{"entity": "journal", "iuid": "4c53a4a33f1546a1a2e3322bccd515ca", "timestamp": "2026-08-09T06:54:48.481Z", "links": {"self": {"href": "https://publications.scilifelab.se/journal/Cardiovasc.%20Res..json"}, "display": {"href": "https://publications.scilifelab.se/journal/Cardiovasc.%20Res."}}, "title": "Cardiovasc. Res.", "issn": "1755-3245", "issn-l": "0008-6363", "publications_count": 10, "publications": [{"entity": "publication", "iuid": "25f828a506934ab9b9291c1869b794f5", "links": {"self": {"href": "https://publications.scilifelab.se/publication/25f828a506934ab9b9291c1869b794f5.json"}, "display": {"href": "https://publications.scilifelab.se/publication/25f828a506934ab9b9291c1869b794f5"}}, "title": "A multi-omics approach uncovers causality of IL6R on endotypes of subclinical carotid atherosclerosis and the possible role of the IL6R/OSMR pathway.", "authors": [{"family": "Chen", "given": "Qiao Sen", "initials": "QS"}, {"family": "Bj\u00f6rck", "given": "Hanna M", "initials": "HM", "orcid": "0000-0002-9155-3609", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d162f3de0f941e0a91387357892d656.json"}}, {"family": "Bergman", "given": "Otto", "initials": "O"}, {"family": "Baldassarre", "given": "Damiano", "initials": "D", "orcid": "0000-0002-2766-8882", "researcher": {"href": "https://publications.scilifelab.se/researcher/0c131cad5784434eb16cf720f7964ecb.json"}}, {"family": "Engstr\u00f6m", "given": "Gunnar", "initials": "G"}, {"family": "Gallo", "given": "Antonio", "initials": "A"}, {"family": "Gummesson", "given": "Anders", "initials": "A"}, {"family": "Hedin", "given": "Ulf", "initials": "U", "orcid": "0000-0001-9212-3945", "researcher": {"href": "https://publications.scilifelab.se/researcher/29a6ec281f5d4f1a8f317dedf0404cdd.json"}}, {"family": "Kurl", "given": "Sudhir", "initials": "S"}, {"family": "Lind", "given": "Lars", "initials": "L", "orcid": "0000-0003-2335-8542", "researcher": {"href": "https://publications.scilifelab.se/researcher/4c517dacca7c4ec58a3e03b59ffb4044.json"}}, {"family": "Matic", "given": "Ljubica", "initials": "L", "orcid": "0000-0002-7294-9667", "researcher": {"href": "https://publications.scilifelab.se/researcher/ee002c0f7f2c4c339a619c56c47e9ab6.json"}}, {"family": "Mulder", "given": "Douw Johannes", "initials": "DJ"}, {"family": "Pirro", "given": "Matteo", "initials": "M"}, {"family": "Savonen", "given": "Kai", "initials": "K"}, {"family": "S\u00f6derberg", "given": "Stefan", "initials": "S"}, {"family": "Veglia", "given": "Fabrizio", "initials": "F"}, {"family": "Tremoli", "given": "Elena", "initials": "E"}, {"family": "\u00d6stgren", "given": "Carl Johan", "initials": "CJ", "orcid": "0000-0003-1617-3179", "researcher": {"href": "https://publications.scilifelab.se/researcher/d4b5d952d50c4801aa88c0c9ae0d5813.json"}}, {"family": "Eriksson", "given": "Per", "initials": "P"}, {"family": "Strawbridge", "given": "Rona J", "initials": "RJ"}, {"family": "Gigante", "given": "Bruna", "initials": "B", "orcid": "0000-0003-4508-7990", "researcher": {"href": "https://publications.scilifelab.se/researcher/3ac1bdc52e3241ea9eb5645f603229a3.json"}}], "type": "journal article", "published": "2025-10-22", "journal": {"title": "Cardiovasc. Res.", "issn": "1755-3245", "issn-l": "0008-6363"}, "abstract": "Endotypes integrate individual clinical and molecular data and can be used to formulate molecular subclassifications of diseases. We previously derived four endotypes of subclinical carotid atherosclerosis in a large European cohort, c-IMT and c-IMT Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE), identifying individuals with a specific cardiovascular (CV) risk, ranging from low (endotype 1) to very high (endotype 4). Here, we investigate the mechanisms underlying the differences in CV risk observed across these four endotypes.\n\nWe validated the four endotypes in SCAPIS (n = 5050) and UK Biobank (n = 50 396) using carotid plaque and carotid intima-media thickness (c-IMT) as subclinical atherosclerosis measures. Endotype 4 associated with a larger number of carotid plaques and increased c-IMT measures as compared to endotype 1. We performed a meta-analysis of individual genome wide association studies in IMPROVE (n = 3711), SCAPIS and UK Biobank, and identified 12 SNPs associated with endotypes. We investigated if they regulated gene expression and circulating protein levels. We found that rs2228145A/C at Interleukin-6 Receptor (IL6R), associated with endotype 4, regulated IL6R expression and circulating levels of OncoStatin M Receptor (OSMR), Complement Factor B (CFB) and Fibrinogen Chain A (FGA). We used rs2228145A/C as an instrument in two-sample Mendelian randomization analyses and showed that a decreasing IL6R expression, associated with increasing CFB, FGA, and OSMR circulating levels. Endotype 4, IL6R, CFB, FGA, and OSMR co-localized within 250 kb surrounding rs2228145A/C. However, only OSMR was up-regulated in advanced carotid atherosclerotic plaques in the presence of the A allele and in aortic region exposed to low wall shear stress. In the UK Biobank, we observed that each additional A allele at rs2228145 increased by 1.28-times the risk of myocardial infarction (MI) in endotype 4.\n\nRs2228145A/C associated with endotype 4 clinical and molecular characteristics and amplified the MI risk in individuals assigned to endotype 4. These effects appeared to be mediated by a crosstalk with OSMR.", "doi": "10.1093/cvr/cvaf177", "pmid": "41124095", "labels": {"Affinity Proteomics Uppsala": "Service"}, "xrefs": [{"db": "pii", "key": "8296653"}], "notes": [], "created": "2025-11-25T19:21:10.519Z", "modified": "2025-11-25T19:21:10.605Z"}, {"entity": "publication", "iuid": "fbe87ad7cdb14ba598144e9efea8ef01", "links": {"self": {"href": "https://publications.scilifelab.se/publication/fbe87ad7cdb14ba598144e9efea8ef01.json"}, "display": {"href": "https://publications.scilifelab.se/publication/fbe87ad7cdb14ba598144e9efea8ef01"}}, "title": "Plasma proteomic and metabolomic profiling of coronary and carotid atherosclerosis in the SCAPIS study-differences and similarities.", "authors": [{"family": "Fall", "given": "Tove", "initials": "T", "orcid": "0000-0003-2071-5866", "researcher": {"href": "https://publications.scilifelab.se/researcher/4ed3f066719f43b291743a8bdaf3d2a0.json"}}, {"family": "Gummesson", "given": "Anders", "initials": "A"}, {"family": "Hammar", "given": "Ulf", "initials": "U"}, {"family": "Ahlstr\u00f6m", "given": "H\u00e5kan", "initials": "H"}, {"family": "Anger\u00e5s", "given": "Oskar", "initials": "O", "orcid": "0000-0002-3474-2438", "researcher": {"href": "https://publications.scilifelab.se/researcher/ffefb8f0aa0b4622b2eb80551a9389c5.json"}}, {"family": "Blomberg", "given": "Anders", "initials": "A"}, {"family": "Brandberg", "given": "John", "initials": "J"}, {"family": "Caidahl", "given": "Kenneth", "initials": "K"}, {"family": "Chorell", "given": "Elin", "initials": "E", "orcid": "0000-0002-8057-1684", "researcher": {"href": "https://publications.scilifelab.se/researcher/e3f7dfbecd6d4f80a9015080ec717ccc.json"}}, {"family": "Engvall", "given": "Jan Edvin", "initials": "JE"}, {"family": "Eriksson", "given": "Per", "initials": "P"}, {"family": "Erlinge", "given": "David", "initials": "D"}, {"family": "Gigante", "given": "Bruna", "initials": "B", "orcid": "0000-0003-4508-7990", "researcher": {"href": "https://publications.scilifelab.se/researcher/3ac1bdc52e3241ea9eb5645f603229a3.json"}}, {"family": "Hjelmgren", "given": "Ola", "initials": "O"}, {"family": "Hultdin", "given": "Johan", "initials": "J"}, {"family": "Jernberg", "given": "Tomas", "initials": "T", "orcid": "0000-0003-1695-379X", "researcher": {"href": "https://publications.scilifelab.se/researcher/cbe08775f7a047ffa46bf6e065c776c9.json"}}, {"family": "Kihlberg", "given": "Johan", "initials": "J"}, {"family": "Lind", "given": "Lars", "initials": "L", "orcid": "0000-0003-2335-8542", "researcher": {"href": "https://publications.scilifelab.se/researcher/4c517dacca7c4ec58a3e03b59ffb4044.json"}}, {"family": "Magnusson", "given": "Martin", "initials": "M"}, {"family": "Nystr\u00f6m", "given": "Fredrik Hans", "initials": "FH"}, {"family": "Pirazzi", "given": "Carlo", "initials": "C"}, {"family": "Schiopu", "given": "Alexandru", "initials": "A", "orcid": "0000-0002-7587-5050", "researcher": {"href": "https://publications.scilifelab.se/researcher/c7d2edf9030a445583f692dc4d884b7f.json"}}, {"family": "Sundstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0003-2247-8454", "researcher": {"href": "https://publications.scilifelab.se/researcher/91a40d3c138d43f2b0d38f66be4b71c7.json"}}, {"family": "S\u00f6derberg", "given": "Stefan", "initials": "S"}, {"family": "\u00d6stgren", "given": "Carl Johan", "initials": "CJ"}, {"family": "Engstr\u00f6m", "given": "Gunnar", "initials": "G", "orcid": "0000-0002-8618-9152", "researcher": {"href": "https://publications.scilifelab.se/researcher/b40c03613a3a46368ed855fc95b79e31.json"}}], "type": "journal article", "published": "2025-09-29", "journal": {"title": "Cardiovasc. Res.", "issn": "1755-3245", "volume": "121", "issue": "11", "pages": "1649-1652", "issn-l": "0008-6363"}, "abstract": null, "doi": "10.1093/cvr/cvaf076", "pmid": "40327543", "labels": {"Affinity Proteomics Uppsala": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12477672"}, {"db": "pii", "key": "8125826"}], "notes": [], "created": "2025-11-25T19:22:38.477Z", "modified": "2025-11-25T19:23:39.737Z"}, {"entity": "publication", "iuid": "7b6d68bef27c42ccbf33580e86f46cdf", "links": {"self": {"href": "https://publications.scilifelab.se/publication/7b6d68bef27c42ccbf33580e86f46cdf.json"}, "display": {"href": "https://publications.scilifelab.se/publication/7b6d68bef27c42ccbf33580e86f46cdf"}}, "title": "Antisense-mediated regulation of exon usage in the elastic spring region of Titin modulates sarcomere function.", "authors": [{"family": "Celik", "given": "Selvi", "initials": "S", "orcid": "0000-0001-7032-3444", "researcher": {"href": "https://publications.scilifelab.se/researcher/5da057ac725d4fb0bdbaddbc06a8ea64.json"}}, {"family": "Hyrefelt", "given": "Ludvig", "initials": "L"}, {"family": "Czuba", "given": "Tomasz", "initials": "T"}, {"family": "Li", "given": "Yuan", "initials": "Y"}, {"family": "Assis", "given": "Juliana", "initials": "J", "orcid": "0000-0001-5995-8684", "researcher": {"href": "https://publications.scilifelab.se/researcher/09d17153a55c4eeaba108c7ecfb8fa3a.json"}}, {"family": "Martinez", "given": "Julia", "initials": "J"}, {"family": "Johansson", "given": "Markus", "initials": "M"}, {"family": "Andr\u00e9", "given": "Oscar", "initials": "O"}, {"family": "Synnergren", "given": "Jane", "initials": "J"}, {"family": "Sandstedt", "given": "Joakim", "initials": "J", "orcid": "0000-0002-6458-9550", "researcher": {"href": "https://publications.scilifelab.se/researcher/070e186990424c4b83225eb93efc2a66.json"}}, {"family": "Nordenfelt", "given": "Pontus", "initials": "P", "orcid": "0000-0002-9481-9951", "researcher": {"href": "https://publications.scilifelab.se/researcher/7aa3418ab23a4ec48c037d6d6ddea5b5.json"}}, {"family": "Vukusic", "given": "Kristina", "initials": "K", "orcid": "0000-0002-4243-0565", "researcher": {"href": "https://publications.scilifelab.se/researcher/342e325123674e74963ae7c4dd307874.json"}}, {"family": "Smith", "given": "J Gustav", "initials": "JG", "orcid": "0000-0001-6285-9935", "researcher": {"href": "https://publications.scilifelab.se/researcher/26e50df6bb7f4194a52546dbd5652e84.json"}}, {"family": "Gidl\u00f6f", "given": "Olof", "initials": "O", "orcid": "0000-0002-7402-3139", "researcher": {"href": "https://publications.scilifelab.se/researcher/83f5453e507041b995e0d69a74540c24.json"}}], "type": "journal article", "published": "2025-03-05", "journal": {"title": "Cardiovasc. Res.", "issn": "1755-3245", "issn-l": "0008-6363"}, "abstract": "Alternative splicing of Titin (TTN) I-band exons produce protein isoforms with variable size and elasticity, but the mechanisms whereby TTN splice factors regulate exon usage and thereby determining cardiomyocyte passive stiffness and diastolic function, is not well understood. Non-coding RNA transcripts from the antisense strand of protein-coding genes have been shown to regulate alternative splicing of the sense gene. The TTN gene locus harbours >80 natural antisense transcripts (NATs) with unknown function in the human heart. The aim of this study was to determine if TTN antisense transcripts play a role in alternative splicing of TTN.\n\nRNA-sequencing and RNA in situ hybridization (ISH) of cardiac tissue from heart failure patients (HF), unused donor hearts and human iPS-derived cardiomyocytes (iPS-CMs) were used to determine the expression and localization of TTN NATs. Live cell imaging was used to analyze the effect of NATs on sarcomere properties. RNA ISH, immunofluorescence was performed in iPS-CMs to study the interaction between NATs, TTN mRNA and splice factor protein RBM20.We found that TTN-AS1-276 was the predominant TTN NAT in the human heart and that it was upregulated in HF. Knock down of TTN-AS1-276 in human iPS-CMs resulted in decreased interaction between the splicing factor RBM20 and TTN pre-mRNA, decreased TTN I-band exon skipping, and markedly lower expression of the less compliant TTN isoform N2B. The effect on TTN exon usage was independent of sense-antisense exon overlap and polymerase II elongation rate. Furthermore, knockdown resulted in longer sarcomeres with preserved alignment, improved fractional shortening and relaxation times.\n\nWe demonstrate a role for TTN-AS1-276 in facilitating alternative splicing of TTN and regulating sarcomere properties. This transcript could constitute a target for improving cardiac passive stiffness and diastolic function in conditions such as heart failure with preserved ejection fraction.", "doi": "10.1093/cvr/cvaf037", "pmid": "40042822", "labels": {"Bioinformatics Support, Infrastructure and Training": "Collaborative", "Bioinformatics (NBIS)": "Collaborative", "Bioinformatics Support and Infrastructure": "Collaborative"}, "xrefs": [{"db": "pii", "key": "8052712"}], "notes": [], "created": "2025-03-31T07:47:55.441Z", "modified": "2025-04-03T08:26:49.969Z"}, {"entity": "publication", "iuid": "d925c6ce825a4cde96a67489dfcef91f", "links": {"self": {"href": "https://publications.scilifelab.se/publication/d925c6ce825a4cde96a67489dfcef91f.json"}, "display": {"href": "https://publications.scilifelab.se/publication/d925c6ce825a4cde96a67489dfcef91f"}}, "title": "Transforming growth factor-\u03b22 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events.", "authors": [{"family": "Edsfeldt", "given": "Andreas", "initials": "A", "orcid": "0000-0002-2691-9192", "researcher": {"href": "https://publications.scilifelab.se/researcher/b4d8310d9d834bd791b791424774b989.json"}}, {"family": "Singh", "given": "Pratibha", "initials": "P"}, {"family": "Matthes", "given": "Frank", "initials": "F", "orcid": "0000-0002-5115-8831", "researcher": {"href": "https://publications.scilifelab.se/researcher/00f734f5167a4de48f38bcdf5e5765ab.json"}}, {"family": "Tengryd", "given": "Christoffer", "initials": "C"}, {"family": "Cavalera", "given": "Michele", "initials": "M"}, {"family": "Bengtsson", "given": "Eva", "initials": "E"}, {"family": "Dun\u00e9r", "given": "Pontus", "initials": "P"}, {"family": "Volkov", "given": "Petr", "initials": "P"}, {"family": "Karadimou", "given": "Glykeria", "initials": "G"}, {"family": "Gister\u00e5", "given": "Anton", "initials": "A", "orcid": "0000-0002-4614-8030", "researcher": {"href": "https://publications.scilifelab.se/researcher/3e2beec3559745a6ba1859252df4a547.json"}}, {"family": "Orho-Melander", "given": "Marju", "initials": "M", "orcid": "0000-0002-3578-2503", "researcher": {"href": "https://publications.scilifelab.se/researcher/7e54fbe6f0fc4eed93108b382e1b2952.json"}}, {"family": "Nilsson", "given": "Jan", "initials": "J", "orcid": "0000-0002-9752-7479", "researcher": {"href": "https://publications.scilifelab.se/researcher/8777140448bc47f0a7984db3c15c0e23.json"}}, {"family": "Sun", "given": "Jiangming", "initials": "J"}, {"family": "Gon\u00e7alves", "given": "Isabel", "initials": "I", "orcid": "0000-0002-2935-0181", "researcher": {"href": "https://publications.scilifelab.se/researcher/53cb42ac6ae8458ea9aaaa1dec1717d9.json"}}], "type": "journal article", "published": "2023-09-05", "journal": {"title": "Cardiovasc. Res.", "issn": "1755-3245", "volume": "119", "issue": "11", "pages": "2061-2073", "issn-l": "0008-6363"}, "abstract": "Transforming growth factor-beta (TGF-\u03b2) exists in three isoforms TGF-\u03b21, -\u03b22, and -\u03b23. TGF-\u03b21 has been suggested to be important for maintaining plaque stability, yet the role of TGF-\u03b22 and -\u03b23 in atherosclerosis remains to be investigated.This study explores the association of the three isoforms of TGF-\u03b2 with plaque stability in the human atherosclerotic disease.\n\nTGF-\u03b21, -\u03b22, and -\u03b23 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-\u03b22 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events.TGF-\u03b22 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-\u03b22 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-\u03b22 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-\u03b22 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-\u03b22 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-\u03b22 levels had a lower risk to suffer from future CV events.\n\nTGF-\u03b22 is the most abundant TGF-\u03b2 isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.", "doi": "10.1093/cvr/cvad079", "pmid": "37200403", "labels": {"Affinity Proteomics Uppsala": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10478752"}, {"db": "pii", "key": "7170345"}], "notes": [], "created": "2023-11-29T19:15:20.896Z", "modified": "2023-11-29T19:15:21.043Z"}, {"entity": "publication", "iuid": "a008d0a0c0f14c8bb8ffab0497dc6037", "links": {"self": {"href": "https://publications.scilifelab.se/publication/a008d0a0c0f14c8bb8ffab0497dc6037.json"}, "display": {"href": "https://publications.scilifelab.se/publication/a008d0a0c0f14c8bb8ffab0497dc6037"}}, "title": "A machine learning based approach to identify carotid subclinical atherosclerosis endotypes.", "authors": [{"family": "Chen", "given": "Qiao Sen", "initials": "QS", "orcid": "0000-0002-5864-7574", "researcher": {"href": "https://publications.scilifelab.se/researcher/84dde05e01624f07a374810c1086f20a.json"}}, {"family": "Bergman", "given": "Otto", "initials": "O"}, {"family": "Ziegler", "given": "Louise", "initials": "L"}, {"family": "Baldassarre", "given": "Damiano", "initials": "D", "orcid": "0000-0002-2766-8882", "researcher": {"href": "https://publications.scilifelab.se/researcher/0c131cad5784434eb16cf720f7964ecb.json"}}, {"family": "Veglia", "given": "Fabrizio", "initials": "F"}, {"family": "Tremoli", "given": "Elena", "initials": "E"}, {"family": "Strawbridge", "given": "Rona J", "initials": "RJ"}, {"family": "Gallo", "given": "Antonio", "initials": "A"}, {"family": "Pirro", "given": "Matteo", "initials": "M"}, {"family": "Smit", "given": "Andries J", "initials": "AJ"}, {"family": "Kurl", "given": "Sudhir", "initials": "S"}, {"family": "Savonen", "given": "Kai", "initials": "K"}, {"family": "Lind", "given": "Lars", "initials": "L", "orcid": "0000-0003-2335-8542", "researcher": {"href": "https://publications.scilifelab.se/researcher/4c517dacca7c4ec58a3e03b59ffb4044.json"}}, {"family": "Eriksson", "given": "Per", "initials": "P"}, {"family": "Gigante", "given": "Bruna", "initials": "B", "orcid": "0000-0003-4508-7990", "researcher": {"href": "https://publications.scilifelab.se/researcher/3ac1bdc52e3241ea9eb5645f603229a3.json"}}, {"family": "IMPROVE study group\n", "given": "", "initials": ""}], "type": "journal article", "published": "2023-07-21", "journal": {"title": "Cardiovasc. Res.", "issn": "1755-3245", "issn-l": "0008-6363"}, "abstract": "To define endotypes of carotid subclinical atherosclerosis.\n\nWe integrated demographic, clinical, and molecular data (n = 124) with ultrasonographic carotid measurements from study participants in the IMPROVE cohort (n = 3340). We applied a neural network algorithm and hierarchical clustering to identify carotid atherosclerosis endotypes. A measure of carotid subclinical atherosclerosis, the c-IMTmean-max, was used to extract atherosclerosis-related features and SHapley Additive exPlanations (SHAP) to reveal endotypes. The association of endotypes with carotid ultrasonographic measurements at baseline, after 30 months, and with the 3-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated by linear (\u03b2, SE) and Cox [hazard ratio (HR), 95% confidence interval (CI)] regression models. Crude estimates were adjusted by common cardiovascular risk factors, and baseline ultrasonographic measures. Improvement in ASCVD risk prediction was evaluated by C-statistic and by net reclassification improvement with reference to SCORE2, c-IMTmean-max, and presence of carotid plaques. An ensemble stacking model was used to predict endotypes in an independent validation cohort, the PIVUS (n = 1061). We identified four endotypes able to differentiate carotid atherosclerosis risk profiles from mild (endotype 1) to severe (endotype 4). SHAP identified endotype-shared variables (age, biological sex, and systolic blood pressure) and endotype-specific biomarkers. In the IMPROVE, as compared to endotype 1, endotype 4 associated with the thickest c-IMT at baseline (\u03b2, SE) 0.36 (0.014), the highest number of plaques 1.65 (0.075), the fastest c-IMT progression 0.06 (0.013), and the highest ASCVD risk (HR, 95% CI) (1.95, 1.18-3.23). Baseline and progression measures of carotid subclinical atherosclerosis and ASCVD risk were associated with the predicted endotypes in the PIVUS. Endotypes consistently improved measures of ASCVD risk discrimination and reclassification in both study populations.\n\nWe report four replicable subclinical carotid atherosclerosis-endotypes associated with progression of atherosclerosis and ASCVD risk in two independent populations. Our approach based on endotypes can be applied for precision medicine in ASCVD prevention.", "doi": "10.1093/cvr/cvad106", "pmid": "37475157", "labels": {"Affinity Proteomics Uppsala": "Service"}, "xrefs": [{"db": "pii", "key": "7226279"}], "notes": [], "created": "2023-11-29T19:27:08.131Z", "modified": "2023-11-29T19:27:08.184Z"}, {"entity": "publication", "iuid": "b736476c34b9439da7adaec3604dbd0c", "links": {"self": {"href": "https://publications.scilifelab.se/publication/b736476c34b9439da7adaec3604dbd0c.json"}, "display": {"href": "https://publications.scilifelab.se/publication/b736476c34b9439da7adaec3604dbd0c"}}, "title": "Vascular endothelial growth factor-D plasma levels and VEGFD genetic variants are independently associated with outcomes in patients with cardiovascular disease.", "authors": [{"family": "Davidsson", "given": "Pia", "initials": "P", "orcid": "0000-0002-4775-5828", "researcher": {"href": "https://publications.scilifelab.se/researcher/23f2792fe59f463dba3e347ff1efb2bc.json"}}, {"family": "Eketj\u00e4ll", "given": "Susanna", "initials": "S"}, {"family": "Eriksson", "given": "Niclas", "initials": "N", "orcid": "0000-0002-2152-4343", "researcher": {"href": "https://publications.scilifelab.se/researcher/64611a83caba46d597f45371b77de26b.json"}}, {"family": "Walentinsson", "given": "Anna", "initials": "A"}, {"family": "Becker", "given": "Richard C", "initials": "RC"}, {"family": "Cavallin", "given": "Anders", "initials": "A"}, {"family": "Bogstedt", "given": "Anna", "initials": "A"}, {"family": "Coll\u00e9n", "given": "Anna", "initials": "A"}, {"family": "Held", "given": "Claes", "initials": "C", "orcid": "0000-0001-9402-7404", "researcher": {"href": "https://publications.scilifelab.se/researcher/88c69f319fce4852aab37e02a75ed525.json"}}, {"family": "James", "given": "Stefan", "initials": "S"}, {"family": "Siegbahn", "given": "Agneta", "initials": "A"}, {"family": "Stewart", "given": "Ralph", "initials": "R", "orcid": "0000-0002-6167-1225", "researcher": {"href": "https://publications.scilifelab.se/researcher/493d2ac878264e0d98736945d8fdbb4d.json"}}, {"family": "Storey", "given": "Robert F", "initials": "RF"}, {"family": "White", "given": "Harvey", "initials": "H"}, {"family": "Wallentin", "given": "Lars", "initials": "L", "orcid": "0000-0003-0378-6531", "researcher": {"href": "https://publications.scilifelab.se/researcher/388a76db2e4d423882d1cf2bf6b7d985.json"}}], "type": "journal article", "published": "2023-07-04", "journal": {"title": "Cardiovasc. Res.", "issn": "1755-3245", "volume": "119", "issue": "7", "pages": "1596-1605", "issn-l": "0008-6363"}, "abstract": "The vascular endothelial growth factor (VEGF) family is involved in pathophysiological mechanisms underlying cardiovascular (CV) diseases. The aim of this study was to investigate the associations between circulating VEGF ligands and/or soluble receptors and CV outcome in patients with acute coronary syndrome (ACS) and chronic coronary syndrome (CCS).\n\nLevels of VEGF biomarkers, including bFGF, Flt-1, KDR (VEGFR2), PlGF, Tie-2, VEGF-A, VEGF-C, and VEGF-D, were measured in the PLATO ACS cohort (n = 2091, discovery cohort). Subsequently, VEGF-D was also measured in the STABILITY CCS cohort (n = 4015, confirmation cohort) to verify associations with CV outcomes. Associations between plasma VEGF-D and outcomes were analysed by multiple Cox regression models with hazard ratios (HR [95% CI]) comparing the upper vs. the lower quartile of VEGF-D. Genome-wide association study (GWAS) of VEGF-D in PLATO identified SNPs that were used as genetic instruments in Mendelian randomization (MR) meta-analyses vs. clinical endpoints. GWAS and MR were performed in patients with ACS from PLATO (n = 10 013) and FRISC-II (n = 2952), and with CCS from the STABILITY trial (n = 10 786). VEGF-D, KDR, Flt-1, and PlGF showed significant association with CV outcomes. VEGF-D was most strongly associated with CV death (P = 3.73e-05, HR 1.892 [1.419, 2.522]). Genome-wide significant associations with VEGF-D levels were identified at the VEGFD locus on chromosome Xp22. MR analyses of the combined top ranked SNPs (GWAS P-values; rs192812042, P = 5.82e-20; rs234500, P = 1.97e-14) demonstrated a significant effect on CV mortality [P = 0.0257, HR 1.81 (1.07, 3.04) per increase of one unit in log VEGF-D].\n\nThis is the first large-scale cohort study to demonstrate that both VEGF-D plasma levels and VEGFD genetic variants are independently associated with CV outcomes in patients with ACS and CCS. Measurements of VEGF-D levels and/or VEGFD genetic variants may provide incremental prognostic information in patients with ACS and CCS.", "doi": "10.1093/cvr/cvad039", "pmid": "36869765", "labels": {"NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "National Genomics Infrastructure": "Service", "NGI SNP genotyping": "Service", "Affinity Proteomics Uppsala": "Service"}, "xrefs": [{"db": "pii", "key": "7069262"}], "notes": [], "created": "2023-04-06T13:50:07.167Z", "modified": "2023-11-29T19:15:31.361Z"}, {"entity": "publication", "iuid": "faf07ebd88b44cbb8159cf13d69f1108", "links": {"self": {"href": "https://publications.scilifelab.se/publication/faf07ebd88b44cbb8159cf13d69f1108.json"}, "display": {"href": "https://publications.scilifelab.se/publication/faf07ebd88b44cbb8159cf13d69f1108"}}, "title": "Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function.", "authors": [{"family": "Laudette", "given": "Marion", "initials": "M"}, {"family": "Lindbom", "given": "Malin", "initials": "M"}, {"family": "Arif", "given": "Muhammad", "initials": "M", "orcid": "0000-0003-2261-0881", "researcher": {"href": "https://publications.scilifelab.se/researcher/fbe369c4e07c44c09dcf64a3c18d833e.json"}}, {"family": "Cinato", "given": "Mathieu", "initials": "M", "orcid": "0000-0002-8490-4335", "researcher": {"href": "https://publications.scilifelab.se/researcher/caecf7dcbc1b47639e00f683617632a2.json"}}, {"family": "Ruiz", "given": "Mario", "initials": "M"}, {"family": "Doran", "given": "Stephen", "initials": "S", "orcid": "0000-0002-9236-5407", "researcher": {"href": "https://publications.scilifelab.se/researcher/52635955f5e24f9c9a6bae8b0ebc0926.json"}}, {"family": "Miljanovic", "given": "Azra", "initials": "A"}, {"family": "Rutberg", "given": "Mikael", "initials": "M"}, {"family": "Andersson", "given": "Linda", "initials": "L"}, {"family": "Klevstig", "given": "Martina", "initials": "M"}, {"family": "Henricsson", "given": "Marcus", "initials": "M", "orcid": "0000-0002-4202-0339", "researcher": {"href": "https://publications.scilifelab.se/researcher/01a323cbf0a24269bd32bfc34539e021.json"}}, {"family": "Bergh", "given": "Per-Olof", "initials": "PO"}, {"family": "Bollano", "given": "Entela", "initials": "E"}, {"family": "Aung", "given": "Nay", "initials": "N", "orcid": "0000-0001-5095-1611", "researcher": {"href": "https://publications.scilifelab.se/researcher/246af6f2f0704302a2919c23d4b831c0.json"}}, {"family": "Gustav Smith", "given": "J", "initials": "J"}, {"family": "Pilon", "given": "Marc", "initials": "M"}, {"family": "Hy\u00f6tyl\u00e4inen", "given": "Tuulia", "initials": "T", "orcid": "0000-0002-1389-8302", "researcher": {"href": "https://publications.scilifelab.se/researcher/33d97cc166ee466aa69ab8c825c28b45.json"}}, {"family": "Ore\u0161i\u010d", "given": "Matej", "initials": "M"}, {"family": "Perkins", "given": "Rosie", "initials": "R"}, {"family": "Mardinoglu", "given": "Adil", "initials": "A"}, {"family": "Levin", "given": "Malin C", "initials": "MC"}, {"family": "Bor\u00e9n", "given": "Jan", "initials": "J", "orcid": "0000-0003-0786-8091", "researcher": {"href": "https://publications.scilifelab.se/researcher/1e85f6d287ce4c60a7b35b287efb4f79.json"}}], "type": "journal article", "published": "2023-07-04", "journal": {"title": "Cardiovasc. Res.", "issn": "1755-3245", "volume": "119", "issue": "7", "pages": "1537-1552", "issn-l": "0008-6363"}, "abstract": "Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9-/- mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells.\n\nMice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9-/- mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9-/- hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9-/- mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9-/- mice. Circulating lipid levels were unchanged in CM-Pcsk9-/- mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9-/- mice had an increased number of mitochondria-endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism.\n\nPCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.", "doi": "10.1093/cvr/cvad041", "pmid": "36880401", "labels": {"Integrated Microscopy Technologies Gothenburg": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10318396"}, {"db": "pii", "key": "7070420"}], "notes": [], "created": "2023-12-01T10:47:21.390Z", "modified": "2023-12-01T10:47:21.524Z"}, {"entity": "publication", "iuid": "a02c0a3eaf1e456fb1859569031908a7", "links": {"self": {"href": "https://publications.scilifelab.se/publication/a02c0a3eaf1e456fb1859569031908a7.json"}, "display": {"href": "https://publications.scilifelab.se/publication/a02c0a3eaf1e456fb1859569031908a7"}}, "title": "Using multimarker screening to identify biomarkers associated with cardiovascular death in patients with atrial fibrillation.", "authors": [{"family": "Pol", "given": "Tymon", "initials": "T", "orcid": "0000-0001-6239-199X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f0bf1df0dd904b579b081a3680627005.json"}}, {"family": "Hijazi", "given": "Ziad", "initials": "Z", "orcid": "0000-0002-7420-743X", "researcher": {"href": "https://publications.scilifelab.se/researcher/03d1c858fbab4b7d9c9574adf5ad51af.json"}}, {"family": "Lindb\u00e4ck", "given": "Johan", "initials": "J"}, {"family": "Oldgren", "given": "Jonas", "initials": "J", "orcid": "0000-0002-9969-3921", "researcher": {"href": "https://publications.scilifelab.se/researcher/14e1774fd1674edeaaa64a3f86d051d7.json"}}, {"family": "Alexander", "given": "John H", "initials": "JH", "orcid": "0000-0002-1444-2462", "researcher": {"href": "https://publications.scilifelab.se/researcher/468ce17f14a04afd9cfe979103f1f849.json"}}, {"family": "Connolly", "given": "Stuart J", "initials": "SJ"}, {"family": "Eikelboom", "given": "John W", "initials": "JW"}, {"family": "Ezekowitz", "given": "Michael D", "initials": "MD", "orcid": "0000-0003-3623-2252", "researcher": {"href": "https://publications.scilifelab.se/researcher/43f3a6f18de74bb6a632b1b16d1b778c.json"}}, {"family": "Granger", "given": "Christopher B", "initials": "CB"}, {"family": "Lopes", "given": "Renato D", "initials": "RD", "orcid": "0000-0003-2999-4961", "researcher": {"href": "https://publications.scilifelab.se/researcher/a98c4a6d5300452b9a3a770cff4d97e9.json"}}, {"family": "Yusuf", "given": "Salim", "initials": "S"}, {"family": "Siegbahn", "given": "Agneta", "initials": "A"}, {"family": "Wallentin", "given": "Lars", "initials": "L", "orcid": "0000-0003-0378-6531", "researcher": {"href": "https://publications.scilifelab.se/researcher/388a76db2e4d423882d1cf2bf6b7d985.json"}}], "type": "clinical study", "published": "2022-07-20", "journal": {"title": "Cardiovasc. Res.", "issn": "1755-3245", "volume": "118", "issue": "9", "pages": "2112-2123", "issn-l": "0008-6363"}, "abstract": "Atrial fibrillation (AF) is associated with higher mortality. Biomarkers may improve the understanding of key pathophysiologic processes in AF that lead to death. Using a new multiplex analytic technique, we explored the association between 268 biomarkers and cardiovascular (CV) death in anticoagulated patients with AF.\n\nA case-cohort design with 1.8- to 1.9-year follow-up. The identification cohort included 517 cases and 4057 randomly selected patients from ARISTOTLE. The validation cohort included 277 cases and 1042 randomly selected controls from RE-LY. Plasma collected at randomization was analysed with conventional immunoassays and the OLINK proximity extension assay panels: CVDII, CVDIII, and Inflammation. Association between biomarkers and CV death was evaluated using Random Survival Forest, Boruta, and adjusted Cox-regression analyses. The biomarkers most strongly and consistently associated with CV death were as follows (hazard ratio for inter-quartile comparison [95% CI]): N-terminal pro-B-type natriuretic peptide [NT-proBNP; 1.63 (1.37-1.93)], cardiac troponin T [cTnT-hs; 1.60 (1.35-1.88)], interleukin-6 [IL-6; 1.29 (1.13-1.47)], growth differentiation factor-15 [GDF-15; 1.30 (1.10-1.53)], fibroblast growth factor 23 [FGF-23; 1.21 (1.10-1.33)], urokinase receptor [uPAR; 1.38 (1.16-1.64)], trefoil factor 3 [TFF3; 1.27 (1.10-1.46)], tumour necrosis factor receptor 1 [TNFR1; 1.21 (1.01-1.45)], TNF-related apoptosis-inducing ligand receptor 2 [TRAILR2; 1.18 (1.04-1.34)], and cathepsin L1 [CTSL1; 1.22 (1.07-1.39)].\n\nIn this comprehensive screening of 268 biomarkers in anticoagulated patients with AF, the underlying mechanisms most strongly associated with CV death were cardiorenal dysfunction (NT-proBNP, cTnT-hs, CTSL1, TFF3), oxidative stress (GDF-15), inflammation (IL-6, GDF-15), calcium balance, vascular and renal dysfunction (FGF-23), fibrinolysis (suPAR), and apoptosis (TNFR1, TRAILR2). These findings provide novel insights into pathophysiologic aspects associated with CV death in AF.\n\nNCT00412984 and NCT00262600.", "doi": "10.1093/cvr/cvab262", "pmid": "34358298", "labels": {"Affinity Proteomics Uppsala": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9302885"}, {"db": "pii", "key": "6343453"}, {"db": "ClinicalTrials.gov", "key": "NCT00412984"}, {"db": "ClinicalTrials.gov", "key": "NCT00262600"}], "notes": [], "created": "2021-12-10T09:12:08.560Z", "modified": "2022-12-02T08:57:56.429Z"}, {"entity": "publication", "iuid": "9f90c4c5c02e4c7eb06ca9ac6ee4f7f7", "links": {"self": {"href": "https://publications.scilifelab.se/publication/9f90c4c5c02e4c7eb06ca9ac6ee4f7f7.json"}, "display": {"href": "https://publications.scilifelab.se/publication/9f90c4c5c02e4c7eb06ca9ac6ee4f7f7"}}, "title": "Chitinase 3 like 1 is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability.", "authors": [{"family": "Tsantilas", "given": "Pavlos", "initials": "P", "orcid": "0000-0002-7097-6776", "researcher": {"href": "https://publications.scilifelab.se/researcher/a76d80217afc4a0987c928829c40da7d.json"}}, {"family": "Lao", "given": "Shen", "initials": "S", "orcid": "0000-0002-0179-9876", "researcher": {"href": "https://publications.scilifelab.se/researcher/bd793dc0fa0f452e9c52fbed83a477f9.json"}}, {"family": "Wu", "given": "Zhiyuan", "initials": "Z"}, {"family": "Eberhard", "given": "Anne", "initials": "A", "orcid": "0000-0002-3158-2686", "researcher": {"href": "https://publications.scilifelab.se/researcher/4493d0b78eb7463b8c7f9cf6ba795a89.json"}}, {"family": "Winski", "given": "Greg", "initials": "G", "orcid": "0000-0002-1832-5423", "researcher": {"href": "https://publications.scilifelab.se/researcher/6411e56b76924101b8aa5fe302d944ee.json"}}, {"family": "Vaerst", "given": "Monika", "initials": "M", "orcid": "0000-0001-8176-0623", "researcher": {"href": "https://publications.scilifelab.se/researcher/8b1cd2afcd154110a65472c31a035ae7.json"}}, {"family": "Nanda", "given": "Vivek", "initials": "V"}, {"family": "Wang", "given": "Ying", "initials": "Y", "orcid": "0000-0002-1444-5778", "researcher": {"href": "https://publications.scilifelab.se/researcher/4a12f8cb63c34498b5f1e203690d43ba.json"}}, {"family": "Kojima", "given": "Yoko", "initials": "Y"}, {"family": "Ye", "given": "Jianqin", "initials": "J"}, {"family": "Flores", "given": "Alyssa", "initials": "A"}, {"family": "Jarr", "given": "Kai-Uwe", "initials": "KU", "orcid": "0000-0003-3376-6478", "researcher": {"href": "https://publications.scilifelab.se/researcher/05a709de97ad4f0bbecadb22dcb66a49.json"}}, {"family": "Pelisek", "given": "Jaroslav", "initials": "J"}, {"family": "Eckstein", "given": "Hans-Henning", "initials": "HH"}, {"family": "Matic", "given": "Ljubica", "initials": "L"}, {"family": "Hedin", "given": "Ulf", "initials": "U", "orcid": "0000-0001-9212-3945", "researcher": {"href": "https://publications.scilifelab.se/researcher/29a6ec281f5d4f1a8f317dedf0404cdd.json"}}, {"family": "Tsao", "given": "Philip S", "initials": "PS"}, {"family": "Paloschi", "given": "Valentina", "initials": "V", "orcid": "0000-0002-5778-8981", "researcher": {"href": "https://publications.scilifelab.se/researcher/e5d6514835f0465a9c1703ae76554e28.json"}}, {"family": "Maegdefessel", "given": "Lars", "initials": "L", "orcid": "0000-0001-5228-2634", "researcher": {"href": "https://publications.scilifelab.se/researcher/79bb494450154c51a70281d20fb07f81.json"}}, {"family": "Leeper", "given": "Nicholas J", "initials": "NJ", "orcid": "0000-0002-0905-2806", "researcher": {"href": "https://publications.scilifelab.se/researcher/3b5f58e37e0c4f768a50911a363a171c.json"}}], "type": "journal article", "published": "2021-12-17", "journal": {"title": "Cardiovasc. Res.", "issn": "1755-3245", "volume": "117", "issue": "14", "pages": "2767-2780", "issn-l": "0008-6363"}, "abstract": "Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals.\n\nUsing two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity.\n\nCHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.", "doi": "10.1093/cvr/cvab014", "pmid": "33471078", "labels": {"Global Proteomics and Proteogenomics": "Service"}, "xrefs": [{"db": "pii", "key": "6104807"}, {"db": "pmc", "key": "PMC8848327"}], "notes": [], "created": "2022-03-29T12:24:11.360Z", "modified": "2022-03-29T12:24:11.703Z"}, {"entity": "publication", "iuid": "cc74f4cd8d9b4314b59b768ea493f52f", "links": {"self": {"href": "https://publications.scilifelab.se/publication/cc74f4cd8d9b4314b59b768ea493f52f.json"}, "display": {"href": "https://publications.scilifelab.se/publication/cc74f4cd8d9b4314b59b768ea493f52f"}}, "title": "Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention.", "authors": [{"family": "Kessler", "given": "Thorsten", "initials": "T"}, {"family": "Wolf", "given": "Bernhard", "initials": "B"}, {"family": "Eriksson", "given": "Niclas", "initials": "N"}, {"family": "Kofink", "given": "Daniel", "initials": "D"}, {"family": "Mahmoodi", "given": "Bakhtawar K", "initials": "BK"}, {"family": "Rai", "given": "Himanshu", "initials": "H"}, {"family": "Tragante", "given": "Vinicius", "initials": "V"}, {"family": "\u00c5kerblom", "given": "Axel", "initials": "A"}, {"family": "Becker", "given": "Richard C", "initials": "RC"}, {"family": "Bernlochner", "given": "Isabell", "initials": "I"}, {"family": "Bopp", "given": "Roman", "initials": "R"}, {"family": "James", "given": "Stefan", "initials": "S"}, {"family": "Katus", "given": "Hugo A", "initials": "HA"}, {"family": "Mayer", "given": "Katharina", "initials": "K"}, {"family": "Munz", "given": "Matthias", "initials": "M"}, {"family": "Nordio", "given": "Francesco", "initials": "F"}, {"family": "O'Donoghue", "given": "Michelle L", "initials": "ML"}, {"family": "Sager", "given": "Hendrik B", "initials": "HB"}, {"family": "Sibbing", "given": "Dirk", "initials": "D"}, {"family": "Solakov", "given": "Linda", "initials": "L"}, {"family": "Storey", "given": "Robert F", "initials": "RF"}, {"family": "Wobst", "given": "Jana", "initials": "J"}, {"family": "Asselbergs", "given": "Folkert W", "initials": "FW"}, {"family": "Byrne", "given": "Robert A", "initials": "RA"}, {"family": "Erdmann", "given": "Jeanette", "initials": "J"}, {"family": "Koenig", "given": "Wolfgang", "initials": "W"}, {"family": "Laugwitz", "given": "Karl-Ludwig", "initials": "KL"}, {"family": "Ten Berg", "given": "Jurrien M", "initials": "JM"}, {"family": "Wallentin", "given": "Lars", "initials": "L"}, {"family": "Kastrati", "given": "Adnan", "initials": "A"}, {"family": "Schunkert", "given": "Heribert", "initials": "H"}], "type": "journal article", "published": "2019-02-14", "journal": {"volume": null, "issn": "1755-3245", "issue": null, "title": "Cardiovasc. Res.", "issn-l": "0008-6363"}, "abstract": "A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention.\n\nThe association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n\u2009=\u20091678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30\u2009days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n\u2009=\u20093236), and the Utrecht Coronary Biobank (n\u2009=\u20091003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91-209) vs. 134 (85-194) AU\u22c5min, P\u2009<\u20090.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203\u2009AU\u22c5min; 29.5 vs. 24.2%, P\u2009=\u20090.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08-2.68; P\u2009=\u20090.02). Bleeding risk was not altered.\n\nWe conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30\u2009days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.", "doi": "10.1093/cvr/cvz015", "pmid": "30768153", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pii", "key": "5320311"}], "notes": [], "created": "2019-03-13T09:21:23.117Z", "modified": "2020-01-21T13:56:14.318Z"}], "created": "2019-03-13T09:21:23.130Z", "modified": "2020-11-27T13:14:06.883Z"}