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1.
  • Ahlsson, Anders, et al. (author)
  • Is There a Weekend Effect in Surgery for Type A Dissection? : Results From the Nordic Consortium for Acute Type A Aortic Dissection Database
  • 2019
  • In: Annals of Thoracic Surgery. - : Elsevier. - 0003-4975 .- 1552-6259. ; 108:3, s. 770-776
  • Journal article (peer-reviewed)abstract
    • Background: Aortic dissection type A requires immediate surgery. In general surgery populations, patients operated on during weekends have higher mortality rates compared with patients whose operations occur on weekdays. The weekend effect in aortic dissection type A has not been studied in detail.Methods: The Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) registry includes data for 1,159 patients who underwent type A dissection surgery at 8 Nordic centers during 2005 to 2014. This study is based on data relating to surgery conducted during weekdays versus weekends and starting between 8:00 AM and 8:00 Pm ("daytime") versus from 8:00 Pm to 8:00 AM ("nighttime"), as well as time from symptoms, admittance, and diagnosis to surgery. The influence of timing of surgery on the 30-day mortality rate was assessed using logistic regression analysis.Results: The 30-day mortality was 18% (204 of 1,159), with no difference in mortality between surgery performed on weekdays (17% [150 of 889]) and on weekends (20% [54 of 270], p = 0.45), or during nighttime (19% [87 of 467]) versus daytime (17% [117 of 680], p = 0.54). Time from symptoms to surgery (median 7.0 hours vs 6.5 hours, p = 0.31) did not differ between patients who survived and those who died at 30 days. Multivariable regression analysis of risk factors for 30-day mortality showed no weekend effect (odds ratio, 1.04; 95% confidence interval, 60.67 to 1.60; p = 0.875), but nighttime surgery was a risk factor (odds ratio, 2.43; 95% confidence interval, 1.29 to 4.56; p = 0.006).Conclusions: The 30-day mortality in surgical repair of aortic dissection type A was not significantly affected by timing of surgery during weekends versus weekdays. Nighttime surgery seems to predict increased 30-day mortality, after correction for other risk factors.
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2.
  • Ahlsson, Anders, et al. (author)
  • Is there a weekend effect in surgery for type A dissection? - Results from the NORCAAD database
  • 2019
  • In: Annals of Thoracic Surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 108:3, s. 770-776
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Aortic dissection type A requires immediate surgery. In general surgery populations, patients operated during weekends have higher mortality rates compared to patients operated on weekdays. The weekend effect in aortic dissection type A has not been studied in detail.METHODS: The Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) registry includes patients (N=1,159) who underwent type A dissection surgery at eight Nordic centers during 2005-2014. This study is based on data relating to surgery conducted during weekdays vs. weekends, and starting between 8 am and 8 pm ("daytime") vs. from 8 pm to 8 am ("nighttime"), as well as time from symptoms/admittance/diagnosis to surgery. The influence of timing of surgery on 30-day mortality was assessed using logistic regression analysis.RESULTS: The 30-day mortality was 18% (204/1,159), with no difference in mortality between surgery performed on weekdays (17%, 150/889) and on weekends (20%, 54/270, p=0.45), or during nighttime (19%, 87/467) vs. daytime (17%, 117/680, p=0.54). Time from symptoms to surgery (median 7.0 hours vs. 6.5 hours, p=0.31) did not differ between patients who survived and those dead at 30 days. Multivariable regression analysis of risk factors for 30-day mortality showed no weekend effect (OR 1.04 [0.67-1.60], p=0.875), but nighttime surgery was a risk factor (OR 2.43 [1.29-4.56], p=0.006).CONCLUSIONS: Thirty-day mortality in surgical repair of aortic dissection type A was not significantly affected by timing of surgery during weekends vs. weekdays. Nighttime surgery seems to predict increased 30-day mortality, after correction for other risk factors.
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3.
  • Geirsson, Arnar, et al. (author)
  • Hospital volumes and later year of operation correlates with better outcomes in acute Type A aortic dissection
  • 2018
  • In: European Journal of Cardio-Thoracic Surgery. - : Oxford University Press. - 1010-7940 .- 1873-734X. ; 53:1, s. 276-281
  • Journal article (peer-reviewed)abstract
    • OBJECTIVES: Acute Type A aortic dissection remains a life-threatening disease, but there are indications that its surgical mortality is decreasing. The aim of this report was to study how surgical mortality has changed and what influences those changes.METHODS: Nordic Consortium for Acute Type A Aortic Dissection is a retrospective database comprising 1159 patients (mean age 61.6 ± 12.2 years, 68% male) treated for acute Type A aortic dissection at 8 centres in Denmark, Finland, Iceland and Sweden from 2005 to 2014. Data gathered included demographics, symptoms, type of procedure, complications and 30-day mortality.RESULTS: The annual number of operations increased significantly from 85 in 2005 to 150 in 2014 (P < 0.001). Chest pain was present in 85% of patients, 24% were hypotensive on presentation and 28% had malperfusion syndrome. Open distal anastomosis technique under hypothermic circulatory arrest was used in 85% of cases and its use increased significantly throughout the study. The 30-day mortality decreased from 24% in 2005 to 13% in 2014 (P = 0.003). Independent predictors for 30-day mortality were preoperative cardiac arrest, malperfusion syndrome, Penn Class C, Penn Class B and C and cardiopulmonary bypass time, whereas later calendar year and higher hospital operative volumes predicted improved survival.CONCLUSIONS: Surgical mortality for acute Type A aortic dissection remains high but has decreased significantly over the last decade. This correlated with later year of operation and increased the number of operations performed per year, indicating that cumulative surgical experience contributes significantly to improved surgical outcomes.
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4.
  • Geirsson, Arnar, et al. (author)
  • The Nordic Consortium for Acute type A Aortic Dissection (NORCAAD) : objectives and design
  • 2016
  • In: Scandinavian Cardiovascular Journal. - : Taylor & Francis. - 1401-7431 .- 1651-2006. ; 50:5-6, s. 334-340
  • Journal article (peer-reviewed)abstract
    • Objectives: The Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) is a collaborative effort of Nordic cardiac surgery centers to study acute type A aortic dissection (ATAAD). Here, we outline the overall objectives and the design of NORCAAD.Design: NORCAAD currently consists of eight centers in Denmark, Finland, Iceland and Sweden. Data was collected for patients undergoing surgery for ATAAD from 2005 to 2014. A total of 194 variables were retrospectively collected including demographics, past medical history, preoperative medications, symptoms at presentation, operative variables, complications, bleeding and blood transfusions, need for late reoperations, 30-day mortality and long-term survival.Results: Information was gathered in the database for 1159 patients, of which 67.6% were male. The mean age was 61.5 +/- 12.1 years. The mean follow-up was 3.1 +/- 2.9 years with a total of 3535 patient years.Conclusions: NORCAAD provides a foundation for close collaboration between cardiac surgery centers in the Nordic countries. Substudies in progress include: short-term outcomes, long-term survival, time interval from diagnosis until operation, effects of surgical techniques, malperfusion syndrome, renal failure, bleeding and neurological complications on outcomes and the rate of late reoperations.
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5.
  • Holmes, Michael V., et al. (author)
  • Secretory Phospholipase A(2)-IIA and Cardiovascular Disease
  • 2013
  • In: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:21, s. 1966-1976
  • Journal article (peer-reviewed)abstract
    • Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
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6.
  • Peden, John F., et al. (author)
  • A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
  • 2011
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:4, s. 339-344
  • Journal article (peer-reviewed)abstract
    • Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)(1-7), a modest number considering the apparent heritability of CAD(8). All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with similar to 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 x 10(-8) in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.
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7.
  • Chernogubova, Ekaterina, et al. (author)
  • Common and Low-Frequency Genetic Variants in the PCSK9 Locus Influence Circulating PCSK9 Levels
  • 2012
  • In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 32:6, s. 1526-1534
  • Journal article (peer-reviewed)abstract
    • Objective- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that influences plasma low-density lipoprotein concentration and susceptibility to coronary heart disease. Circulating PCSK9 levels show considerable interindividual differences, but the factors responsible for this variation are largely unknown. Methods and Results- We analyzed circulating PCSK9 levels in 4 cohorts of healthy, middle-aged Swedes (n=5722) and found that PCSK9 levels varied over approximate to 50-fold range, showed a positive relationship with plasma low-density lipoprotein-cholesterol concentration, and were associated with plasma triglyceride, fibrinogen, insulin, and glucose concentrations. A genome-wide association study conducted in 2 cohorts (n=1215) failed to uncover common genetic variants robustly associated with variation in circulating PCSK9 level. As expected, the minor allele of the PCSK9 R46L variant was in all cohorts associated with reduced PCSK9 levels and decreased plasma low-density lipoprotein-cholesterol concentrations, but no relationship was observed with the plasma triglyceride concentration. Further mapping of the PCSK9 locus revealed a common polymorphism (rs2479415, minor allele frequency 43.9%), located approximate to 6 kb upstream from PCSK9, which is independently associated with increased circulating PCSK9 levels. Conclusion- Common and low-frequency genetic variants in the PCSK9 locus influence the pronounced interindividual variation in circulating PCSK9 levels in healthy, middle-aged white (predominantly Swedish) subjects.
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8.
  • Folkersen, Lasse, et al. (author)
  • Association of genetic risk variants with expression of proximal genes identifies novel susceptibility genes for cardiovascular disease
  • 2010
  • In: Circulation. - 1942-325X .- 1942-3268. ; 3:4, s. 365-373
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown. METHODS AND RESULTS: To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected (P<0.005). More than 20 of these genes had not previously been identified as candidate genes for cardiovascular or related metabolic traits. SNP-associated gene effects were tissue-specific and the tissue specificity was phenotype-dependent. CONCLUSIONS: This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting.
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9.
  • Folkersen, Lasse, et al. (author)
  • Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
  • 2017
  • In: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:4
  • Journal article (peer-reviewed)abstract
    • Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.
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10.
  • Folkersen, Lasse, et al. (author)
  • Unraveling Divergent Gene Expression Profiles in Bicuspid and Tricuspid Aortic Valve Patients with Thoracic Aortic Dilatation: The ASAP Study
  • 2011
  • In: Molecular Medicine. - : Feinstein Institute for Medical Research. - 1076-1551 .- 1528-3658. ; 17:11-12, s. 1365-1373
  • Journal article (peer-reviewed)abstract
    • Thoracic aortic aneurysm (TAA) is a common complication in patients with a bicuspid aortic valve (BAV), the most frequent congenital heart disorder. For unknown reasons TAA occurs at a younger age, with a higher frequency in BAV patients than in patients with a tricuspid aortic valve (TAV), resulting in an increased risk for aortic dissection and rupture. To investigate the increased TAA incidence in BAV patients, we obtained tissue biopsy samples from nondilated and dilated aortas of 131 BAV and TAV patients. Global gene expression profiles were analyzed from controls and from aortic intima-media and adventitia of patients (in total 345 samples). Of the genes found to be differentially expressed with dilation, only a few (less than4%) were differentially expressed in both BAV and TAV patients. With the use of gene set enrichment analysis, the cell adhesion and extracellular region gene ontology sets were identified as common features of TAA in both BAV and TAV patients. Immune response genes were observed to be particularly overexpressed in the aortic media of dilated TAV samples. The divergent gene expression profiles indicate that there are fundamental differences in TAA etiology in BAV and TAV patients. Immune response activation solely in the aortic media of TAV patients suggests that inflammation is involved in TAA formation in TAV but not in BAV patients. Conversely, genes were identified that were only differentially expressed with dilation in BAV patients. The result has bearing on future clinical studies in which separate analysis of BAV and TAV patients is recommended.
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11.
  • Gertow, Karl, et al. (author)
  • Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk
  • 2012
  • In: Circulation: Cardiovascular Genetics. - 1942-325X .- 1942-3268. ; 5:6, s. 656-665
  • Journal article (peer-reviewed)abstract
    • Background-Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results-To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMTmean, IMTmax, and IMTmean-max), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMTmax; replication P=7.24x10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53x10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83x10(-4), n= 82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). Conclusions-This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent. (Circ Cardiovasc Genet. 2012;5:656-665.)
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12.
  • Gretarsdottir, Solveig, et al. (author)
  • Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm
  • 2010
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:8, s. 71-692
  • Journal article (peer-reviewed)abstract
    • We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
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13.
  • Locke, Adam E, et al. (author)
  • Genetic studies of body mass index yield new insights for obesity biology.
  • 2015
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
  • Journal article (peer-reviewed)abstract
    • Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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14.
  • Shungin, Dmitry, et al. (author)
  • New genetic loci link adipose and insulin biology to body fat distribution.
  • 2015
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
  • Journal article (peer-reviewed)abstract
    • Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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15.
  • Harrison, Seamus C., et al. (author)
  • A gene-centric study of common carotid artery remodelling
  • 2013
  • In: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 226:2, s. 440-446
  • Journal article (peer-reviewed)abstract
    • Background: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 x 10(-8)). A proxy SNP (rs4916251, R-2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 x 10(-3), I-2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.
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16.
  • Helgadottir, Anna, et al. (author)
  • Genome-wide analysis yields new loci associating with aortic valve stenosis
  • 2018
  • In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
  • Journal article (peer-reviewed)abstract
    • Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10-22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10-10) and aortic root diameter (P = 1.30 × 10-8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10-3) and coronary artery disease (OR = 1.05, P = 9.3 × 10-5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.
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17.
  • Hägg, Sara, et al. (author)
  • Molecular Phenotypes of Coronary Artery Disease : The Stockholm Atherosclerosis Gene Expression (STAGE) Study
  • Other publication (other academic/artistic)abstract
    • BACKGROUNDBy offering a comprehensive view of the molecular underpinnings of pathology, high-dimensional data have the potential to revolutionize the diagnosis and management of complex disorders such as coronary artery disease (CAD). To identify molecular phenotypes of CAD, we performed multi organ gene expression profiling of subjects enrolled in the Stockholm Atherosclerosis Gene Expression (STAGE) study.METHODSAtherosclerotic and unaffected arterial wall, liver, skeletal muscle, and mediastinal fat biopsies were obtained during coronary artery bypass grafting from 114 well-characterized CAD patients. RNA samples were isolated, and 278 transcription profiles were obtained using Affymetrix HG-U133_Plus_2 GeneChips.RESULTSThe most prominent molecular phenotype of the CAD patients was represented by 733 genes in mediastinal fat, which were involved in extracellular matrix organization, response to stress and regulation of programmed cell death. Other aspects of this phenotype were shared with liver (e.g., oxidoreductase activity), skeletal muscle (insulin-like growth factor binding), and atherosclerotic arterial wall (cell motility and adhesion, fatty acid metabolism). In addition, the activity of 400 genes exclusively in mediastinal fat was associated with the extent of coronary stenosis and atherosclerosis. Immune-cell activation in mediastinal fat defined CAD patients with poor blood glucose control and prolonged hospitalization.CONCLUSIONSThe molecular phenotype of mediastinal fat appears to be central in CAD and should be useful for early identification of CAD risk.
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18.
  • Hägg, Sara, 1977-, et al. (author)
  • Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2 : The Stockholm Atherosclerosis Gene Expression (STAGE) Study
  • 2009
  • In: PLoS Genetics. - : PLoS Genetics. - 1553-7390 .- 1553-7404. ; 5:12, s. e1000754-
  • Journal article (peer-reviewed)abstract
    • Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n=66/tissue) and atherosclerotic and unaffected arterial wall (n=40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n=15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n=3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n=49/48) and one visceral fat (n=59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P=0.008 and P=0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n=55/54) relating to carotid stenosis (P=0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n=16/17, P<10-27and-30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, cellular and lesion expression of LDB2, and the expression of 13 TEML genes in Ldb2-deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and together with LDB2 merits further attention in CAD research.
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19.
  • Lagou, Vasiliki, et al. (author)
  • Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
  • 2021
  • In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
  • Journal article (peer-reviewed)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.
  •  
20.
  • Nastase Mannila, Maria, et al. (author)
  • Identification of a Functional Apolipoprotein E Promoter Polymorphism Regulating Plasma Apolipoprotein E Concentration
  • 2013
  • In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 33:5, s. 1063-1069
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE:There is compelling evidence that the plasma apolipoprotein E (APOE) concentration, in addition to the APOE ε2/ε3/ε4 genotype, influences plasma lipoprotein levels, but the functional genetic variants influencing the plasma APOE concentration have not been identified.APPROACH AND RESULTSGenome-wide association studies in 2 cohorts of healthy, middle-aged subjects identified the APOE locus as the only genetic locus showing robust associations with the plasma APOE concentration. Fine-mapping of the APOE locus confirmed that the rs7412 ε2-allele is the primary genetic variant responsible for the relationship with plasma APOE concentration. Further mapping of the APOE locus uncovered that rs769446 (-427T/C) in the APOE promoter is independently associated with the plasma APOE concentration. Expression studies in 199 human liver samples demonstrated that the rs769446 C-allele is associated with increased APOE mRNA levels (P=0.015). Transient transfection studies and electrophoretic mobility shift assays in human hepatoma HepG2 cells corroborated the role of rs769446 in transcriptional regulation of APOE. However, no relationships were found between rs769446 genotype and plasma lipoprotein levels in 2 cohorts (n=1648 and n=1039) of healthy middle-aged carriers of the APOE ε3/ε3 genotype.CONCLUSIONS:rs769446 is a functional polymorphism involved in the regulation of the plasma APOE concentration.
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21.
  • Paloschi, Valentina, et al. (author)
  • Impaired Splicing of Fibronectin Is Associated With Thoracic Aortic Aneurysm Formation in Patients With Bicuspid Aortic Valve
  • 2011
  • In: Arteriosclerosis, Thrombosis and Vascular Biology. - : American Heart Association. - 1079-5642 .- 1524-4636. ; 31:3, s. 691-697
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE:Thoracic aortic aneurysm is a common complication in patients with bicuspid aortic valve (BAV). Alternatively spliced extra domain A (EDA) of fibronectin (FN) has an essential role in tissue repair. Here we analyze the expression of FN spliceforms in dilated and nondilated ascending aorta of tricuspid aortic valve (TAV) and BAV patients.METHODS AND RESULTS:The mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=40) and BAV (n=69). EDA and extra domain B (EDB) expression was increased in dilated aorta from TAV patients compared with nondilated aorta (P<0.001 and P<0.05, respectively). In contrast, EDA expression was not increased in dilated aorta from BAV patients (P=0.25), whereas EDB expression was upregulated (P<0.01). The expression of EDA correlated with maximum aortic diameter in TAV (ρ=0.58) but not in BAV (ρ=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-β treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in cultured medial cells from TAV patients but not in cells derived from BAV patients. Gene set enrichment analysis together with multivariate and univariate data analyses of mRNA expression suggested that differences in the transforming growth factor-β signaling pathway may explain the impaired EDA inclusion in BAV patients.CONCLUSIONS:Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.
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22.
  • Scott, Robert A., et al. (author)
  • Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
  • 2012
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
  • Journal article (peer-reviewed)abstract
    • Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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23.
  • Sennblad, Bengt, et al. (author)
  • Genome- wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels
  • 2017
  • In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 26:3, s. 637-649
  • Journal article (peer-reviewed)abstract
    • Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators. We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays. Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 x 10(-302)), F11 (rs4253417, P-value = 2.86 x 10(-193)), and a novel association in GCKR (rs780094, P-value = 3.56 x 10(-09)), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR. These results should open the door to new therapeutic targets for thrombosis prevention.
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24.
  • Aminoff, A, et al. (author)
  • Allele-specific regulation of MTTP expression influences the risk of ischemic heart disease.
  • 2010
  • In: Journal of lipid research. - 0022-2275 .- 1539-7262. ; 51:1, s. 103-11
  • Journal article (peer-reviewed)abstract
    • Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that MTTP influences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/EBP binds to the polymorphic region in an allele-specific manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage.
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25.
  • Artiach, Gonzalo, et al. (author)
  • Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease through the Resolvin E1 and ChemR23 Axis.
  • 2020
  • In: Circulation. - 0009-7322 .- 1524-4539. ; 142, s. 776-789
  • Journal article (peer-reviewed)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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26.
  •  
27.
  • Fegraeus, Kim, et al. (author)
  • An endothelial regulatory module links blood pressure regulation with elite athletic performance
  • 2024
  • In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 20:6
  • Journal article (peer-reviewed)abstract
    • The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans.
  •  
28.
  • Forsell, Caroline, et al. (author)
  • Biomechanical Properties of the Thoracic Aneurysmal Wall : Differences Between Bicuspid Aortic Valve and Tricuspid Aortic Valve Patients
  • 2014
  • In: Annals of Thoracic Surgery. - : Elsevier BV. - 0003-4975 .- 1552-6259. ; 98:1, s. 65-71
  • Journal article (peer-reviewed)abstract
    • Background. The prevalence for thoracic aortic aneurysms (TAAs) is significantly increased in patients with a bicuspid aortic valve (BAV) compared with patients who have a normal tricuspid aortic valve (TAV). TAA rupture is a life-threatening event, and biomechanics-based simulations of the aorta may help to disentangle the molecular mechanism behind its development and progression. The present study used polarized microscopy and macroscopic in vitro tensile testing to explore collagen organization and mechanical properties of TAA wall specimens from BAV and TAV patients. Methods. Circumferential sections of aneurysmal aortic tissue from BAV and TAV patients were obtained during elective operations. The distribution of collagen orientation was captured by a Bingham distribution, and finite element models were used to estimate constitutive model parameters from experimental load-displacement curves. Results. Collagen orientation was almost identical in BAV and TAV patients, with a highest probability of alignment along the circumferential direction. The strength was almost two times higher in BAV samples (0.834 MPa) than in TAV samples (0.443 MPa; p < 0.001). The collagen-related stiffness (C-f) was significantly increased in BAV compared with TAV patients (C-f = 7.45 MPa vs 3.40 MPa; p = 0.003), whereas the elastin-related stiffness was similar in both groups. A trend toward a decreased wall thickness was seen in BAV patients (p = 0.058). Conclusions. The aneurysmal aortas of BAV patients show a higher macroscopic strength, mainly due to an increased collagen-related stiffness, compared with TAV patients. The increased wall stiffness in BAV patients may contribute to the higher prevalence for TAAs in this group.
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29.
  • Freiholtz, David, et al. (author)
  • SPP1/osteopontin : a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm?
  • 2023
  • In: Journal of Molecular Medicine. - : Springer Nature. - 0946-2716 .- 1432-1440. ; 101:10, s. 1323-1333
  • Journal article (peer-reviewed)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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30.
  • Jackson, Veronica, et al. (author)
  • Matrix metalloproteinase 14 and 19 expression is associated with thoracic aortic aneurysms
  • 2012
  • In: Journal of Thoracic and Cardiovascular Surgery. - : Elsevier. - 0022-5223 .- 1097-685X. ; 144:2, s. 459-466
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE:It is hypothesized that an altered turnover of extracellular matrix mediated by matrix metalloproteinases (MMPs) is present in thoracic aortic aneurysms. Here, we analyzed the occurrence of MMPs and MMP inhibitors in ascending aortic aneurysms in patients with bicuspid and tricuspid aortic valves.METHODS:Expression of 23 MMPs and their inhibitors was measured in aortic intima/media and adventitia in 109 patients (40 tricuspid, 69 bicuspid, 68 with aortic diameter≥4.5 cm, and 41 with ≤4.0 cm) using Affymetrix Exon arrays (Affymetrix, Santa Clara, Calif). Gene expression was confirmed by quantitative real-time polymerase chain reaction. Principal components analysis was used to study differences in gene expression. Immunohistochemistry was used to study protein expression.RESULTS:We detected messenger RNA expression for gelatinases (MMP2 and MMP9), stromelysin 3 (MMP11), all membrane bound MMPs (MMP14, MMP15, MMP16, MMP17, MMP24, MMP25), MMP19, MMP21, and MMP28 in ascending aorta. No expression of collagenases was detected. Principal components analysis showed that changes in mRNA expression between dilated and nondilated aorta were mainly detected in patients with tricuspid aortic valves. MMP14 and MMP19 showed higher expression in dilated aortas and MMP19 expression correlated positively to maximal aortic diameter in patients with tricuspid aortic valves (Rho=0.61, P=.004, and Rho=0.57, P=.008, using raw and body surface area-corrected aortic diameter, respectively). Immunohistochemical staining demonstrated increased medial expression of MMP14 and MMP19 in dilated aorta.CONCLUSIONS:The present study identifies MMP14 and MMP19 as proteolytic enzymes potentially involved in aneurysm formation in the ascending aorta of patients with tricuspid aortic valves
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31.
  • Jones, Gregory T., et al. (author)
  • Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci
  • 2017
  • In: Circulation Research. - 0009-7330 .- 1524-4571. ; 120:2, s. 341-
  • Journal article (peer-reviewed)abstract
    • Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
  •  
32.
  • Klevstig, Martina, et al. (author)
  • Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia
  • 2019
  • In: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 0022-2828 .- 1095-8584. ; 137, s. 1-8
  • Journal article (peer-reviewed)abstract
    • Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. Materials and methods: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. Results: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. Conclusions: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events.
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33.
  • Kolak, Maria, et al. (author)
  • Expression of ceramide-metabolising enzymes in subcutaneous and intra-abdominal human adipose tissue
  • 2012
  • In: Lipids in Health and Disease. - : BioMed Central (BMC). - 1476-511X. ; 11
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Inflammation and increased ceramide concentrations characterise adipose tissue of obese women with high liver fat content compared to equally obese women with normal liver fat content. The present study characterises enzymes involved in ceramide metabolism in subcutaneous and intra-abdominal adipose tissue.METHODS: Pathways leading to increased ceramide concentrations in inflamed versus non-inflamed adipose tissue were investigated by quantifying expression levels of key enzymes involved in ceramide metabolism. Sphingomyelinases (sphingomyelin phosphodiesterases SMPD1-3) were investigated further using immunohistochemistry to establish their location within adipose tissue, and their mRNA expression levels were determined in subcutaneous and intra-abdominal adipose tissue from both non-obese and obese subject.RESULTS: Gene expression levels of sphingomyelinases, enzymes that hydrolyse sphingomyelin to ceramide, rather than enzymes involved in de novo ceramide synthesis, were higher in inflamed compared to non-inflamed adipose tissue of obese women (with high and normal liver fat contents respectively). Sphingomyelinases were localised to both macrophages and adipocytes, but also to blood vessels and to extracellular regions surrounding vessels within adipose tissue. Expression levels of SMPD3 mRNA correlated significantly with concentrations of different ceramides and sphingomyelins. In both non-obese and obese subjects SMPD3 mRNA levels were higher in the more inflamed intra-abdominal compared to the subcutaneous adipose tissue depot.CONCLUSIONS: Generation of ceramides within adipose tissue as a result of sphingomyelinase action may contribute to inflammation in human adipose tissue.
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34.
  • Kurtovic, Sanela, et al. (author)
  • Diverging alternative splicing fingerprints in the transforming growth factor-β signaling pathway identified in thoracic aortic aneurysms.
  • 2011
  • In: Molecular medicine (Cambridge, Mass.). - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 17:7-8, s. 665-75
  • Journal article (peer-reviewed)abstract
    • Impaired regulation of the transforming growth factor-β (TGFβ) signaling pathway has been linked to thoracic aortic aneurysm (TAA). Previous work has indicated that differential splicing is a common phenomenon, potentially influencing the function of proteins. In the present study we investigated the occurrence of differential splicing in the TGFβ pathway associated with TAA in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). Affymetrix human exon arrays were applied to 81 intima/media tissue samples from dilated (n = 51) and nondilated (n = 30) aortas of TAV and BAV patients. To analyze the occurrence of alternative splicing in the TGFβ pathway, multivariate techniques, including principal component analysis and OPLS-DA (orthogonal partial least squares to latent structures discriminant analysis), were applied on all exons (n = 614) of the TGFβ pathway. The scores plot, based on the splice index of individual exons, showed separate clusters of patients with both dilated and nondilated aorta, thereby illustrating the potential importance of alternative splicing in TAA. In total, differential splicing was detected in 187 exons. Furthermore, the pattern of alternative splicing is clearly differs between TAV and BAV patients. Differential splicing was specific for BAV and TAV patients in 40 and 86 exons, respectively, and splicings of 61 exons were shared between the two phenotypes. The occurrence of differential splicing was demonstrated in selected genes by reverse transcription-polymerase chain reaction. In summary, alternative splicing is a common feature of TAA formation. Our results suggest that dilatation in TAV and BAV patients has different alternative splicing fingerprints in the TGFβ pathway.
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35.
  • Magné, Joelle, et al. (author)
  • ATG16L1 Expression in Carotid Atherosclerotic Plaques Is Associated With Plaque Vulnerability.
  • 2015
  • In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 35:5, s. 1226-1235
  • Journal article (peer-reviewed)abstract
    • Autophagy has emerged as a cell survival mechanism critical for cellular homeostasis, which may play a protective role in atherosclerosis. ATG16L1, a protein essential for early stages of autophagy, has been implicated in the pathogenesis of Crohn's disease. However, it is unknown whether ATG16L1 is involved in atherosclerosis. Our aim was to analyze ATG16L1 expression in carotid atherosclerotic plaques in relation to markers of plaque vulnerability.
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36.
  • Nagy, Edit, et al. (author)
  • Valvular osteoclasts in calcification and aortic valve stenosis severity
  • 2013
  • In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 168:3, s. 2264-2271
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Bone remodeling in calcified aortic valves is thought to originate from microfractures at multiple sites of the valve, at which osteoclasts and osteoblasts are recruited. The aim of the present study was to assess circulating mediators of bone homeostasis, correlate them to the severity of stenosis and explore the spatio-temporal distribution of bone turnover in different parts of calcified aortic valve tissue.METHODS AND RESULTS: Plasma and explanted aortic valves were obtained from 46 patients undergoing aortic valve replacement surgery. Plasma levels of tartrate-resistant acid phosphatase (TRAP), receptor activator of nuclear-κB (RANK) ligand and Runt-related transcription factor 2 (Runx2/Cbfa1) exhibited a significant correlation to the severity of aortic stenosis. mRNA levels in normal, thickened and calcified parts of aortic valves assessed by quantitative real-time PCR were significantly elevated in calcified parts of valves for TRAP (5.08 ± 1.6-fold, P<0.001) RANK ligand (8.6 ± 4.2-fold, P<0.001) and RANK (1.98 ± 0.78-fold, P=0.015). In an age, gender and aortic valve anatomy-adjusted multivariable regression analysis the local transcript levels of TRAP correlated significantly with echocardiographic parameters quantifying stenosis severity in early stages, whereas the expression level of Runx2/Cbfa1 was a predictor of the stenosis severity in advanced stages.CONCLUSIONS: These findings suggest a critical role of bone turnover as a determinant of aortic stenosis severity.
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37.
  • Persson, Michael, et al. (author)
  • ABO blood type and risk of porcine bioprosthetic aortic valve degeneration : SWEDEHEART observational cohort study
  • 2019
  • In: BMJ Open. - : BMJ. - 2044-6055. ; 9:5
  • Journal article (peer-reviewed)abstract
    • Objective Blood type A antigen on porcine aortic bioprostheses might initiate an immune reaction leading to an increased frequency of structural valve deterioration in patients with blood type B or O. The aim was to analyse the association between ABO blood type and porcine bioprosthetic aortic valve degeneration. Design Observational nationwide cohort study. Setting Swedish population-based study. Participants Adult patients (n=3417) who underwent surgical aortic valve replacement and received porcine bioprosthetic aortic valves between 1995 and 2012 from the Swedish Web system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies register. The study database was enriched with information from other national registers. Exposure The patients were categorised into type A/AB and type B/O blood groups. Primary and secondary outcome measures Primary outcome measure was aortic valve reoperation, and secondary outcomes were heart failure and all-cause mortality. We report risk estimates that account for the competing risk of death. Results In total, 3417 patients were identified: 1724 (50.5%) with blood type A/AB and 1693 (49.5%) with blood type B/O. Both groups had similar baseline characteristics. The cumulative incidence of aortic valve reoperation was 3.4% (95% CI 2.5% to 4.4%) and 3.6% (95% CI 2.6% to 4.6%) in the type B/O and the A/AB group, respectively, at 15 years of follow-up (absolute risk difference: -0.2% (95% CI -1.5% to 1.2%)). There was no significantly increased risk for aortic valve reoperation in patients with blood type B/O compared with type A/AB (HR 0.95, 95% CI 0.62 to 1.45). There was no significant difference in absolute or relative risk of heart failure or death between the groups. Conclusions We found no significant association between patient blood type and clinical manifestations of structural valve deterioration following porcine aortic valve replacement. Our findings suggest that it is safe to use porcine bioprosthetic valves without consideration of ABO blood type in the recipient.
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38.
  • Persson, Michael, et al. (author)
  • Comparison of Long-term Performance of Bioprosthetic Aortic Valves in Sweden from 2003 to 2018
  • 2022
  • In: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 5:3
  • Journal article (peer-reviewed)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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39.
  • Persson, Michael, et al. (author)
  • Porcine vs Bovine Bioprosthetic Aortic Valves: Long-Term Clinical Results
  • 2021
  • In: Annals of Thoracic Surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 111:2, s. 529-535
  • Journal article (peer-reviewed)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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40.
  • Plunde, Oscar, et al. (author)
  • FADS1 (Fatty Acid Desaturase 1) Genotype Associates With Aortic Valve FADS mRNA Expression, Fatty Acid Content and Calcification
  • 2020
  • In: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 2574-8300. ; 13:3, s. 139-148
  • Journal article (peer-reviewed)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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41.
  • Sainz-Jaspeado, Miguel, et al. (author)
  • Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium
  • 2021
  • In: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 144:20, s. 1629-1645
  • Journal article (peer-reviewed)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.
  •  
42.
  • Trenkwalder, Teresa, et al. (author)
  • Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis
  • 2019
  • In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 276, s. 212-217
  • Journal article (peer-reviewed)abstract
    • Background: Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. Methods: We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. Results: In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24–1.52, p = 6.9 × 10−10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31–1.79) compared to those with CAD (OR 1.27; 95%CI 1.12–1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88–0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27–1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95–1.02). Conclusions: Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.
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43.
  • Wågsäter, Dick, et al. (author)
  • Impaired collagen biosynthesis and cross-linking in aorta of patients with bicuspid aortic valve
  • 2013
  • In: Journal of the American Heart Association. - : Wiley-Blackwell. - 2047-9980. ; 2:1, s. e000034-
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Patients with bicuspid aortic valve (BAV) have an increased risk of developing ascending aortic aneurysm. In the present study, collagen homeostasis in nondilated and dilated aorta segments from patients with BAV was studied, with normal and dilated aortas from tricuspid aortic valve (TAV) patients as reference.METHODS AND RESULTS: Ascending aortas from 56 patients were used for biochemical and morphological analyses of collagen. mRNA expression was analyzed in 109 patients. Collagen turnover rates were similar in nondilated and dilated aortas of BAV patients, showing that aneurysmal formation in BAV is, in contrast to TAV, not associated with an increased collagen turnover. However, BAV in general was associated with an increased aortic collagen turnover compared with nondilated aortas of TAV patients. Importantly, the ratio of hydroxylysyl pyridinoline (HP) to lysyl pyridinoline (LP), 2 distinct forms of collagen cross-linking, was lower in dilated aortas from patients with BAV, which suggests that BAV is associated with a defect in the posttranslational collagen modification. This suggests a deficiency at the level of lysyl hydroxylase (PLOD1), which was confirmed by mRNA and protein analyses that showed reduced PLOD1 expression but normal lysyl oxidase expression in dilated aortas from patients with BAV. This suggests that impaired collagen cross-linking in BAV patients may be attributed to changes in the expression and/or activity of PLOD1.CONCLUSIONS: Our results demonstrate an impaired biosynthesis and posttranslational modification of collagen in aortas of patients with BAV, which may explain the increased aortic aneurysm formation in BAV patients.
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