| 1. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 2. |
- Artiach, Gonzalo, et al.
(författare)
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Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease through the Resolvin E1 and ChemR23 Axis.
- 2020
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 142, s. 776-789
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aortic valve stenosis (AVS), which is the most common valvular heart disease, causes a progressive narrowing of the aortic valve as a consequence of thickening and calcification of the aortic valve leaflets. The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in cardiovascular prevention have been recently demonstrated in a large randomized controlled trial. In addition, n-3 PUFA serve as the substrate for the synthesis of specialized pro-resolving mediators (SPMs), which are known by their potent beneficial anti-inflammatory, pro-resolving and tissue-modifying properties in cardiovascular disease. However, the effects of n-3 PUFA and SPMs on AVS have not yet been determined. The aim of this study was to identify the role of n-3 PUFA-derived SPMs in relation to the development of AVS. Methods: Lipidomic and transcriptomic analyses were performed in human tricuspid aortic valves. Apoe-/- mice and wire injury in C57BL/6J mice were used as models for mechanistic studies. Results: We found that n-3 PUFA incorporation into human stenotic aortic valves was higher in non-calcified regions compared with calcified regions. LC-MS-MS based lipid mediator lipidomics identified that the n-3 PUFA-derived SPM resolvin E1 (RvE1) was dysregulated in calcified regions and acted as a calcification inhibitor. Apoe-/- mice expressing the Caenorhabditis elegans Fat-1 transgene (Fat-1tgxApoe-/-), which enables the endogenous synthesis of n-3 PUFA, increased valvular n-3 PUFA content, exhibited reduced valve calcification, lower aortic valve leaflet area, increased M2 macrophage polarization and improved echocardiographic parameters. Finally, abrogation of the RvE1 receptor ChemR23 enhanced disease progression, and the beneficial effects of Fat-1tg were abolished in the absence of ChemR23. Conclusions: n-3 PUFA-derived RvE1 and its receptor ChemR23 emerge as a key axis in the inhibition of AVS progression, and may represent a novel potential therapeutic opportunity to be evaluated in patients with AVS.
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| 3. |
- Freiholtz, David, et al.
(författare)
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SPP1/osteopontin : a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm?
- 2023
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Ingår i: Journal of Molecular Medicine. - : Springer Nature. - 0946-2716 .- 1432-1440. ; 101:10, s. 1323-1333
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Degenerative ascending aortic aneurysm (AscAA) is a silent and potentially fatal disease characterized by excessive vascular inflammation and fibrosis. We aimed to characterize the cellular and molecular signature for the fibrotic type of endothelial mesenchymal transition (EndMT) that has previously been described in degenerative AscAA. Patients undergoing elective open-heart surgery for AscAA and/or aortic valve repair were recruited. Gene expression in the intima-media of the ascending aorta was measured in 22 patients with non-dilated and 24 with dilated aortas, and candidate genes were identified. Protein expression was assessed using immunohistochemistry. Interacting distal gene enhancer regions were identified using targeted chromosome conformation capture (HiCap) in untreated and LPS-treated THP1 cells, and the associated transcription factors were analyzed. Differential expression analysis identified SPP1 (osteopontin) as a key gene in the signature of fibrotic EndMT in patients with degenerative AscAA. The aortic intima-media expression of SPP1 correlated with the expression of inflammatory markers, the level of macrophage infiltration, and the aortic diameter. HiCap analysis, followed by transcription factor binding analysis, identified ETS1 as a potential regulator of SPP1 expression under inflammatory conditions. In conclusion, the present findings suggest that SPP1 may be involved in the development of the degenerative type of AscAA. Key messages: In the original manuscript titled “SPP1/osteopontin, a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm?” by David Freiholtz, Otto Bergman, Saliendra Pradhananga, Karin Lång, Flore-Anne Poujade, Carl Granath, Christian Olsson, Anders Franco-Cereceda, Pelin Sahlén, Per Eriksson, and Hanna M Björck, we present novel findings on regulatory factors on osteopontin (SPP1) expression in immune cells involved in degenerative ascending aortic aneurysms (AscAA). The central findings convey: SPP1 is a potential driver of the fibrotic endothelial-to-mesenchymal transition in AscAA.SPP1/osteopontin expression in AscAA is predominately by immune cells.ETS1 is a regulatory transcription factor of SPP1 expression in AscAA immune cells.
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| 4. |
- Persson, Michael, et al.
(författare)
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Comparison of Long-term Performance of Bioprosthetic Aortic Valves in Sweden from 2003 to 2018
- 2022
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- Importance: The performance of bioprosthetic aortic valves is usually assessed in single valve models or head-to-head comparisons. National databases or registries offer the opportunity to investigate all available valve models in the population and allows for a comparative assessment of their performance. Objective: To analyze the long-term rates of reintervention, all-cause mortality, and heart failure hospitalization associated with commonly used bioprosthetic aortic valves and to identify valve model groups with deviation in clinical performance. Design, Setting, and Participants: This population-based, nationwide cohort study included all adult patients who underwent surgical aortic valve replacement (with or without concomitant coronary artery bypass surgery or ascending aortic surgery) in Sweden between January 1, 2003, and December 31, 2018. Patients were identified from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry. Patients with concomitant valve surgery, previous cardiac surgery, and previous transcatheter valve replacement were excluded. Follow-up was complete for all participants. Data were analyzed from March 9, 2020, to October 12, 2021. Exposures: Primary surgical aortic valve replacement with the Perimount, Mosaic/Hancock, Biocor/Epic, Mitroflow/Crown, Soprano, and Trifecta valve models. Main Outcomes and Measures: The primary outcome was cumulative incidence of reintervention, defined as a subsequent aortic valve operation or transcatheter valve replacement. Secondary outcomes were all-cause mortality and heart failure hospitalization. Regression standardization and flexible parametric survival models were used to account for intergroup differences. Mean follow-up time was 7.1 years, and maximum follow-up time was 16.0 years. Results: A total of 16983 patients (mean [SD] age, 72.6 [8.5] years; 10 685 men [62.9%]) were included in the analysis. The Perimount valve model group had the lowest and the Mitroflow/Crown valve model group had the highest cumulative incidence of reintervention. The estimated cumulative incidence of reintervention at 10 years was 3.6% (95% CI, 3.1%-4.2%) in the Perimount valve model group and 12.2% (95% CI, 9.8%-15.1%) in the Mitroflow/Crown valve model group. The estimated incidence of reintervention at 10 years was 9.3% (95% CI, 7.3%-11.3%) in the Soprano valve model group. Conclusions and Relevance: Results of this study showed that the Perimount valve was the most commonly used and had the lowest incidence of reintervention, all-cause mortality, and heart failure hospitalization, whereas the Mitroflow/Crown valve had the highest rates. These findings highlight the need for clinical vigilance in patients who receive either a Soprano or Mitroflow/Crown aortic bioprosthesis..
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| 5. |
- Persson, Michael, et al.
(författare)
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Porcine vs Bovine Bioprosthetic Aortic Valves: Long-Term Clinical Results
- 2021
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Ingår i: Annals of Thoracic Surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 111:2, s. 529-535
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPrevious studies have reported superior hemodynamic performance with bovine bioprosthetic aortic valves compared with porcine valves. However, conflicting results mean the long-term effect on survival is not well known. The aim of this study was to examine long-term survival, rate of aortic valve reoperations, and heart failure hospitalizations after surgical aortic valve replacement (AVR) with porcine vs bovine bioprosthetic valves.MethodsThis was a population-based cohort study including all patients who had undergone AVR in Sweden from 1995 to 2012, with or without concomitant coronary artery bypass grafting. Patients were identified through the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) registry. Baseline and outcome data were gathered from national registries. Propensity scores and inverse probability of treatment weighting were used to control for intergroup differences. Analyses accounted for competing risk of death when appropriate.ResultsA total of 12,845 patients underwent AVR with porcine (n = 4198) or bovine (n = 8647) prostheses. We found a small but significant difference in mortality favoring porcine prostheses: 78% vs 76%, 47% vs 43%, and 17% vs 15% at 5, 10, and 15 years, respectively (hazard ratio, 0.90; 95% confidence interval, 0.85-0.96). Porcine prostheses were associated with an increased risk of reoperation (hazard ratio, 1.48; 95% confidence interval, 1.11-1.98), but no difference in the risk of heart failure hospitalization. Results were similar in patients who underwent isolated AVR.ConclusionsConsistent with previous reports, we found that patients receiving porcine prostheses had a higher rate of reoperation compared with bovine prostheses. However, porcine prostheses were associated with improved long-term survival compared with bovine prostheses.
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| 6. |
- Plunde, Oscar, et al.
(författare)
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FADS1 (Fatty Acid Desaturase 1) Genotype Associates With Aortic Valve FADS mRNA Expression, Fatty Acid Content and Calcification
- 2020
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 2574-8300. ; 13:3, s. 139-148
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aortic stenosis (AS) contributes to cardiovascular mortality and morbidity but disease mechanisms remain largely unknown. Recent evidence associates a single nucleotide polymorphism rs174547 within theFADS1gene, encoding FADS1 (fatty acid desaturase 1), with risk of several cardiovascular outcomes, including AS.FADS1encodes a rate-limiting enzyme for omega-3 and omega-6 fatty acid metabolism. The aim of this study was to decipher the local transcriptomic and lipidomic consequences of rs174547 in tricuspid aortic valves from patients with AS. Methods: Expression quantitative trait loci study was performed using data from Illumina Human610-Quad BeadChip, Infinium Global Screening Arrays, and Affymetrix Human Transcriptome 2.0 arrays in calcified and noncalcified aortic valve tissue from 58 patients with AS (mean age, 74.2; SD, 5.9). Fatty acid content was assessed in aortic valves from 25 patients with AS using gas chromatography.Delta 5 and Delta 6 desaturase activity was assessed by the product-to-precursor ratio. Results: The minor C-allele of rs174547, corresponding to the protective genotype for AS, was associated with higher FADS2 mRNA levels in calcified valve tissue, whereas FADS1 mRNA and other transcripts in proximity of the single nucleotide polymorphism were unaltered. In contrast, the FADS1 Delta 5-desaturase activity and the FADS2 Delta 6-desaturase activity were decreased. Finally, docosahexaenoic acid was decreased in calcified tissue compared with non-calcified tissue and C-allele carriers exhibited increased docosahexaenoic acid levels. Overall desaturase activity measured with omega-3 fatty acids was higher in C-allele carriers. Conclusions: The association between the FADS1 genotype and AS may implicate effects on valvular fatty acids.
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| 7. |
- Sainz-Jaspeado, Miguel, et al.
(författare)
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Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium
- 2021
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 144:20, s. 1629-1645
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Tidskriftsartikel (refereegranskat)abstract
- Background: PALMD (palmdelphin) belongs to the family of paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms in the PALMD locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis and predict severity of the disease.Methods: Immunodetection and public database screening showed dominant expression of PALMD in endothelial cells (ECs) in brain and cardiovascular tissues including aortic valves. Mass spectrometry, coimmunoprecipitation, and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in small interferring RNA-treated EC cultures, knockout mice, and human valve samples. RNA sequencing of ECs and transcript arrays on valve samples from an aortic valve study cohort including patients with the single nucleotide polymorphism rs7543130 informed about gene regulatory changes.Results: ECs express the cytosolic PALMD-KKVI splice variant, which associated with RANGAP1 (RAN GTP hydrolyase activating protein 1). RANGAP1 regulates the activity of the GTPase RAN and thereby nucleocytoplasmic shuttling via XPO1 (Exportin1). Reduced PALMD expression resulted in subcellular relocalization of RANGAP1 and XPO1, and nuclear arrest of the XPO1 cargoes p53 and p21. This indicates an important role for PALMD in nucleocytoplasmic transport and consequently in gene regulation because of the effect on localization of transcriptional regulators. Changes in EC responsiveness on loss of PALMD expression included failure to form a perinuclear actin cap when exposed to flow, indicating lack of protection against mechanical stress. Loss of the actin cap correlated with misalignment of the nuclear long axis relative to the cell body, observed in PALMD-deficient ECs, Palmd(-/-) mouse aorta, and human aortic valve samples derived from patients with calcific aortic valve stenosis. In agreement with these changes in EC behavior, gene ontology analysis showed enrichment of nuclear- and cytoskeleton-related terms in PALMD-silenced ECs.Conclusions: We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex alters the subcellular localization of RANGAP1 and XPO1, and leads to nuclear arrest of the XPO1 cargoes p53 and p21, accompanied by gene regulatory changes and loss of actin-dependent nuclear resilience. Combined, these consequences of reduced PALMD expression provide a mechanistic underpinning for PALMD's contribution to calcific aortic valve stenosis pathology.
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