Publications by authors named "Oscar Plunde"

7 Publications

  • Page 1 of 1

Artificial Intelligence Models Reveal Sex-Specific Gene Expression in Aortic Valve Calcification.

JACC Basic Transl Sci 2021 May 14;6(5):403-412. Epub 2021 Apr 14.

Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

Male and female aortic stenosis patients have distinct valvular phenotypes, increasing the complexities in the evaluation of valvular pathophysiology. In this study, we present cutting-edge artificial intelligence analyses of transcriptome-wide array data from stenotic aortic valves to highlight differences in gene expression patterns between the sexes, using both sex-differentiated transcripts and unbiased gene selections. This approach enabled the development of efficient models with high predictive ability and determining the most significant sex-dependent contributors to calcification. In addition, analyses of function-related gene groups revealed enriched fibrotic pathways among female patients. Ultimately, we demonstrate that artificial intelligence models can be used to accurately predict aortic valve calcification by carefully analyzing sex-specific gene transcripts.
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http://dx.doi.org/10.1016/j.jacbts.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165113PMC
May 2021

Fatty acids and aortic valve stenosis.

Kardiol Pol 2021 18;79(6):614-621. Epub 2021 May 18.

Translational Cardiology, Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet and Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.

Aortic valve stenosis (AVS), a valvulopathy that threatens life quality and longevity, in particular in an aging population. Yet no medical treatment is to date available emphasizing the need for more mechanistic insight into the disease to provide future treatment targets. Obesity and genetic variants within genes involved in lipid metabolisms and lipoprotein (a) have emerged as risk factors for AVS as these variants have significant genome-wide associations. The metamorphosis of the aortic valve to severe calcification involves lipid infiltration, inflammation, and oxidative stress which promotes further calcification in a viscous cycle in tandem with biomechanical factors that trigger further recruitment of inflammatory cells. The resolution of inflammation is an active and regulated process which therefore offers new possible targets. Fatty acids serve as substrate for many lipid mediators involved in the resolution of inflammation which may counterbalance the inflammation by promoting macrophage-mediated healing leading to a dampened inflammatory response. Recent data have put fatty acids in the spotlight as an important mechanism in the development of aortic valve disease. This review discusses possible mechanisms exerted by fatty acids in the context of AVS to facilitate future search for therapeutic targets.
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http://dx.doi.org/10.33963/KP.a2021.0003DOI Listing
July 2021

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis.

Cells 2020 07 16;9(7). Epub 2020 Jul 16.

Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, 171 77 Stockholm, Sweden.

Calcific aortic valve stenosis (CAVS) is a common age-related disease characterized by active calcification of the leaflets of the aortic valve. How innate immune cells are involved in disease pathogenesis is not clear. In this study we investigate the role of the pattern recognition receptor Toll-like receptor 7 (TLR7) in CAVS, especially in relation to macrophage subtype. Human aortic valves were used for mRNA expression analysis, immunofluorescence staining, or ex vivo tissue assays. Response to TLR7 agonist in primary macrophages and valvular interstitial cells (VICs) were investigated in vitro. In the aortic valve, TLR7 correlated with M2 macrophage markers on mRNA levels. Expression was higher in the calcified part compared with the intermediate and healthy parts. TLR7 cells were co-stained with M2-type macrophage receptors CD163 and CD206. Ex vivo stimulation of valve tissue with the TLR7 ligand imiquimod significantly increased secretion of IL-10, TNF-α, and GM-CSF. Primary macrophages responded to imiquimod with increased secretion of IL-10 while isolated VICs did not respond. In summary, in human aortic valves TLR7 expression is associated with M2 macrophages markers. Ex vivo tissue challenge with TLR7 ligand led to secretion of immunomodulatory cytokine IL-10. These results connect TLR7 activation in CAVS to reduced inflammation and improved clearance.
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http://dx.doi.org/10.3390/cells9071710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407122PMC
July 2020

Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease Through the Resolvin E1 and ChemR23 Axis.

Circulation 2020 Aug 8;142(8):776-789. Epub 2020 Jun 8.

Theme Heart and Vessels, Division of Valvular and Coronary Disease, Karolinska University Hospital, Stockholm, Sweden. (A.F.-C., M.B.).

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 PUFAs) in cardiovascular prevention have recently been demonstrated in a large randomized, controlled trial. In addition, n-3 PUFAs serve as the substrate for the synthesis of specialized proresolving mediators, which are known by their potent beneficial anti-inflammatory, proresolving, and tissue-modifying properties in cardiovascular disease. However, the effects of n-3 PUFA and specialized proresolving mediators on AVS have not yet been determined. The aim of this study was to identify the role of n-3 PUFA-derived specialized proresolving mediators 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 noncalcified regions compared with calcified regions. Liquid chromatography tandem mass spectrometry-based lipid mediator lipidomics identified that the n-3 PUFA-derived specialized proresolving mediator resolvin E1 was dysregulated in calcified regions and acted as a calcification inhibitor. Apoe mice expressing the Fat-1 transgene (Fat-1×Apoe), which enables the endogenous synthesis of n-3 PUFA and 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 resolvin E1 receptor ChemR23 enhanced disease progression, and the beneficial effects of Fat-1 were abolished in the absence of ChemR23.

Conclusions: n-3 PUFA-derived resolvin E1 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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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439935PMC
August 2020

FADS1 (Fatty Acid Desaturase 1) Genotype Associates With Aortic Valve FADS mRNA Expression, Fatty Acid Content and Calcification.

Circ Genom Precis Med 2020 06 12;13(3):e002710. Epub 2020 May 12.

Department of Medicine Solna, Unit of Cardiovascular Medicine (O.P., G.A., M.C., P.E., M.B.), Karolinska Institutet, Stockholm.

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 the gene, encoding FADS1 (fatty acid desaturase 1), with risk of several cardiovascular outcomes, including AS. encodes a rate-limiting enzyme for ω-3 and ω-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. 5 and 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 5-desaturase activity and the FADS2 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 ω-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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http://dx.doi.org/10.1161/CIRCGEN.119.002710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299231PMC
June 2020

Proteoglycan 4 is Increased in Human Calcified Aortic Valves and Enhances Valvular Interstitial Cell Calcification.

Cells 2020 03 11;9(3). Epub 2020 Mar 11.

Department of Medicine, Karolinska Institutet, 17177 Stockholm, Sweden.

Aortic valve stenosis (AVS), a consequence of increased fibrosis and calcification of the aortic valve leaflets, causes progressive narrowing of the aortic valve. Proteoglycans, structural components of the aortic valve, accumulate in regions with fibrosis and moderate calcification. Particularly, proteoglycan 4 (PRG4) has been identified in fibrotic parts of aortic valves. However, the role of PRG4 in the context of AVS and aortic valve calcification has not yet been determined. Here, transcriptomics, histology, and immunohistochemistry were performed in human aortic valves from patients undergoing aortic valve replacement. Human valve interstitial cells (VICs) were used for calcification experiments and RNA expression analysis. PRG4 was significantly upregulated in thickened and calcified regions of aortic valves compared with healthy regions. In addition, mRNA levels of PRG4 positively associated with mRNA for proteins involved in cardiovascular calcification. Treatment of VICs with recombinant human PRG4 enhanced phosphate-induced calcification and increased the mRNA expression of bone morphogenetic protein 2 and the runt-related transcription factor 2. In summary, PRG4 was upregulated in the development of AVS and promoted VIC osteogenic differentiation and calcification. These results suggest that an altered valve leaflet proteoglycan composition may play a role in the progression of AVS.
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http://dx.doi.org/10.3390/cells9030684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140654PMC
March 2020

Aortic Valve Calcium Associates with All-Cause Mortality Independent of Coronary Artery Calcium and Inflammation in Patients with End-Stage Renal Disease.

J Clin Med 2020 Feb 24;9(2). Epub 2020 Feb 24.

Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 86 Huddinge, Stockholm, Sweden.

Background: Aortic valve calcium (AVC) and coronary artery calcium (CAC) are common complications in end-stage renal disease (ESRD). We investigated the prognostic significance of overlapping presence of AVC and CAC, and whether AVC was associated with all-cause mortality independent of the presence of CAC in ESRD.

Methods: 259 ESRD patients (median age 55 years, 67% males) undergoing cardiac computed tomography were included. Framingham risk score (FRS), presence of cardiovascular disease (CVD), statin use, nutritional status and other relevant laboratory data were determined at baseline. During follow-up for median 36 months, 44 patients died, and 68 patients underwent renal transplantation.

Results: The baseline overlap presence of AVC and CAC was 37%. Multivariate regression analysis showed that FRS (odds ratio (OR) 2.25; 95% confidence interval (95% CI), 1.43-3.55) and CAC score (OR (95% CI), 2.18 (1.34-3.59)) were independent determinants of AVC. In competing-risk regression models adjusted for presence of CAC, inflammation, nutritional status, CVD, FRS and statin use, AVC remained independently associated with all-cause mortality (sub-hazard ratio (95% CI), 2.57 (1.20-5.51)).

Conclusions: The overlap of AVC and CAC was 37% in this ESRD cohort. AVC was associated with increased all-cause mortality independent of presence of CAC, traditional risk factors and inflammation.
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http://dx.doi.org/10.3390/jcm9020607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074421PMC
February 2020
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