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
RV
‐
pulmonary 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
Cited by
57 articles.
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