Vascular endothelial growth factor-D plasma levels and VEGFD genetic variants are independently associated with outcomes in patients with cardiovascular disease.

Autor:	Davidsson P; Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83 Mölndal, Sweden., Eketjäll S; Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83 Mölndal, Sweden., Eriksson N; Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 38, 751 85 Uppsala, Sweden., Walentinsson A; Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83 Mölndal, Sweden., Becker RC; Division of Cardiovascular Health and Disease, Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 0542, Cincinnati, OH, 45267, USA., Cavallin A; Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83 Mölndal, Sweden., Bogstedt A; Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83 Mölndal, Sweden., Collén A; Projects, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83 Mölndal, Sweden., Held C; Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 38, 751 85 Uppsala, Sweden.; Department of Medical Sciences, Cardiology, Uppsala University, Akademiska Sjukhuset, 751 85 Uppsala, Sweden., James S; Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 38, 751 85 Uppsala, Sweden.; Department of Medical Sciences, Cardiology, Uppsala University, Akademiska Sjukhuset, 751 85 Uppsala, Sweden., Siegbahn A; Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 38, 751 85 Uppsala, Sweden.; Department of Medical Sciences, Cardiology, Uppsala University, Akademiska Sjukhuset, 751 85 Uppsala, Sweden.; Clinical Chemistry, Uppsala University, Akademiska Sjukhuset, 751 85 Uppsala, Sweden., Stewart R; Green Lane Cardiovascular Service, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand., Storey RF; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK., White H; Green Lane Cardiovascular Service, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand., Wallentin L; Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 38, 751 85 Uppsala, Sweden.; Department of Medical Sciences, Cardiology, Uppsala University, Akademiska Sjukhuset, 751 85 Uppsala, Sweden.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Jul 04; Vol. 119 (7), pp. 1596-1605.
DOI:	10.1093/cvr/cvad039
Abstrakt:	Aims: 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). Methods and Results: Levels 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]. Conclusion: This 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. Competing Interests: Conflict of interest: the current study was sponsored by AstraZeneca. A.B., A.Ca., A.Co., A.W., P.D., and S.E. are employees of AstraZeneca. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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