| 1. |
- Andersson, Linda, 1973, et al.
(författare)
-
Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking
- 2021
-
Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:43, s. 4481-4492
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 2. |
- Andréasson, Karin, et al.
(författare)
-
Body mass index in adolescence, risk of type 2 diabetes and associated complications: A nationwide cohort study of men
- 2022
-
Ingår i: EClinicalMedicine. - : Elsevier BV. - 2589-5370. ; 46
-
Tidskriftsartikel (refereegranskat)abstract
- Background Obesity is a predominant factor in development of type 2 diabetes but to which extent adolescent obesity influences adult diabetes is unclear. We investigated the association between body mass index (BMI) in young men and subsequent type 2 diabetes and how, in diagnosed diabetes, adolescent BMI relates to glycemic control and diabetes complications. Methods Baseline data from the Swedish Conscript Register for men drafted 1968-2005 was combined with data from the National Diabetes and Patient registries. Diabetes risk was estimated through Cox regression and Kaplan-Meier survival estimates. Relationships between BMI, glycemic control and diabetes complications were assessed through multiple linear and logistic regression. Findings Among 1,647,826 men, 63,957 (3.88%) developed type 2 diabetes over a median follow-up of 29.0 years (IQR[21.0-37.0]). The risk of diabetes within 40 years after conscription was nearly 40% in individuals with adolescent BMI >= 35 kg/m(2). Compared to BMI 18.5-<20 kg/m(2) (reference), diabetes risk increased in a linear fashion from HR 1.18(95%CI 1.15-1.21) for BMI 20-<22.5 kg/m(2) to HR 15.93(95%CI 14.88-17.05) for BMI >= 35 kg/m(2), and a difference in age at onset of 11.4 years was seen. Among men who developed diabetes, higher adolescent BMI was associated with higher HbA1c levels and albuminuria rates. Interpretation Rising adolescent BMI was associated with increased risk of type 2 diabetes diagnosed at a younger age, with poorer metabolic control, and a greater prevalence of albuminuria, all suggestive of worse prognosis. Copyright (C) 2022 The Authors. Published by Elsevier Ltd.
|
|
| 3. |
- Bergström, Göran, 1964, et al.
(författare)
-
Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population
- 2021
-
Ingår i: Circulation. - Philadelphia : American Heart Association. - 0009-7322 .- 1524-4539. ; 144:12, s. 916-929
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 4. |
- Robertson, Josefina, et al.
(författare)
-
Body mass index and fitness in late adolescence and risk of cardiovascular disease, respiratory disease, and overall death after COVID-19
- 2023
-
Ingår i: Obesity Science and Practice. - 2055-2238. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Since obesity and poor fitness appear to be unfavorable for both cardiovascular health and coping with viral infections such as COVID-19, they are of specific interest in light of the increased risk of cardiovascular and respiratory events now seen after infection with SARS-CoV-2. Therefore, the aim of the present study was to investigate how body mass index (BMI) and cardiorespiratory fitness (CRF) in late adolescence are associated with the risk of cardiovascular disease (CVD), respiratory disease, and mortality after COVID-19. Methods: In this study, 1.5 million 18-year-old Swedish men with BMI and CRF measured during enlistment for military service 1968–2005 were included. Hospitalized and non-hospitalized COVID-19 cases were identified through the Patient Register or positive polymerase chain reaction tests, and age-matched with non-infected controls. CVD, respiratory disease, and mortality after COVID-19 were divided into <60days, 60-180days, >180days post-infection. Cox regression models were used. Results: Hospitalized COVID-19 cases (n=9839), compared to controls, had >10-fold, 50 to 70-fold, and >70-fold hazards of CVD, respiratory disease, and mortality over the initial 60days post-infection with little variation across BMI or CRF categories. The elevated risks persisted at declining levels >180days. For non-hospitalized COVID-19 cases (n=181,822), there was a 4- to 7-fold increased acute mortality risk, and high CRF was associated with lower risk of post-infectious respiratory disease. Conclusions: The high hazards of adverse outcomes during the first two months after COVID-19 hospitalization, and across BMI and CRF categories, declined rapidly but were still elevated after six months. Adolescent CRF was associated with respiratory disease after COVID-19 without hospitalization, which gives further support to the health benefits of physical activity.
|
|
| 5. |
- Åberg, N David, 1970, et al.
(författare)
-
Diverging trends for onset of acute myocardial infarction, heart failure, stroke and mortality in young males: role of changes in obesity and fitness
- 2021
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 290:2, s. 373-385
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 6. |
- af Geijerstam, Agnes, et al.
(författare)
-
Fitness, strength and severity of COVID-19: a prospective register study of 1 559 187 Swedish conscripts
- 2021
-
Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 11:7
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate the possible connection between cardiorespiratory fitness (CRF) and muscle strength in early adulthood and severity of COVID-19 later in life. Design Prospective registry-based cohort study. Participants 1 559 187 Swedish men, undergoing military conscription between 1968 and 2005 at a mean age of 18.3 (SD 0.73) years. Main outcome measures Hospitalisation, intensive care or death due to COVID-19 from March to September 2020, in relation to CRF and muscle strength. Results High 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. Conclusions Physical 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.
|
|
| 7. |
- Borén, Jan, 1963, et al.
(författare)
-
Effects of pnpla3 i148m on hepatic lipid and very low-density lipoprotein metabolism in humans.
- 2022
-
Ingår i: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 291:2, s. 218-223
-
Tidskriftsartikel (refereegranskat)abstract
- The PNPLA3-148M variant is associated with liver steatosis but its influence on metabolism of triglyceride-rich lipoproteins remains unclear. Here we investigated the kinetics of large, triglyceride-rich VLDL1 and smaller VLDL2 in homozygotes for the PNPLA3-148M variant.The kinetics of apoB100 and triglyceride in VLDL subfractions was 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.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. This article is protected by copyright. All rights reserved.
|
|
| 8. |
- Borén, Jan, 1963, et al.
(författare)
-
Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans.
- 2020
-
Ingår i: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:24
-
Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic 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 TM6SF2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion, and studied the kinetics of apolipoprotein B100 (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 two major VLDL subfractions: large triglyceride-rich VLDL1 and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared to controls. Likewise, VLDL1-triglyceride production was 35% lower in the TM6SF2 E167K carriers. In contrast, the direct production rates for VLDL2-apoB100 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.Trial registration: Clinical Trials NCT04209816.
|
|
| 9. |
- Edqvist, Jon, 1988, et al.
(författare)
-
Severe COVID-19 Infection in Type 1 and Type 2 Diabetes During the First Three Waves in Sweden.
- 2023
-
Ingår i: Diabetes care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 46:3, s. 570-578
-
Tidskriftsartikel (refereegranskat)abstract
- 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.Using nationwide health registries, we identified all patients aged ≥18 years with type 1 and type 2 diabetes in Sweden. Odds ratios (ORs) describe the general and age-specific risk of being hospitalized, need for intensive care, or dying, adjusted for age, socioeconomic factors, and coexisting conditions, compared with individuals without diabetes. Machine learning models were used to find predictors of outcomes among individuals with diabetes positive for COVID-19.Until 30 June 2021, we identified 365 (0.71%) and 11,684 (2.31%) hospitalizations in 51,402 and 504,337 patients with type 1 and 2 diabetes, respectively, with 67 (0.13%) and 2,848 (0.56%) requiring intensive care unit (ICU) care and 68 (0.13%) and 4,020 (0.80%) dying (vs 7,824,181 individuals without diabetes [41,810 hospitalizations (0.53%), 8,753 (0.11%) needing ICU care, and 10,160 (0.13%) deaths). Although those with type 1 diabetes had moderately raised odds of being hospitalized (multiple-adjusted OR 1.38 [95% CI 1.24-1.53]), there was no independent effect on ICU care or death (OR of 1.21 [95% CI 0.94-1.52] and 1.13 [95% CI 0.88-1.48], respectively). Age and socioeconomic factors were the dominating features for predicting hospitalization and death in both types of diabetes.Type 2 diabetes was associated with increased odds for all outcomes, whereas patients with type 1 diabetes had moderately increased odds of hospitalization but not ICU care and death.
|
|
| 10. |
- Edqvist, Jon, 1988, et al.
(författare)
-
Trajectories in HbA1c and other risk factors among adults with type 1 diabetes by age at onset
- 2021
-
Ingår i: BMJ Open Diabetes Research and Care. - : BMJ. - 2052-4897. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- In 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. We stratified 30005 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. Individuals aged ≥16 years at onset displayed a relatively low mean HbA1c level (~55–57mmol/mol) that gradually increased. In contrast, individuals diagnosed at ≤15 years old entered adulthood with a mean HbA1c of approximately 70mmol/mol. For all groups, HbA1c levels stabilized at a mean of approximately 65mmol/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. Young 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. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.
|
|
