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

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          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.

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          Most cited references 44

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          Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure

          We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
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            Experimental investigation of collagen waviness and orientation in the arterial adventitia using confocal laser scanning microscopy.

            Mechanical properties of the adventitia are largely determined by the organization of collagen fibers. Measurements on the waviness and orientation of collagen, particularly at the zero-stress state, are necessary to relate the structural organization of collagen to the mechanical response of the adventitia. Using the fluorescence collagen marker CNA38-OG488 and confocal laser scanning microscopy, we imaged collagen fibers in the adventitia of rabbit common carotid arteries ex vivo. The arteries were cut open along their longitudinal axes to get the zero-stress state. We used semi-manual and automatic techniques to measure parameters related to the waviness and orientation of fibers. Our results showed that the straightness parameter (defined as the ratio between the distances of endpoints of a fiber to its length) was distributed with a beta distribution (mean value 0.72, variance 0.028) and did not depend on the mean angle orientation of fibers. Local angular density distributions revealed four axially symmetric families of fibers with mean directions of 0°, 90°, 43° and -43°, with respect to the axial direction of the artery, and corresponding circular standard deviations of 40°, 47°, 37° and 37°. The distribution of local orientations was shifted to the circumferential direction when measured in arteries at the zero-load state (intact), as compared to arteries at the zero-stress state (cut-open). Information on collagen fiber waviness and orientation, such as obtained in this study, could be used to develop structural models of the adventitia, providing better means for analyzing and understanding the mechanical properties of vascular wall.
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              Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure.

              The most important determinant of longevity in pulmonary arterial hypertension is right ventricular (RV) function, but in contrast to experimental work elucidating the pathobiology of left ventricular failure, there is a paucity of data on the cellular and molecular mechanisms of RV failure. A mechanical animal model of chronic progressive RV pressure overload (pulmonary artery banding, not associated with structural alterations of the lung circulation) was compared with an established model of angioproliferative pulmonary hypertension associated with fatal RV failure. Isolated RV pressure overload induced RV hypertrophy without failure, whereas in the context of angioproliferative pulmonary hypertension, RV failure developed that was associated with myocardial apoptosis, fibrosis, a decreased RV capillary density, and a decreased vascular endothelial growth factor mRNA and protein expression despite increased nuclear stabilization of hypoxia-induced factor-1alpha. Induction of myocardial nuclear factor E2-related factor 2 and heme-oxygenase 1 with a dietary supplement (Protandim) prevented fibrosis and capillary loss and preserved RV function despite continuing pressure overload. These data brought into question the commonly held concept that RV failure associated with pulmonary hypertension is due strictly to the increased RV afterload.
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                Author and article information

                Contributors
                simonma@upmc.edu
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                18 June 2020
                07 July 2020
                : 9
                : 13 ( doiID: 10.1002/jah3.v9.13 )
                Affiliations
                [ 1 ] Department of Bioengineering University of Pittsburgh PA
                [ 2 ] Heart and Vascular Institute University of Pittsburgh Medical Center (UPMC) Pittsburgh PA
                [ 3 ] Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute University of Pittsburgh and University of Pittsburgh Medical Center (UPMC) Pittsburgh PA
                [ 4 ] Division of Cardiology School of Medicine University of Pittsburgh PA
                [ 5 ] McGowan Institute for Regenerative Medicine University of Pittsburgh PA
                [ 6 ] Department of Mechanical Engineering and Materials Science University of Pittsburgh PA
                [ 7 ] Center for Ultrasound Molecular Imaging and Therapeutics University of Pittsburgh PA
                Author notes
                [* ] Correspondence to: Marc A. Simon, MD, MSc, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Presbyterian University Hospital C‐701, 200 Lothrop St, Pittsburgh, PA. E‐mail: simonma@ 123456upmc.edu

                Article
                JAH35163
                10.1161/JAHA.119.015708
                7670537
                32552157
                © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 6, Tables: 0, Pages: 13, Words: 8285
                Product
                Funding
                Funded by: Novartis Pharmaceutical Corporation
                Funded by: NIH , open-funder-registry 10.13039/100000002;
                Award ID: 1R01AG058659
                Award ID: 2P01HL103455
                Award ID: UL1 TR001857
                Funded by: American Heart Association , open-funder-registry 10.13039/100000968;
                Award ID: 20PRE35210429
                Categories
                Original Research
                Original Research
                Heart Failure
                Custom metadata
                2.0
                07 July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.1 mode:remove_FC converted:30.09.2020

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