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

Figures

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  Figure 1. Summary of the framework developed to study the effects of sac/val on RV remodeling in PH. Sprague–Dawley rats were assigned to one of the control, PH‐placebo treated, or PH‐sac/val treated cohorts, followed by terminal invasive hemodynamic measurements, morphological measurements, quantitative histological analysis, biaxial mechanical characterization, and constitutive modeling. OT indicates outflow tract; PA banding, pulmonary artery banding; PH, pulmonary hypertension; RV, right ventricle; Sac/Val, sacubitril/valsartan; and S‐D Rats, Sprague–Dawley Rats.

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  Figure 2. Hemodynamic measurements of the effects of PH and sac/val treatment on (A) RV maximum pressure, (B) stroke volume, (C) heart rate, (D) dp/dt max, (E) dp/dt min, (F) PA elastance (Ea), (G) RV elastance (Ees), and (H) ratio of RV to PA elastance (EesEa). Sac/val treatment significantly lowered RV maximum pressure (Pmax), decreased the load‐dependent measure of contractility (dp/dtmax), increased the load‐dependent measure of relaxation (dp/dtmin) and decreased PA elastance (Ea) in addition to preventing RV‐PA uncoupling. Horizontal line (―) and cross (✕) representing median and mean of distributions, respectively. Kruskal–Wallis tests with pairwise Wilcoxon rank sum post hoc testing. *P<0.05 compared with control, † P<0.05 compared with PH. dpdtmax and min indicates maximum and minimum of the time derivative of pressure; BPM, beats per minute; PA, pulmonary artery; PH, pulmonary hypertension; RV, right ventricle; RVU, relative volume units; and Sac/Val, sacubitril/valsartan.

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  Figure 3. Effects of PH and sac/val treatment on (A) RV hypertrophy (RVFW thickness) and (B) RV to LV mass ratio. Sac/val resulted in significantly lower RV wall thickness, while not demonstrating significant effects on RV to LV mass ratio. Horizontal line (―) and cross (✕) representing median and mean of distributions, respectively. Kruskal–Wallis tests with pairwise Wilcoxon rank sum post hoc testing. *P<0.05 compared with control, † P<0.05 compared with PH. LV indicates left ventricle; PH, pulmonary hypertension; RV, right ventricle; RVFW, right ventricular free wall; and Sac/Val, sacubitril/valsartan.

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  Figure 4. Histological analysis of the effects of sac/val treatment on RV remodeling in PH. A, Representative transmural histological sections of RV myocardium from each cohort (Red: Myofiber, Blue: Collagen). Coordinates used to measure fiber orientations indicated on the top. Dashed square representing the specimen orientation used for biaxial testing. B, Effects of sac/val treatment on transmural myofiber orientations. C, Effects of sac/val treatment on transmural collagen fiber orientations. D, Dominant myofiber orientation in each cohort (Watson–Williams test). E, Effects of sac/val on RV collagen area fraction (1‐way ANOVA followed by post hoc t tests). F, Effects of sac/val on RV collagen fiber coherency (1‐way ANOVA followed by post hoc t tests). Error bars representing SD. *P<0.05 compared with control, † P<0.05 compared with PH. CTRL indicates control; Epi, epicardium; Endo, endocardium; PH, pulmonary hypertension; RV, right ventricle; and Sac/Val, sacubitril/valsartan.

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  Figure 5. Effects of sac/val treatment on (A) biaxial mechanical properties of RVFW, (B) fiber‐level mechanical properties of combined collagen and myofiber bundles, (C) intrinsic myofiber stiffness, (D) collagen recruitment strain. Sac/val treatment resulted in improved tissue‐level biomechanical properties. At the fiber level, sac/val prevented an increase in myofiber stiffness in PH but did not affect collagen recruitment strains. Horizontal line (―) and cross (✕) representing median and mean of distributions, respectively. Error bars in part (A) and (B) representing SD. Kruskal–Wallis tests with pairwise Wilcoxon rank sum post hoc testing. *P<0.05 compared with control, † P<0.05 compared with PH. 2nd P‐K Stress indicates second Piola‐Kirchhoff stress; Circ., circumferential; CTRL, control; Long., longitudinal; PH, pulmonary hypertension; RVFW, right ventricular free wall; and Sac/Val, sacubitril/valsartan.

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  Figure 6. A, Longitudinal, circumferential, and coupled stiffness of RV myocardium revealed by constitutive modeling, (B) cohort‐specific strain energy maps of RV myocardium, indicating increased stiffness in PH and improved biomechanical performance with sac/val treatment. Sac/val improved RV stiffness in both circumferential and longitudinal directions with no significant effects on in‐plane coupling. Dashed lines indicate the strain energy levels for the control cohort at 3 μJmm3.Horizontal line (―) and cross (✕) representing median and mean of distributions, respectively. Kruskal–Wallis tests with pairwise Wilcoxon rank sum post hoc testing. *P<0.05 compared with control, † P<0.05 compared with PH. Circ. indicates circumferential; Long., longitudinal; and PH, pulmonary hypertension.