Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation release_qterhmew5bbdxapxzjad5mlvwm

by Brian Aguado, Katherine B. Schuetze, Joseph C. Grim, CIERRA WALKER, Anne C. Cox, Tova L. Ceccato, Aik Choon Tan, Carmen C. Sucharov, Leslie A. Leinwand, Matthew Taylor, Timothy, Brian Aguado

Published in Science Translational Medicine by American Association for the Advancement of Science (AAAS).

2019   Volume 11, Issue 509, eaav3233

Abstract

The transcatheter aortic valve replacement (TAVR) procedure has emerged as a minimally invasive treatment for patients with aortic valve stenosis (AVS). However, alterations in serum factor composition and biological activity after TAVR remain unknown. Here, we quantified the systemic inflammatory effects of the TAVR procedure and hypothesized that alterations in serum factor composition would modulate valve and cardiac fibrosis. Serum samples were obtained from patients with AVS immediately before their TAVR procedure (pre-TAVR) and about 1 month afterward (post-TAVR). Aptamer-based proteomic profiling revealed alterations in post-TAVR serum composition, and ontological analysis identified inflammatory macrophage factors implicated in myofibroblast activation and deactivation. Hydrogel biomaterials used as valve matrix mimics demonstrated that post-TAVR serum reduced myofibroblast activation of valvular interstitial cells relative to pre-TAVR serum from the same patient. Transcriptomics and curated network analysis revealed a shift in myofibroblast phenotype from pre-TAVR to post-TAVR and identified p38 MAPK signaling as one pathway involved in pre-TAVR–mediated myofibroblast activation. Post-TAVR serum deactivated valve and cardiac myofibroblasts initially exposed to pre-TAVR serum to a quiescent fibroblast phenotype. Our in vitro deactivation data correlated with patient disease severity measured via echocardiography and multimorbidity scores, and correlations were dependent on hydrogel stiffness. Sex differences in cellular responses to male and female sera were also observed and may corroborate clinical observations regarding sex-specific TAVR outcomes. Together, alterations in serum composition after TAVR may lead to an antifibrotic fibroblast phenotype, which suggests earlier interventions may be beneficial for patients with advanced AVS to prevent further disease progression.
In application/xml+jats format

Archived Files and Locations

application/pdf  3.6 MB
file_logruzyqxvh5jambpknwnq4dgi
europepmc.org (repository)
web.archive.org (webarchive)
Read Archived PDF
Preserved and Accessible
Type  article-journal
Stage   published
Date   2019-09-11
Language   en ?
Container Metadata
Not in DOAJ
In Keepers Registry
ISSN-L:  1946-6234
Work Entity
access all versions, variants, and formats of this works (eg, pre-prints)
Catalog Record
Revision: 11a6e6e3-1f1e-4232-8546-4f42148308ea
API URL: JSON