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      Clinical Significance of Guanylate Cyclase Stimulator, Riociguat, on Right Ventricular Functional Improvement in Patients with Pulmonary Hypertension

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          Abstract

          Background: Riociguat is a soluble guanylate cyclase stimulator that improves hemodynamics in patients with pulmonary hypertension (PH). Accumulating evidence implicates the additional effect of riociguat on the increase in cardiac output. However, its mechanisms have not been fully understood. This study aimed to investigate whether riociguat could ameliorate right ventricular (RV) contraction as well as hemodynamics. Methods: We studied 45 patients with pulmonary arterial hypertension (14) or chronic thromboembolic pulmonary hypertension (31) and evaluated hemodynamics, using right-sided heart catheterization, before and after the administration of riociguat. RV function was assessed by echocardiography, including speckle-tracking echocardiography. Results: Riociguat significantly improved the WHO functional class and reduced the mean pulmonary arterial pressure and vascular resistance. In addition, the cardiac index increased. RV remodeling was ameliorated after riociguat administration as assessed by the echocardiographic parameters, such as RV diameter and RV area index. RV function, including RV fractional area change and RV global longitudinal strain, also significantly improved, and their improvement was even observed in patients with mild PH after pulmonary endarterectomy or balloon pulmonary angioplasty. Furthermore, covariance analysis revealed that RV global longitudinal strain and RV fractional area change improved after riociguat administration, even with the same mean pulmonary arterial pressure, implicating the improvement of RV contractile function by riociguat, regardless of RV loading. Conclusions: Riociguat not only improved the hemodynamics of patients with PH but also ameliorated the echocardiographic parameters with RV function. RV strain could detect the subtle improvement in mild PH, and riociguat may have a benefit even after intervention, as assessed by speckle-tracking echocardiography.

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          Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

          Roberto Lang, Luigi Badano, Victor Mor-Avi … (2015)
          The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
          Article 0 comments Cited 1513 times – based on 0 reviews     Review now
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            Riociguat for the treatment of pulmonary arterial hypertension.

            Hossein-Ardeschir Ghofrani, Nazzareno Galiè, Friedrich Grimminger … (2013)
            Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension. In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg-maximum group). The 1.5 mg-maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety. By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg-maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001). Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002). The most common serious adverse event in the placebo group and the 2.5 mg-maximum group was syncope (4% and 1%, respectively). Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension. (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.).
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              Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.

              Hossein-Ardeschir Ghofrani, Andrea D'Armini, Friedrich Grimminger … (2013)
              Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension. In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)
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                Author and article information

                Journal
                Journal ID (publisher-id): CRD
                Journal ID (nlm-ta): Cardiology
                Journal ID (doi): 10.1159/issn.0008-6312
                Title: Cardiology
                Publisher: S. Karger AG
                ISSN (Print): 0008-6312
                ISSN (Electronic): 1421-9751
                Publication date Subscription-year: 2021
                Publication date (Print): January 2021
                Publication date (Electronic): 25 November 2020
                Volume: 146
                Issue: 1
                Pages: 130-136
                Affiliations
                [_a] aDepartment of Laboratory Medicine, Tokai University Hachioji Hospital, Tokyo, Japan
                [_b] bDepartment of Cardiology, School of Medicine, Keio University, Tokyo, Japan
                [_c] cDivision of Cardiology, Kyorin University, School of Medicine, Tokyo, Japan
                [_d] dDepartment of Laboratory Medicine, School of Medicine, Keio University, Tokyo, Japan
                Author notes
                *Mitsushige Murata, Department of Laboratory Medicine, Tokai University Hachioji Hospital, 1838 Ishikawamachi, Tokyo 192-0032 (Japan), muratam@tsc.u-tokai.ac.jp
                Article
                Publisher ID: 510860 Other ID: Cardiology 2021;146:130–136
                DOI: 10.1159/000510860
                PubMed ID: 33238268
                SO-VID: 09eb4102-bae8-4011-9f60-d5329e235749
                Copyright © © 2020 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 15 May 2020
                Date accepted : 09 August 2020
                Page count
                Figures: 2, Tables: 4, Pages: 7
                Categories
                Subject: Pulmonary Circulation and RV: Research Article

                ScienceOpen disciplines: General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Keywords: Guanylate cyclase stimulator,Right ventricular function,Pulmonary hypertension
                Data availability:
                ScienceOpen disciplines: General medicine, Neurology, Cardiovascular Medicine, Internal medicine, Nephrology
                Keywords: Guanylate cyclase stimulator, Right ventricular function, Pulmonary hypertension

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