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

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.

Effects of Healthy Aging on Right Ventricular Structure and Biomechanical Properties

“…2d-e ). This is similar to previous observations of RV hypertrophy in PH and increased contractility to overcome the elevated afterload (Hill et al, 2014; Sharifi Kia et al, 2020).…”

“…4e ). Similar patterns of fiber reorientation were noted in animal models of PH (Avazmohammadi et al, 2017a; Sharifi Kia et al, 2020). Consistent with prior work (Anversa et al, 1990; Walker et al, 2006), cardiomyocyte loss ( Fig.…”

“…All animal procedures were approved by University of Pittsburgh’s IACUC (protocol# 18113872 and 19126652). Details of our experimentation/analysis techniques have been extensively discussed in prior studies (Hill et al, 2014; Sharifi Kia et al, 2020). Please see supplementary materials for details on our methods.…”

“…In recent years, biomechanical analysis techniques have been employed to better understand the underlying mechanisms of RV remodeling (Avazmohammadi et al, 2017b, 2019; Hill et al, 2014; Sharifi Kia et al, 2020) and have closely linked RV biomechanics to function (Jang et al, 2017). Despite the evidence suggesting an association between aging and alterations in RV structure/function and higher prevalence of PH in the elderly (Hoeper and Gibbs, 2014), a large body of the literature has employed younger animal models and limited data exist on age-associated differences in RV biomechanics.…”

Animal models of pulmonary hypertension: Getting to the heart of the problem

“…In SuHx rats, this approach was found to reduce pulmonary vascular remodelling, RVH and fibrosis, yet no effects on TAPSE, CO, exercise capacity or mortality were observed (Clements et al, 2019). Consistent results were found in PAB rats, whereby prophylactic treatment with sacubitril/valsartan attenuated the development of RVH, but did not affect fibrosis or SV (Sharifi Kia et al, 2020). Combining neprilysin inhibitors with conventional PAH therapy (phosphodiesterase type 5 inhibition)…”