Angiotensin Receptor‐Neprilysin Inhibition Attenuates Right Ventricular Remodeling in Pulmonary Hypertension

Author:

Sharifi Kia Danial1,Benza Evan2,Bachman Timothy N.13,Tushak Claire1,Kim Kang12345,Simon Marc A.12345ORCID

Affiliation:

1. Department of BioengineeringUniversity of PittsburghPA

2. Heart and Vascular InstituteUniversity of Pittsburgh Medical Center (UPMC)Pittsburgh PA

3. Pittsburgh Heart, Lung, Blood and Vascular Medicine InstituteUniversity of Pittsburgh and University of Pittsburgh Medical Center (UPMC)Pittsburgh PA

4. Division of CardiologySchool of MedicineUniversity of PittsburghPA

5. McGowan Institute for Regenerative MedicineUniversity of PittsburghPA

Abstract

Background Pulmonary hypertension ( PH ) results in increased right ventricular ( RV ) afterload and ventricular remodeling. Sacubitril/valsartan (sac/val) is a dual acting drug, composed of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, that has shown promising outcomes in reducing the risk of death and hospitalization for chronic systolic left ventricular heart failure. In this study, we aimed to examine if angiotensin receptor‐neprilysin inhibition using sac/val attenuates RV remodeling in PH . Methods and Results RV pressure overload was induced in Sprague–Dawley rats via banding the main pulmonary artery. Three different cohorts of controls, placebo‐treated PH , and sac/val‐treated PH were studied in a 21‐day treatment window. Terminal invasive hemodynamic measurements, quantitative histological analysis, biaxial mechanical testing, and constitutive modeling were employed to conduct a multiscale analysis on the effects of sac/val on RV remodeling in PH . Sac/val treatment decreased RV maximum pressures (29% improvement, P =0.002), improved RV contractile (30%, P =0.012) and relaxation (29%, P =0.043) functions, reduced RV afterload (35% improvement, P =0.016), and prevented RVpulmonary artery uncoupling. Furthermore, sac/val attenuated RV hypertrophy (16% improvement, P =0.006) and prevented transmural reorientation of RV collagen and myofibers ( P =0.011). The combined natriuresis and vasodilation resulting from sac/val led to improved RV biomechanical properties and prevented increased myofiber stiffness in PH (61% improvement, P =0.032). Conclusions Sac/val may prevent maladaptive RV remodeling in a pressure overload model via amelioration of RV pressure rise, hypertrophy, collagen, and myofiber reorientation as well as tissue stiffening both at the tissue and myofiber level.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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