Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement
Background—Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The aetiological 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 that later underwent surgery for AS (median age (interquartile range) 59.9 (10.4) years at survey and 68.3 (12.7) at surgery, 48% females). For each case, 2 matched referents were allocated. Plasma was analysed with the multiplex Proximity Extension Assay (PEA) 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 (GDF-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 1.25-1.37 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) that showed no visible coronary artery disease (CAD) at the time of surgery in the index person, supported associations between AS and GDF-15 (OR: 1.40, (1.10, 1.78)) and Galectin-4 (OR: 1.27 (1.02, 1.59)), but these associations were attenuated after excluding individuals that donated blood samples within 5 years prior to surgery. In triplets (n=201) that included index individuals with concurrent CAD at the time of surgery, all six proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but one (Interleukin 17 receptor A) of these proteins were replicated in AS patients with concurrent CAD but not in AS patients without CAD.
Conclusions—We provide evidence that five proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.
- Received July 7, 2017.
- Revision received January 29, 2018.
- Accepted February 15, 2018.