GSE133529
Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation
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 one month afterwards (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 echocardiography data and multi-morbidity scores, and correlations were dependent upon 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, our observations support the hypothesis that alterations in serum composition after a TAVR procedure may promote an anti-fibrotic fibroblast phenotype. Overall design: Male and female porcine VICs were isolated, seeded on PEG-norbornene hydrogels (elastic modulus ~5.8 kPa), and cultured in Media 199 (Life Technologies) supplemented with 1% human serum, 50 U/mL penicillin, 50 µg/mL streptomycin, and 1 µg/mL amphotericin B for 48 hours. Pre-TAVR and post-TAVR serum from 8 patients (4 male and 4 female) were tested in this experiment, resulting in 16 total samples.