Abstract Body: Background: Human aortic stenosis (AS) induces adverse cardiac remodeling and heart failure by pressure overload. Reducing pressure overload (e.g., Trans-catheter aortic valve replacement (TAVR) mitigates or reverses adverse remodeling but these benefits are limited in many TAVR patients. Here we established a murine transverse-aortic-constriction (TAC)-debanding model to mimic TAVR and identify ways to enhance reverse remodeling.
Methods: 10-week-old wild-type C57BL/6 mice were subjected to TAC surgery and debanding by suture removal, or sham-debanding, between 4 (short duration) and 10 weeks (long duration) after TAC. Echocardiography was performed to assess cardiac function. RNA sequencing (RNAseq) of TAC and debanded hearts demonstrated activation of activin signaling with TAC that was relieved by debanding. Based on this, TAC-debanded animals were treated with an investigational modified activin receptor type IIB ligand trap, RKER-012 (10 mg/kg IP, bi-weekly), to inhibit signaling downstream of activin and related ligands.
Results: Serial echocardiography of TAC-debanded animals showed greater dysfunction with longer duration TAC (Fractional shortening [FS]=39.2±3.84 for 4 weeks-TAC vs Sham: 61.2±0.94, p<0.05; FS=18.2±1.80 for 10 weeks-TAC vs Sham-TAC: 64.7±0.43, p<0.05). Cardiac functional recovery was slower and less complete in animals with longer duration TAC (10 weeks after debanding with TAC for 4 weeks, FS=57.8±1.41 vs 46.6±3.4 TAC for 10 weeks). RNAseq analysis of hearts post-debanding (10 weeks TAC+10 weeks debanding) showed a 5.73-fold decrease (p=2.57x10^-16) in FSTL3 expression, a biomarker of activin pathway signaling, suggesting a decrease in activin signaling accompanied functional recovery. To assess functional contribution of activin signaling to incomplete recovery and therapeutic potential of pathway inhibitors, we treated debanded animals (debanded 8 weeks post-TAC) with RKER-012 or placebo (TBS) for 4 weeks. RKER-012-treated mice showed significantly increased ejection fraction (54.12±1.50 vs placebo control 42.88±3.21; p=0.001) and reduced heart weight (p=0.01).
Conclusions: Debanding after TAC mitigates adverse remodeling that is slower and less complete with longer duration TAC. A ligand trap (RKER-012) that was designed to inhibit signaling downstream of activin enhanced recovery after debanding and warrants further study as a potential therapeutic intervention in patients with incomplete functional recovery after TAVR.