Sushi, von Willebrand Factor Type A, EGF and Pentraxin Domain-Containing Protein 1: A Novel Fibroblast-Derived Circulating Biomarker Reflecting Cardiac Fibrosis.

Abstract

BACKGROUND: Cardiac fibrosis is a hallmark of heart failure and can be quantified by the extracellular volume fraction (ECV) derived from diagnostic imaging. However, noninvasive assessment is limited by the lack of specific circulating biomarkers. Recent large plasma proteome analyses have identified SVEP1 (Sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1) as candidate molecules reflecting cardiac fibrosis. This study aimed to evaluate SVEP1 as a biomarker for cardiac fibrosis. METHODS: In 72 patients with heart failure due to aortic stenosis, computed tomography-based ECV, serum SVEP1, and BNP (brain natriuretic peptide) levels were assessed. Multivariable regression was used to determine independent predictors of ECV. Publicly available single-nucleus RNA sequencing of human hearts revealed the cellular origin of. SVEP1 secretion was assessed in human cardiac fibroblasts after TGF-β (transforming growth factor-β) stimulation or small interfering RNA knockdown. Plasma Svep1 and cardiac hydroxyproline levels were measured in mice with angiotensin II- and phenylephrine-induced cardiac fibrosis. RESULTS: Serum SVEP1 correlated with ECV and outperformed BNP in detecting fibrosis. Multivariable analysis revealed SVEP1 as an independent predictor of ECV. In addition, snRNA-seq revealed fibroblast-specific expression, expanded in failing hearts consistent with activated fibroblast emergence. Furthermore, TGF-β increased SVEP1 secretion in human cardiac fibroblasts, whereas its knockdown reduced SVEP1 secretion. Plasma Svep1 and cardiac hydroxyproline levels were elevated and positively correlated in mice. CONCLUSIONS: Compared with BNP, SVEP1, derived from cardiac fibroblasts, is more strongly associated with ECV-defined fibrosis and may serve as a novel fibrosis-specific circulating biomarker in heart failure.