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Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement
Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Umea Univ, Dept Biobank Res, Umea, Sweden..
Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden..
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2018 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 138, no 6, p. 590-599Article in journal (Refereed) Published
Abstract [en]

Background: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights.

Methods: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study.

Results: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease.

Conclusions: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS , 2018. Vol. 138, no 6, p. 590-599
Keywords [en]
aortic stenosis, aortic valve surgery, prospective study, proteomics, risk markers
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-364985DOI: 10.1161/CIRCULATIONAHA.117.030414ISI: 000440866500011PubMedID: 29487139OAI: oai:DiVA.org:uu-364985DiVA, id: diva2:1261445
Funder
Swedish Heart Lung Foundation, 20140799Swedish Heart Lung Foundation, 20120631Swedish Heart Lung Foundation, 20100635Swedish Heart Lung Foundation, 20150429Västerbotten County Council, VLL-548791Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Research Council, 2015-03477Swedish Research Council, K2013-65X-11568-18-5
Note

Tove Fall och Stefan Söderberg delar på sistaförfattarskapet.

Available from: 2018-11-07 Created: 2018-11-07 Last updated: 2019-02-13Bibliographically approved

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