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Abstract 14397: Sotatercept Analog RAP-011 Inhibits Right Ventricular Remodeling and Restores Function in a Mouse Model of Pressure Overload
- Source :
- Circulation. 142
- Publication Year :
- 2020
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2020.
-
Abstract
- IIntroduction: Right ventricular (RV) failure is the primary cause of death in patients with pulmonary arterial hypertension (PAH). Beneficial effects of sotatercept - an activin receptor type IIA-Fc fusion protein that traps activins and growth differentiation factors - have been reported in PAH patients treated with standard-of-care therapies in a recent phase 2 study (PULSAR). We have reported that therapeutic treatment with sotatercept analog RAP-011 reverses RV remodeling and function in rats with severe angio-obliterative PAH, providing benefits on top of standard care. Hypothesis: To determine whether RAP-011 exerts a direct cardioprotective effect in a mouse model of pressure overload-induced RV failure. Methods: RV failure was induced in male C57BL/6 mice by pulmonary artery banding (PAB). RAP-011 or vehicle were administered subcutaneously twice weekly for 3 weeks beginning one day post surgery. RV remodeling and function were assessed by echocardiography and RV pressure measured by catheterization. RV fibrosis was assessed by Masson’s trichrome staining. Results: PAB caused RV hypertrophy and increased RV wall thickness in comparison to sham surgery. RAP-011 treatment markedly attenuated these PAB-induced changes (by 72% and 41%, respectively; P < 0.0001). PAB significantly reduced tricuspid annular plane systolic excursion (0.68 ± 0.03 vs. 0.98 ± 0.03 mm), which was partially restored by RAP-011 (0.84 ± 0.04 mm; P < 0.01). In addition, the PAB-induced increase in myocardial performance index was reversed by RAP-011 (1.86 vs. 1.48, P < 0.0001). RAP-011 attenuated PAB-induced RV developed pressure (by 82%, P < 0.0001) and partially normalized peak rates of RV pressure change (+dP/dt max and -dP/dt min , P < 0.05). RAP-011 also reduced the extent of PAB-induced RV fibrosis (19.5% vs. 10.5%, P < 0.001). Conclusions: Consistent with our previous findings in a rat model of severe angio-obliterative PAH, RAP-011 treatment reduces RV remodeling and improves function in a PAB model, thus implicating direct cardioprotective actions of RAP-011 as an important component of its therapeutic effects in severe experimental PAH.
- Subjects :
- Pressure overload
medicine.medical_specialty
business.industry
medicine.disease
Pulmonary hypertension
Activin receptor type IIA
Physiology (medical)
Internal medicine
SOTATERCEPT
Cardiology
Medicine
In patient
Cardiology and Cardiovascular Medicine
business
Ventricular remodeling
Function (biology)
Cause of death
Subjects
Details
- ISSN :
- 15244539 and 00097322
- Volume :
- 142
- Database :
- OpenAIRE
- Journal :
- Circulation
- Accession number :
- edsair.doi...........d7cc2ba4b36db8a5f1a13e00bb3c0960