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

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.

One-sentence summary:

Transcatheter aortic valve replacement alters a patient’s serum proteome, reversing valvular interstitial cell and cardiac myofibroblast activation.

Editor’s Summary: Responding to replacement

Aortic valve stenosis (narrowing of the aortic valve) contributes to inadequate blood flow, fibrosis, hypertrophy, and, ultimately, heart failure. Transcatheter aortic valve replacement (TAVR) improves blood flow, but little is known about cardiac remodeling after the procedure. Aguado and colleagues performed proteomics on serum samples collected from patients before and after TAVR and studied the effects of serum on valve and cardiac cells using hydrogel culture platforms. A role for p38 MAPK signaling in activating cells was identified using pre-TAVR serum, whereas post-TAVR serum returned cells to a quiescent state. Along with preliminary insights into sex-specific differences, the authors’ research supports a role for TAVR-induced alteration of circulating inflammatory cytokines in regulating valve cell phenotype.