Vascular endothelial growth factor-D plasma levels and VEGFD genetic variants are independently associated with outcomes in patients with cardiovascular disease
© 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.permissionsoup.com..
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.
| Errataetall: |
ErratumIn: Cardiovasc Res. 2023 Jun 13;119(6):1454. - PMID 36972152 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:119 |
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| Enthalten in: |
Cardiovascular research - 119(2023), 7 vom: 04. Juli, Seite 1596-1605 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Davidsson, Pia [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.09.2023 Date Revised 12.09.2023 published: Print ErratumIn: Cardiovasc Res. 2023 Jun 13;119(6):1454. - PMID 36972152 Citation Status MEDLINE |
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| doi: |
10.1093/cvr/cvad039 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM353756539 |
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| 245 | 1 | 0 | |a Vascular endothelial growth factor-D plasma levels and VEGFD genetic variants are independently associated with outcomes in patients with cardiovascular disease |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 12.09.2023 | ||
| 500 | |a Date Revised 12.09.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a ErratumIn: Cardiovasc Res. 2023 Jun 13;119(6):1454. - PMID 36972152 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 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.permissionsoup.com. | ||
| 520 | |a 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) | ||
| 520 | |a 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] | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Biomarkers | |
| 650 | 4 | |a Cardiovascular diseases | |
| 650 | 4 | |a Single nucleotide polymorphisms | |
| 650 | 4 | |a VEGF-D | |
| 650 | 7 | |a Vascular Endothelial Growth Factor A |2 NLM | |
| 650 | 7 | |a Vascular Endothelial Growth Factor D |2 NLM | |
| 650 | 7 | |a VEGFD protein, human |2 NLM | |
| 700 | 1 | |a Eketjäll, Susanna |e verfasserin |4 aut | |
| 700 | 1 | |a Eriksson, Niclas |e verfasserin |4 aut | |
| 700 | 1 | |a Walentinsson, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Becker, Richard C |e verfasserin |4 aut | |
| 700 | 1 | |a Cavallin, Anders |e verfasserin |4 aut | |
| 700 | 1 | |a Bogstedt, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Collén, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Held, Claes |e verfasserin |4 aut | |
| 700 | 1 | |a James, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Siegbahn, Agneta |e verfasserin |4 aut | |
| 700 | 1 | |a Stewart, Ralph |e verfasserin |4 aut | |
| 700 | 1 | |a Storey, Robert F |e verfasserin |4 aut | |
| 700 | 1 | |a White, Harvey |e verfasserin |4 aut | |
| 700 | 1 | |a Wallentin, Lars |e verfasserin |4 aut | |
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