 min. These observations are consistent with a sequential assembly model of VLDL and suggest that the TG is added to a primordial apoB-containing particle in the liver.

Low plasma high-density lipoprotein (HDL) cholesterol is a major abnormality in abdominal obesity. This relates due to accelerated HDL catabolism, but the underlying mechanism requires further elucidation. The relationships between HDL catabolism and other variables that may be modified in abdominal obesity, such as very low-density lipoprotein (VLDL) subspecies (VLDL1, VLDL2) kinetics, liver fat, or visceral adiposity, remain to be investigated.Our aim was to study the associations between HDL apolipoprotein (apo)-A-I fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and estimates of liver and visceral and sc fat.We carried out a multicenter in vivo kinetic study using stable isotopes (deuterated leucine and glycerol) in 62 individuals with abdominal obesity.In a multivariate analysis, among the morphological and biological parameters that may predict apoA-I FCR, liver fat (β = .400, P = .003), and VLDL1-apoB (β = .307, P = .020) were independently associated with apoA-I FCR. In a multivariate analysis, among the kinetic parameters, VLDL1-triglycerides (TGs) indirect FCR (β = -.357, P = .001), VLDL1-TG production rate (β = 0.213, P = .048), and apoA-II FCR (β = .667, P.0001) were independently associated with apoA-I FCR. After adjustment for VLDL1-TG production rate, liver fat was no more correlated with apoA-I FCR. No association between apoA-I FCR and visceral fat was observed.We show that VLDL1 is an important independent determinant of apoA-I FCR and more precisely that apoA-I FCR is independently associated with both catabolism and the production of VLDL1-TG. In addition, we show an association between liver fat and apoA-I FCR that is mostly mediated by VLDL1-TG production. These data indicate that, in abdominal obesity, dysfunctional VLDL1 metabolism is an important modulator of HDL apoA-I catabolism.

Dietary medium chain fatty acids (MCFA) and linoleic acid follow different metabolic routes, and linoleic acid activates PPAR receptors. Both these mechanisms may modify lipoprotein and fatty acid metabolism after dietary intervention. Our objective was to investigate how dietary MCFA and linoleic acid supplementation and body fat distribution affect the fasting lipoprotein subclass profile, lipoprotein kinetics, and postprandial fatty acid kinetics. In a randomized double blind cross-over trial, 12 male subjects (age 51±7 years; BMI 28.5±0.8 kg/m2), were divided into 2 groups according to waist-hip ratio. They were supplemented with 60 grams/day MCFA (mainly C8:0, C10:0) or linoleic acid for three weeks, with a wash-out period of six weeks in between. Lipoprotein subclasses were measured using HPLC. Lipoprotein and fatty acid metabolism were studied using a combination of several stable isotope tracers. Lipoprotein and tracer data were analyzed using computational modeling. Lipoprotein subclass concentrations in the VLDL and LDL range were significantly higher after MCFA than after linoleic acid intervention. In addition, LDL subclass concentrations were higher in lower body obese individuals. Differences in VLDL metabolism were found to occur in lipoprotein lipolysis and uptake, not production; MCFAs were elongated intensively, in contrast to linoleic acid. Dietary MCFA supplementation led to a less favorable lipoprotein profile than linoleic acid supplementation. These differences were not due to elevated VLDL production, but rather to lower lipolysis and uptake rates.

Postprandial hypertriglyceridemia is now established as an important risk factor for cardiovascular disease (CVD). This metabolic abnormality is principally initiated by overproduction and/or decreased catabolism of triglyceride-rich lipoproteins (TRLs) and is a consequence of predisposing genetic variations and medical conditions such as obesity and insulin resistance. Accumulation of TRLs in the postprandial state promotes the retention of remnant particles in the artery wall. Because of their size, most remnant particles cannot cross the endothelium as efficiently as smaller low-density lipoprotein (LDL) particles. However, since each remnant particle contains approximately 40 times more cholesterol compared with LDL, elevated levels of remnants may lead to accelerated atherosclerosis and CVD. The recognition of postprandial hypertriglyceridemia in the clinical setting has been severely hampered by technical difficulties and the lack of established clinical protocols for investigating postprandial lipemia. In addition, there are currently no internationally agreed management guidelines for this type of dyslipidemia. Here we review the mechanism for and consequences of excessive postprandial hypertriglyceridemia, epidemiological evidence in support of high triglycerides and remnant particles as risk factors for CVD, the definition of hypertriglyceridemia, methods to measure postprandial hypertriglyceridemia and apolipoproteins and, finally, current and future treatment opportunities.

In this study we have used mass spectrometry in order to characterize the HDL lipidome in three groups of women from the DIWA cohort; one control group, plus two groups with type 2 diabetes with insulin resistance; one dyslipidemic and one normolipidemic. The aim was to investigate whether dyslipidemia is required in addition to insulin resistance for the occurrence of an altered HDL lipidome, which in turn might impact HDL functionality. The dyslipidemic type 2 diabetic subjects were distinguished by obesity, hypertriglyceridemia with elevated apoC3, low HDL-cholesterol and chronic low grade inflammation. In a stepwise multivariate linear regression analysis, including biomarkers of dyslipidemia and insulin resistance as independent variables, only dyslipidemia showed a significant correlation with HDL lipid classes. Small HDL-particles predominated in dyslipidemic subjects in contrast to the normolipidemic diabetic and control groups, and were enriched in lysophosphatidylcholine (+13%), a product of proinflammatory phospholipases, and equally in two core lipids, palmitate-rich triacylglycerols and diacylglycerols (+77 %), thereby reflecting elevated CETP activity. Dyslipidemic small HDL particles were further distinguished not only as the primary carrier of ceramides, which promote inflammation and insulin resistance, but also by a subnormal plasmalogen/apoAI ratio, consistent with elevated oxidative stress typical of type 2 diabetes. From these data we conclude that in type 2 diabetes, dyslipidemia predominates relative to hyperglycemia for the occurrence of an altered HDL lipidome. Furthermore, dyslipidemia alters the cargo of bioactive lipids, with implications for HDL function.

ContextNonfasting (postprandial) triglyceride concentrations have emerged as a clinically significant cardiovascular disease risk factor that results from accumulation of remnant triglyceride-rich lipoproteins (TRLs) in the circulation. The remnant TRLs are cleared from the circulation by hepatic uptake, but the specific mechanisms involved are unclear. The syndecan-1 heparan sulfate proteoglycan (HSPG) pathway is important for the hepatic clearance of remnant TRLs in mice, but its relevance in humans is unclear.ObjectiveWe sought to determine whether polymorphisms of the genes responsible for HSPG assembly and disassembly contribute to atherogenic dyslipoproteinemias in humans.Patients and designWe performed an oral fat load in 68 healthy subjects. Lipoproteins (chylomicrons and very low density lipoproteins 1 and 2) were isolated from blood, and the area under curve and incremental area under curve for postprandial variables were calculated. Single nucleotide polymorphisms in genes encoding syndecan-1 and enzymes involved in the synthesis or degradation of HSPG were genotyped in the study subjects.ResultsOur results indicate that the genetic variation rs2281279 in SULF2 associates with postprandial clearance of remnant TRLs and triglyceride levels in healthy subjects. Furthermore, the SNP rs2281279 in SULF2 associates with hepatic SULF2 mRNA levels.ConclusionsIn humans, mild but clinically relevant postprandial hyperlipidemia due to reduced hepatic clearance of remnant TRLs may result from genetic polymorphisms that affect hepatic HSPG.

Background & Aims: The robust association between non-alcoholic fatty liver disease (NAFLD) and the genetic variant I148M (rs738409) in PNPLA3 has been widely replicated. The aim of this study was to investigate the effect of the PNPLA3 I148M mutation on: (1) hepatic secretion of very low density lipoproteins (VLDL) in humans; and (2) secretion of apolipoprotein B (apoB) from McA-RH 7777 cells, which secrete VLDL-sized apoB-containing lipoproteins. Methods: VLDL kinetics was analyzed after a bolus infusion of stable isotopes in 55 overweight/obese men genotyped for the PNPLA3 I148M variant. Intracellular lipid content, apoB secretion and glycerolipid metabolism were studied in McA-RH 7777 cells overexpressing the human 1481 wild type or 148M mutant PNPLA3 protein. Results: In humans, carriers of the PNPLA3 148M allele had increased liver fat compared to 1481 homozygotes, and kinetic analysis showed a relatively lower secretion of the large, triglyceride-rich VLDL (VLDL1) in 148M carriers vs. 1481 homozygotes for the same amount of liver fat. McA-RH 7777 cells overexpressing the 148M mutant protein showed a higher intracellular triglyceride content with a lower apoB secretion and fatty acid efflux, compared to cells overexpressing the 1481 wild type protein. The responses with 148M matched those observed in cells expressing the empty vector, indicating that the mutation results in loss of function. Conclusions: We have shown that PNPLA3 affects the secretion of apoB-containing lipoproteins both in humans and in vitro and that the 148M protein is a loss-of-function mutation. We propose that PNPLA3 148M promotes intracellular lipid accumulation in the liver by reducing the lipidation of VLDL.

Background: Obesity is a risk factor for cancer, including hepatocellular carcinoma. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) genetic variant has been associated with hepatocellular carcinoma (HCC) in individuals with chronic alcohol abuse or hepatic viral infection. In the present study we examined the association between the PNPLA3I148M genetic variant and hepatocellular carcinoma in obese individuals from the Swedish Obese Subjects cohort (n=4047). Methods: We performed a matched, prospective, controlled, interventional trial, investigating the effect of bariatric surgery (surgery group) compared to conventional treatment (control group) for obesity. Results: A total of 9 events were observed in the 15-year median follow up (5 in the control group and 4 in the surgery group). A significantly higher incidence of hepatocellular carcinoma in PNPLA3 148M allele carriers was found in obese individuals in the control group (log-rank P-value=0.001), but not in the surgery group (log-rank P-value=0.783). Consistently, an increased risk (for each PNPLA3 148M allele, hazard ratio: 5.9; 95% confidence interval 1.5-23.8; P-value=0.013) of developing hepatocellular carcinoma was observed only in the control group. Conclusion: The current study is the first prospective report showing the association of the PNPLA3I148M genetic variant and hepatocellular carcinoma in severely obese individuals.