14
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil

      review-article
      , MD 1 , , , PhD 2
      Drugs in Context
      BioExcel Publishing Ltd
      heart failure, myosin activator, omecamtiv mecarbil

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Heart failure continues to be a major global health problem with a pronounced impact on morbidity and mortality and very limited drug treatment options especially with regard to inotropic therapy. Omecamtiv mecarbil is a first-in-class cardiac myosin activator, which increases the proportion of myosin heads that are tightly bound to actin and creates a force-producing state that is not associated with cytosolic calcium accumulation. Phase I and phase II studies have shown that it is safe and well tolerated. It produces dose-dependent increases in systolic ejection time (SET), stroke volume (SV), left ventricular ejection fraction (LVEF), and fractional shortening. In the ATOMIC-AHF trial, intravenous (IV) omecamtiv mecarbil did not improve dyspnoea overall but may have improved it in a high-dose group of acute heart failure patients. It did, however, increase SET, decrease left ventricular end-systolic diameter, and was well tolerated. The COSMIC-HF trial showed that a pharmacokinetic-based dose-titration strategy of oral omecamtiv mecarbil improved cardiac function and reduced ventricular diameters compared to placebo and had a similar safety profile. It also significantly reduced plasma N-terminal-pro B-type natriuretic peptide compared with placebo. The GALACTIC-HF trial is now underway and will compare omecamtiv mecarbil with placebo when added to current heart failure standard treatment in patients with chronic heart failure and reduced LVEF. It is expected to be completed in January 2021. The ongoing range of preclinical and clinical research on omecamtiv mecarbil will further elucidate its full range of pharmacological effects and its clinical usefulness in heart failure.

          Related collections

          Most cited references29

          • Record: found
          • Abstract: found
          • Article: not found

          The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries.

          Heart failure is a global pandemic affecting an estimated 26 million people worldwide and resulting in more than 1 million hospitalizations annually in both the United States and Europe. Although the outcomes for ambulatory HF patients with a reduced ejection fraction (EF) have improved with the discovery of multiple evidence-based drug and device therapies, hospitalized heart failure (HHF) patients continue to experience unacceptably high post-discharge mortality and readmission rates that have not changed in the last 2 decades. In addition, the proportion of HHF patients classified as having a preserved EF continues to grow and may overtake HF with a reduced EF in the near future. However, the prognosis for HF with a preserved EF is similar and there are currently no available disease-modifying therapies. HHF registries have significantly improved our understanding of this clinical entity and remain an important source of data shaping both public policy and research efforts. The authors review global HHF registries to describe the patient characteristics, management, outcomes and their predictors, quality improvement initiatives, regional differences, and limitations of the available data. Moreover, based on the lessons learned, they also propose a roadmap for the design and conduct of future HHF registries. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

            Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure.

              Because physicians have traditionally considered heart failure to be a hemodynamic disorder, they have described the syndrome of heart failure using hemodynamic concepts and have designed treatment strategies to correct the hemodynamic derangements of the disease. However, although hemodynamic abnormalities may explain the symptoms of heart failure, they are not sufficient to explain the progression of heart failure and, ultimately, the death of the patient. Therapeutic interventions may improve the hemodynamic status of patients but adversely affect their long-term outcome. These findings have raised questions about the validity of the hemodynamic hypothesis and suggest that alternative mechanisms must play a primary role in advancing the disease process. Several lines of evidence suggest that neurohormonal mechanisms play a central role in the progression of heart failure. Activation of the sympathetic nervous system and renin-angiotensin system exerts a direct deleterious effect on the heart that is independent of the hemodynamic actions of these endogenous mechanisms. Therapeutic interventions that block the effects of these neurohormonal systems favorably alter the natural history of heart failure, and such benefits cannot be explained by the effect of these treatments on cardiac contractility and ejection fraction. Conversely, pharmacologic agents that adversely influence neurohormonal systems in heart failure may increase cardiovascular morbidity and mortality, even though they exert favorable hemodynamic effects. These observations support the formulation of a neurohormonal hypothesis of heart failure and provide the basis for the development of novel therapeutic strategies in the next decade.
                Bookmark

                Author and article information

                Journal
                Drugs Context
                Drugs Context
                DIC
                Drugs in Context
                BioExcel Publishing Ltd
                1745-1981
                1740-4398
                2018
                23 April 2018
                : 7
                : 212518
                Affiliations
                [1 ]Cardiology Unit, Medicine Department, Hospital Municipal de Badalona, Badalona, Spain
                [2 ]BioExcel Publishing Ltd, London, UK
                Author notes
                Correspondence: Edgardo Kaplinsky, Cardiology Unit, Medicine Department, Hospital Municipal de Badalona, Vía Augusta Av. 9–13 (08911), Badalona, Spain. ejkaplinsky@ 123456gmail.com
                Article
                dic-7-212518
                10.7573/dic.212518
                5916097
                dd6f1a96-0f3a-4e2d-b754-978434590d2b
                Copyright © 2018 Kaplinsky E, Mallarkey G.

                Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

                History
                : 28 November 2017
                : 02 April 2018
                : 03 April 2018
                Categories
                Review

                heart failure,myosin activator,omecamtiv mecarbil
                heart failure, myosin activator, omecamtiv mecarbil

                Comments

                Comment on this article