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      Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy

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          Abstract

          Background: Pressure unloading induces the regression of left ventricular myocardial hypertrophy (LVH). Recent findings indicate that pharmacological activation of the soluble guanylate cyclase (sGC) – cyclic guanosine monophosphate (cGMP) pathway may also exert reverse-remodeling properties in the myocardium. Therefore, we aimed to investigate the effects of the sGC activator cinaciguat in a rat model of LVH and compare it to the “gold standard” pressure unloading therapy.

          Methods: Abdominal aortic banding was performed for 6 or 12 weeks. Sham operated animals served as controls. Pressure unloading was induced by removing the aortic constriction after week 6. The animals were treated from week 7 to 12, with 10 mg/kg/day cinaciguat or with placebo p.o., respectively. Cardiac function and morphology were assessed by left ventricular pressure-volume analysis and echocardiography. Additionally, key markers of myocardial hypertrophy, fibrosis, nitro-oxidative stress, apoptosis and cGMP signaling were analyzed.

          Results: Pressure unloading effectively reversed LVH, decreased collagen accumulation and provided protection against oxidative stress and apoptosis. Regression of LVH was also associated with a full recovery of cardiac function. In contrast, chronic activation of the sGC enzyme by cinaciguat at sustained pressure overload only slightly influenced pre-established hypertrophy. However, it led to increased PKG activity and had a significant impact on interstitial fibrosis, nitro-oxidative stress and apoptosis. Amelioration of the pathological structural alterations prevented the deterioration of LV systolic function (contractility and ejection fraction) and improved myocardial stiffness.

          Conclusion: Our results indicate that both cinaciguat treatment and pressure unloading evoked anti-remodeling effects and improved LV function, however in a differing manners.

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          Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings.

          Richard Devereux, Daniel R. Alonso, Elizabeth M. Lutas … (1986)
          To determine the accuracy of echocardiographic left ventricular (LV) dimension and mass measurements for detection and quantification of LV hypertrophy, results of blindly read antemortem echocardiograms were compared with LV mass measurements made at necropsy in 55 patients. LV mass was calculated using M-mode LV measurements by Penn and American Society of Echocardiography (ASE) conventions and cube function and volume correction formulas in 52 patients. Penn-cube LV mass correlated closely with necropsy LV mass (r = 0.92, p less than 0.001) and overestimated it by only 6%; sensitivity in 18 patients with LV hypertrophy (necropsy LV mass more than 215 g) was 100% (18 of 18 patients) and specificity was 86% (29 of 34 patients). ASE-cube LV mass correlated similarly to necropsy LV mass (r = 0.90, p less than 0.001), but systematically overestimated it (by a mean of 25%); the overestimation could be corrected by the equation: LV mass = 0.80 (ASE-cube LV mass) + 0.6 g. Use of ASE measurements in the volume correction formula systematically underestimated necropsy LV mass (by a mean of 30%). In a subset of 9 patients, 3 of whom had technically inadequate M-mode echocardiograms, 2-dimensional echocardiographic (echo) LV mass by 2 methods was also significantly related to necropsy LV mass (r = 0.68, p less than 0.05 and r = 0.82, p less than 0.01). Among other indexes of LV anatomy, only measurement of myocardial cross-sectional area was acceptably accurate for quantitation of LV mass (r = 0.80, p less than 0.001) or diagnosis of LV hypertrophy (sensitivity = 72%, specificity = 94%).(ABSTRACT TRUNCATED AT 250 WORDS)
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            Peroxynitrite: biochemistry, pathophysiology and development of therapeutics.

            Csaba Szabo, Harry Ischiropoulos, Rafael Radi (2007)
            Peroxynitrite--the product of the diffusion-controlled reaction of nitric oxide with superoxide radical--is a short-lived oxidant species that is a potent inducer of cell death. Conditions in which the reaction products of peroxynitrite have been detected and in which pharmacological inhibition of its formation or its decomposition have been shown to be of benefit include vascular diseases, ischaemia-reperfusion injury, circulatory shock, inflammation, pain and neurodegeneration. In this Review, we first discuss the biochemistry and pathophysiology of peroxynitrite and then focus on pharmacological strategies to attenuate the toxic effects of peroxynitrite. These include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases.
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              Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats.

              Pál Pacher, Takahiro Nagayama, Partha Mukhopadhyay … (2008)
              Ventricular pressure-volume relationships have become well established as the most rigorous and comprehensive ways to assess intact heart function. Thanks to advances in miniature sensor technology, this approach has been successfully translated to small rodents, allowing for detailed characterization of cardiovascular function in genetically engineered mice, testing effects of pharmacotherapies and studying disease conditions. This method is unique for providing measures of left ventricular (LV) performance that are more specific to the heart and less affected by vascular loading conditions. Here we present descriptions and movies for procedures employing this method (anesthesia, intubation and surgical techniques, calibrations). We also provide examples of hemodynamics measurements obtained from normal mice/rats, and from animals with cardiac hypertrophy/heart failure, and describe values for various useful load-dependent and load-independent indexes of LV function obtained using different types of anesthesia. The completion of the protocol takes 1-4 h (depending on the experimental design/end points).
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Physiol
                Journal ID (iso-abbrev): Front Physiol
                Journal ID (publisher-id): Front. Physiol.
                Title: Frontiers in Physiology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-042X
                Publication date (Electronic): 08 January 2019
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 1869
                Affiliations
                [1] 1Experimental Research Laboratory, Heart and Vascular Center, Semmelweis University , Budapest, Hungary
                [2] 2Laboratory of Experimental Cardiac Surgery, Department of Cardiac Surgery, Heidelberg University , Heidelberg, Germany
                [3] 3Laboratory of Oxidative Stress, Department of Physiology, Institute of Clinical Experimental Research, Semmelweis University , Budapest, Hungary
                [4] 4Laboratory for Molecular and Translational Cardiology, Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg , Heidelberg, Germany
                [5] 5Research Group on Epidermal Systems Biology, Hamamatsu Tissue Imaging and Analysis Center, Bioquant, Heidelberg University , Heidelberg, Germany
                [6] 6National Center for Tumor Diseases, Medical Oncology, Heidelberg University Hospital, Heidelberg University , Heidelberg, Germany
                Author notes

                Edited by: Giuseppe Vergaro, Fondazione Toscana Gabriele Monasterio (CNR), Italy

                Reviewed by: Alberto Giannoni, Fondazione Toscana Gabriele Monasterio (CNR), Italy; Xuejun Wang, University of South Dakota, United States

                *Correspondence: Mihály Ruppert, ruppertmis@ 123456gmail.com

                †These authors have contributed equally to this work

                This article was submitted to Clinical and Translational Physiology, a section of the journal Frontiers in Physiology

                Article
                DOI: 10.3389/fphys.2018.01869
                PMC ID: 6331535
                SO-VID: 284a9627-ef35-49ff-a35e-3d664e4c0b96
                Copyright © Copyright © 2019 Ruppert, Korkmaz-Icöz, Li, Brlecic, Németh, Oláh, Horváth, Veres, Pleger, Grabe, Merkely, Karck, Radovits and Szabó.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 03 September 2018
                Date accepted : 11 December 2018
                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 42, Pages: 16, Words: 0
                Categories
                Subject: Physiology
                Subject: Original Research

                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: left ventricular hypertrophy,pressure unloading,reverse remodeling,cinaciguat,cgmp
                Data availability:
                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: left ventricular hypertrophy, pressure unloading, reverse remodeling, cinaciguat, cgmp

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